EuroTimes Sept 2019 | Vol 24 Issue 9 by EUROTIMES

SPECIAL FOCUS CATARACT & REFRACTIVE

September 2019 | Vol 24 Issue 9

ARTIFICIAL INTELLIGENCE in Ophthalmology CORNEA | RETINA | GLAUCOMA PAEDIATRIC OPHTHALMOLOGY | OCULAR

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Publisher Carol Fitzpatrick Executive Editor Colin Kerr Editors Sean Henahan Paul McGinn Managing Editor Caroline Brick Content Editor Aidan Hanratty Senior Designer Lara Fitzgibbon Designer Ria Pollock Circulation Manager Angela Morrissey Contributing Editors Howard Larkin Dermot McGrath Roibeard Ó hÉineacháin Contributors Maryalicia Post Leigh Spielberg Gearóid Tuohy Priscilla Lynch Soosan Jacob Colour and Print W&G Baird Printers Advertising Sales Amy Bartlett ESCRS Tel: 353 1 209 1100 email: amy.bartlett@escrs.org

Published by the European Society of Cataract and Refractive Surgeons, Temple House, Temple Road, Blackrock, Co Dublin, Ireland. No part of this publication may be reproduced without the permission of the managing editor. Letters to the editor and other unsolicited contributions are assumed intended for this publication and are subject to editorial review and acceptance. ESCRS EuroTimes is not responsible for statements made by any contributor. These contributions are presented for review and comment and not as a statement on the standard of care. Although all advertising material is expected to conform to ethical medical standards, acceptance does not imply endorsement by ESCRS EuroTimes. ISSN 1393-8983

CONTENTS

A EUROPEAN OUTLOOK ON THE WORLD OF OPHTHALMOLOGY

SPECIAL FOCUS

CATARACT & REFRACTIVE 04 Cover Story:

AI can increase efficiency and effectiveness in all aspects of ophthalmology

08 Determining the value

of machine learning for geographic atrophy

10 Managing co-existing

cataract and glaucoma

12 French surgeons move

towards benchmarking

14 Most patients with

diabetes attain good VA after cataract surgery

16 Corneal inlays show high

efficacy but vigilance is needed for adverse events

18 SMILE is gaining ground against LASIK

20 A new marker improves accuracy for toric IOLs

is a beneficial adaptation

31 Novel diagnostic and

treatment methods can help treat tear instability

33 Fighting the vicious

cycle of inflammation in Sjögren’s syndrome

CORNEA cross-linking – epithelium on or off?

27 Pre-stripped and pre-

loaded tissue for DMEK

28 More studies needed for

latest dry eye treatments

48 Increasing rates of ROP call for new guidelines

49 Care plans for patients

help DME patients

36 Unlocking the potential of AI in diagnosing AMD

37 Discontinued subretinal

with inherited retinal disease

51 Many countries ill prepared for hazardous material emergencies

implant provides insights

38 Non-invasive imaging

technique shows promise

39 Novel biomarkers

are proving useful in management of DME

40 An inverted ILM peeling

technique is effective for larger macular holes

41 New IOP-lowering

25 JCRS update

exams for children with behavioural difficulties

35 A new app is designed to

24 Automated capsulotomy may reduce complications

47 Oral sedation can aid

OCULAR

GLAUCOMA

in intracameral injections

PAEDIATRIC OPHTHALMOLOGY

RETINA

22 Greater precision needed

26 Corneal collagen As certified by ABC, the EuroTimes average net circulation for the 10 issues distributed between February and December 2018 was 48,900

30 Ocular immune privilege

www.eurotimes.org

REGULARS

53 Hospital Diary 55 Books 56 Outlook on Industry 58 Industry News 59 Calendar

agents bring hope of more effective treatment

42 Implant may provide durable IOP control

43 Combination therapy is

an effective approach in managing uveitis

44 Long-term glaucoma

drug delivery platforms are near market

45 New device may control

IOP by shunting aqueous directly to the surface

Supplement September 2019

Optimising Combination Therapies and Modern MIGS for Early-to-Advanced Glaucoma Reviewing the Impact of Glaucoma on the Cataract Patient and the Beneﬁts of Earlier Intervention A range of diagnostic and treatment options are available to manage glaucoma in cataract patients Simonetta Morselli, MD

efore performing surgery on a patient with glaucoma, we need to determine the disease severity — assessing the optic nerve, extent of visual ﬁeld damage and the patient’s imaging studies — and identify the target intraocular pressure (IOP). The more damage the patient has, the lower the target IOP should be. In patients with mild disease, IOP should be in the upper teens; moderate disease, mid-teens; and severe disease, low teens. Therefore, postoperative IOP should be nearly 10 or 11mmHg if glaucoma is very severe. The targeted IOP decrease narrows our minimally invasive glaucoma surgery (MIGS) choices, guiding our choice of procedure.

Diagnosis and Treatment Key tests are used to diagnose glaucoma — visual fields, optical coherence tomography (OCT) and anterior segment OCT. In addition, gonioscopy should be used for planning and to check the angle before surgery. Additional tests include aqueous angiography, ocular surface and tear film assessments, and corneal hysteresis. We also need to check the lens and corneal refractive error. When I initially see a patient with glaucoma and cataract, my first step is to try to reduce the IOP with drops, considering glaucoma progression. Patient compliance is an important consideration with glaucoma drops. If patients do not adhere to their treatment regimen, glaucoma will progress.1 We also need to keep in mind the tolerability of topical therapy.2 If a patient has cataracts, the second step after topical medication is MIGS, which reduces IOP and takes an ab interno approach with no conjunctival dissection, and the third step is filtering surgeries, in which IOP is reduced through artificial drainage between the anterior chamber and subconjunctival space.

Considering Options When making a surgical decision, we need to balance safety and eﬃcacy (Figure 1). The risk of the procedure should not exceed the risk of disease. We use diagnostic testing to stage disease, determine target IOP and decide which MIGS procedures are indicated. It can be overwhelming to choose among the available MIGS procedures, but we cannot ignore them. Ophthalmologists should learn to access all of the spaces of the angle where MIGS devices can be

placed. It is also important to understand what you can do and which cases you should refer to colleagues. Assessing and addressing glaucoma in cataract patients is critical to achieve successful outcomes. Early intervention with a stepwise treatment approach should be considered in all cataract patients with glaucoma.

References 1. Sleath B, et al. The relationship between glaucoma medication adherence, eye drop technique, and visual ﬁeld defect severity. Ophthalmology. 2011; 118:2398–2402. 2. Mastropasqua L, et al. In vivo laser scanning confocal microscopy of the ocular surface in glaucoma. Microsc Microanal. 2014; 20:879–894. Dr Morselli is chief of the ophthalmic unit, San Bassiano Hospital, Bassano del Grappa, Italy. She has no ﬁnancial disclosures related to the products mentioned in this article. Email: simonetta.morselli@gmail.com

Safer procedures have lower efficacy Trabecular/Canal based Safer Less efficacious Transscleral More efficacious More risk/post-op care Risk of procedure should not exceed the risk of the disease

Eﬃcacy

Safety

Figure 1. When making surgical decisions, it is important to balance safety with eﬃcacy

Implementing Ocular Surface Disease Treatment Strategies For Today’s Cataract Patient

Included with this issue... ESCRS Education Forum Supplement ESCRS/EuCornea Education Forum Supplement EUROTIMES | SEPTEMBER 2019

EDITORIAL A WORD FROM BÉATRICE COCHENER-LAMARD MD, PhD

GUEST EDITORIAL

ESCRS in Paris Extensive scientific programme aimed at all levels of experience

Béatrice Cochener-Lamard

MEDICAL EDITORS

Emanuel Rosen Chief Medical Editor

José Güell

Thomas Kohnen

Paul Rosen

INTERNATIONAL EDITORIAL BOARD Noel Alpins (Australia), Bekir Aslan (Turkey), Roberto Bellucci (Italy), Hiroko Bissen-Miyajima (Japan), John Chang (China), Béatrice Cochener-Lamard (France), Oliver Findl (Austria), Nino Hirnschall (Austria), Soosan Jacob (India), Vikentia Katsanevaki (Greece), Daniel Kook (Germany), Boris Malyugin (Russia), Marguerite McDonald (USA), Cyres Mehta (India), Sorcha Ní Dhubhghaill (Ireland) Rudy Nuijts (The Netherlands), Leigh Spielberg (The Netherlands), Sathish Srinivasan (UK), Robert Stegmann (South Africa), Ulf Stenevi (Sweden), Marie-José Tassignon (Belgium), Manfred Tetz (Germany), Carlo Enrico Traverso (Italy)

EUROTIMES | SEPTEMBER 2019

t is a pleasure to be invited to write this editorial as a French president of ESCRS, coinciding with the convening of the 37th Congress of the ESCRS in Paris, France. I am delighted to welcome delegates to Paris for what promises to be an exciting and informative meeting. Our extensive scientific programme is aimed at cataract and refractive surgeons of all levels of experience and includes numerous expert symposia, covering major current topics, and nearly 200 instructional and surgical skills training courses. The 2019 Binkhorst Medal Lecture will be given by Ehud Assia during the Opening Ceremony and the title of his lecture is ‘Thinking outside the box: new perspective on current surgical technologies’. I am also looking forward to this year’s Heritage Lecture, where David Spalton will focus on “The origins of Our extensive cataract surgery”. We will conclude with scientific the ‘Best of the Best’ programme is review session, which will aimed at cataract take a look at some of the most interesting ideas and refractive that emerge during the surgeons of Congress. all levels of Our pocket programme experience... will be a useful guide for those wishing to navigate their way through the Congress using the highlighted programme tracks. You can also find the tracks and all the programme information on the Congress app. With so much on offer it will be impossible to attend every session. However, if you log on to the Education Portal on the ESCRS website at www.escrs.org you can access the sessions and didactic courses on ESCRS On Demand and ESCRS iLearn, as well as discovering a wide range of video content and other materials. There will also be regular updates in our daily newspaper ET Today, on the EuroTimes website at www.eurotimes.org and on the ESCRS Facebook and Twitter pages. An excellent scientific programme takes a lot of planning, and I would like to thank the members of the Programme and Education committees for their time and dedication. Paris is a beautiful city and I am delighted to welcome you to my native country. I hope you will find this Congress enriching and that you will have time to enjoy some of the sights and unique gastronomic delights that the city has to offer.

Béatrice Cochener-Lamard is the President of the ESCRS and Professor and Chairman of the ophthalmology department at the University Hospital of Brest, France

COVER STORY: ARTIFICIAL INTELLIGENCE

ARTIFICIAL INTELLIGENCE in Ophthalmology

Machines mimicking human skills emerge to meet growing global eye care need. Howard Larkin reports

t’s said that necessity is the mother of invention – and converging global trends make multiplying eye care efficiency an increasingly urgent necessity. New therapies make many previously intractable eye diseases treatable. Yet exploding demand and a tsunami of new diagnostic images, EUROTIMES | SEPTEMBER 2019

tests and electronic patient data to review mean there aren’t enough ophthalmologists in practice or in training to keep up. Enter artificial intelligence, or AI. Already in clinical use in ophthalmic applications ranging from detecting retinal disease to increasing the accuracy of intraocular lens (IOL) power selection, AI can automate repetitive clinical steps

while greatly expanding researchers’ and clinicians’ capacity to make sense of geometrically expanding data sets. AI has the potential to dramatically increase the efficiency and effectiveness of nearly every aspect of ophthalmology, particularly when integrated with eye outreach and primary care clinics in health systems. Properly applied, AI will not replace

COVER STORY: ARTIFICIAL INTELLIGENCE ophthalmologists. Rather, it is emerging as a powerful tool for streamlining routine tasks, allowing clinicians to find and focus their clinical expertise on cases requiring their patient insights and diagnostic skills. Combining broad human intelligence with narrow machine intelligence may well give rise to new practice models that can more effectively reduce the global scourge of low vision and blindness.

IMPROVING DIAGNOSIS AND ACCESS

Diabetic retinopathy (DR) screening is a case in point. For decades, conducting widely recommended annual DR checks of diabetic patients has been a challenge that is rapidly worsening due to growing aged and overweight populations. AI reduces the need for highly trained personnel to screen patients while greatly expanding access. Several AI-enabled devices are now available that extend DR screening into eye clinics and primary care settings. These include IDx-DR (IDx Technologies, USA), which is the first medical device for autonomously diagnosing disease ever approved by the FDA. OphtAI (ADCIS & Evolucare, France) and EyeArt (EyeNuk, UK) are both CE marked. Yet another system has been tested by Google Research, Verily Life Sciences and the Aravind Eye Hospitals in India. All four devices use AI deep learning algorithms to screen digital fundus images for DR cases that should be referred to a retina specialist. In validation and prospective clinical studies, these and other AI systems have demonstrated sensitivity and specificity in identifying cases that rival or exceeded analysis by trained non-physician graders and retinal specialists (Abràmoff MD et al. NPJ Digit Med. 2018;1(1):39. Gulshan V et al. JAMA Ophthalmol. 2019 Jun 13: e192004. Nielsen KB et al. Ophthalmol Retina. 2019 Apr;3(4):294-304). The benefits for patients are clear. Noting that 60 million people in India have diabetes for which no systematic DR screening programme exists, the authors of a recently published Google-Aravind paper concluded that their prospective study “demonstrates the feasibility of using an automated DR grading system to expand screening programs”. In low-resource settings AI technology increases access to screening and

As anterior segment surgeons, we are primarily being judged by our patients and peers by our refractive outcomes Warren E Hill MD

immediate referrals to retinal specialists, while in high-resource areas it provides a backup to manual screening that may increase accuracy, the same study said (Gulshan V et al. JAMA Ophthalmol. 2019). This finding was confirmed in a second Google-Aravind study (Sayres R et al. JAMA Ophthalmol. April 2019; 126(4): 552–564).

AI AT HOME

AI devices for screening age-related macular degeneration (AMD) and glaucoma based on fundus photography and OCT images are also in use or near market, said Gwenolé Quellec PhD. He is a machine learning researcher who developed the AI inside OphtAI with colleagues including Béatrice CochenerLamard MD, PhD, and Mathieu Lamard PhD at France’s LaTIM, or Laboratory of Medical Information Processing. “In the near future, I also expect AMD monitoring using home-OCT to emerge. These tools will allow AMD patients to self-assess the need for anti-VEGF injections, for instance,” Dr Quellec said. Home OCT devices for detecting retinal fluid accumulation are in development by Switzerland’s Mimo Artificial Intelligence and Robotics, and Notal Vision, based in the USA and Israel. Notal currently offers a home monitoring device using a hyperacuity test to detect neovascular AMD progression – and the need for antiVEGF injections – based on its refractive effects (Quellec G et al. Acta Ophthalmol. 2019 Mar 6. doi: 10.1111/aos.14055. Chakravarthy U et al. Ophthalmology. 2016;123(8):1731-1736) . Such devices clearly offer potential to improve treatment efficacy by giving earlier warning of disease progression. They are also convenient for patients and may relieve the strain of frequent progression check-ups in ophthalmology offices.

These tools will allow AMD patients to self-assess the need for anti-VEGF injections... Gwenolé Quellec PhD

PREDICTING CONNECTIONS

More significant yet may be emerging AI tools for predicting progression, Dr Quellec said. Current examples include methods for predicting progression to advanced AMD (Schmidt-Erfuth U et al. IOVS. 2018; 59: 3199-3208) and geographic atrophy (GA) growth (Normand G et al. ARVO, 2019). The French government has funded a programme in which LaTIM will design AI tools to predict progression to advanced DR. Such tools could make it possible to target high-risk patients for intensive early treatment. In the EU-funded NECESSITY project, AI analysis of slit-lamp videos is being used to assess the effect of Sjögren’s Syndrome treatments in clinical trials, and possibly identify biomarkers that identify patients with different disease subtypes, Dr Quellec added. AI is being used to identify new drug targets and chemical treatment candidates, and model their potential effects and toxicity. These applications have the potential to greatly increase the productivity of clinical research. A recent analysis by the trade association BIO of new chemical entities found that development programmes that used biomarkers were three times more likely to advance from phase I clinical trials to FDA approval than those that did not.

AI IN CATARACT SURGERY

AI is already addressing the most common unanticipated outcome in cataract surgery, which is missing the target refraction, said Warren E Hill MD, of Mesa, Arizona, USA, and Case Western Reserve University, Cleveland, USA. “As anterior segment surgeons, we are primarily being judged by our patients and peers by our refractive outcomes,” he said. Dr Hill used a neural network approach to develop a new IOL power calculator that resulted in 90% of patients being within 0.5D of target refraction – better than even the most highly refined modern formulae based on conventional methods. The formula, which is available online, was used in nearly 300,000 cases around the world in 2018, said Dr Hill, who presented a detailed account of how the formula was developed at the ASCRS ASOA 2019 Annual Meeting in San Diego USA. He believes that expanding its reference database could push 0.5D accuracy to 94% EUROTIMES | SEPTEMBER 2019

COVER STORY: ARTIFICIAL INTELLIGENCE and is now working with 41 investigators in 19 countries to refine it. AI pattern recognition holds several advantages over modern formulae based on vergence, intraoperative aberrometry and ray tracing, Dr Hill explained. Where these approaches limit possible solutions to situations that are already understood, adaptive learning creates the ability to optimise outcomes based solely on observed data. “This makes it ideal for addressing real-world problems where ideal models are not available, and the eye is one of these.” Moreover, AI does away with calculation bias built into limited theoretical models. Instead, adaptive learning derives its algorithms from relationships observed within the data set itself through an iterative process that increases in accuracy as more data are added. AI processing mimics the basic function of neurons, Dr Hill said. Nerve cells process multiple inputs that come in through dendrites and outputs to multiple other neurons. The relative value of and connections between inputs – which to pay attention to and which to ignore – is learned by experience, which strengthens functional connections while irrelevant connections fade. In a learning AI system, the original work involved looking at 13 parameters including pupil size, central corneal thickness, spherical aberration and whiteto-white measurements based on 3,445 eyes measured with the Haag-Streit Lenstar. Dr Hill developed tens of thousands of models using various combinations of these input parameters. By a process that mimics Darwinian evolution and employing a genetic algorithm, the best candidate models were developed and then further refined. It turned out that a four-factor model using postoperative SphEq, axial length, central corneal power and anterior chamber depth resulted in the best overall accuracy, validated by independent datasets. Paradoxically, models that were based on additional parameters resulted in a decrease in overall accuracy, he observed. “What happens is that with too much information we ended up overfitting the data with a reduction in accuracy." Using another tool available for this type of calculation, Dr Hill and his team developed six pair-wise boundary models for the four preoperative measurements. If any of the preoperative measurements were seen to fall outside one or more of these six boundary models, an “outof-bounds” indication is displayed, alerting the surgeon that not enough data is present to accurately support the calculation at a 90% accuracy for ±0.50D. As the number of cases has increased for the Hill-RBF method from 3,400 for version 1.0 to 12,400 for version 2.0 and 20,000 for version 3.0, the breadth and EUROTIMES | SEPTEMBER 2019

It has entered our practices without anyone having seemed to have measured it for over a decade Béatrice Cochener-Lamard MD, PhD

depth of each of these boundary models increases dramatically. Version 3.0 of the Hill-RBF method will be available as an online calculator by autumn 2019 at RBFCalculator.com For the first prospective study of 459 eyes, the overall ±0.50D accuracy for eyes with an “in-bounds” indication was 91%. “This is exactly what the boundary models predicted,” Dr Hill explained. Dr Hill anticipates the development of artificial intelligence models specific to ethnic groups, such as ethnic Chinese, which often differ anatomically from ethnic Caucasians.

MAKING AI INTELLIGIBLE

Despite these successes, AI often engenders scepticism if not outright distrust, related to the “black box” problem. Iterative models created by finding statistical connections in large data sets emphatically do not follow logic or causality, making them difficult to understand and predict. In fact, machine algorithms may turn causality on its head, as did one algorithm that diagnosed tuberculosis by reading chest x-rays. The device considered not only the x-ray image but also film metadata, assigning greater weight to images taken by mobile machines used in hospitals than by stationary machines in clinics – apparently having “learned” that patients with lung complaints severe enough for hospitalisation were indeed more likely to have TB. More to the point, minor alterations to retinal images have been sufficient in some cases to fool AI readers, but not experienced clinicians (Abramoff MD et al. Invest Ophthalmol Vis Sci. 2016;57(13):5200-06). Dr Quellec and colleagues addressed the issue by developing “deep image mining”, which shows exactly which pixels the AI device is examining. “For screening tasks, it turns out the AI looks at the exact same pixels as clinicians do,” he said (Quellec G et al. Med Image Anal. 2017 jul;39:178-193). As implemented in OphtAI, this also provides accurate segmentations of all DR lesions, which Dr Quellec expects will boost confidence in AI-based predictions. Opening the “black box” in this way also promotes new knowledge. For example, training AI models for predicting GA growth led to the discovery that the shape complexity of GA at baseline is a powerful

indicator of future growth, he added. Institutional safeguards also have developed to ensure AI is safe for patients. The EU’s new Medical Device Regulation, which takes full effect next year, explicitly defines software that diagnoses or predicts disease progression as medical devices, with sticker registration standards for higher risk devices. Similarly, FDA guidance recommends disclosure of data and methods used to develop and validate software devices, as well as a review of any change that significantly alters its capabilities or range of application, even if it improves performance. Likewise, peer-reviewed journals, including PLoS One and the Nature and JAMA journals, require disclosure of data sets and analytic tools sufficient to replicate results upon request after publication of papers involving machine learning and computer analysis. The Journal of the American Statistical Association goes a step further, requiring disclosure of data sets and computer code for peer review as a condition of publication. Professor Béatrice Cochener-Lamard offers some words of caution, but also encouragement about the future of artificial intelligence. “AI has elicited various reactions ranging from enthusiasm from those who see it as an aid to medical performance, to anguish among those who fear it will usurp the role of the doctor,” she said. “It has entered our practices without anyone having seemed to have measured it for over a decade,” said Prof Cochener-Lamard. Prof Cochener-Lamard also suggests that it should be up to doctors to define the mission to be fulfilled by AI. “That mission should be to assist in diagnosis and to ensure remote expertise with proposals for aetiology or decisionmaking. It is also important that we have guidelines, which will depend on the ethical rules and regulations of individual countries. No one stops progress; it is up to us doctors to do everything to support and control it,” said Prof Cochener-Lamard. Gwenolé Quellec: gwenole.quellec@inserm.fr Warren Hill: hill@doctor-hill.com Dr Quellec will be speaking at the Artificial Intelligence in Ophthalmology Symposium on Monday 16 September during the 37th Congress of the ESCRS in Paris, France

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SPECIAL FOCUS: CATARACT & REFRACTIVE

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AI holds promise in diagnosing GA Trials needed to determine value of artificial intelligence in geographic atrophy. Dermot McGrath reports

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rtificial intelligence and machine learningbased approaches hold promise for the differential diagnosis of geographic atrophy (GA) and prediction of future progression rates, according to Maximilian Pfau MD. “We have made a lot of progress in recent years in applying algorithms to the quantification of lesions and other diseaseassociated features such as drusen or hyper-reflective foci in eyes with GA. However, the real problem holding us back is the lack of publicly or commercially available software solutions in order for proper validation studies to be carried out by independent research groups,” he told delegates attending the European Society of Ophthalmology (SOE) meeting in Nice, France. Dr Pfau noted that GA is the late manifestation of agerelated macular degeneration (AMD) with the highest incidence in patients over 85 years of age. It is characterised by the atrophy of the choriocapillaris, retinal pigment epithelium and photoreceptors. No treatment is currently available despite more than 45 clinical trials of various therapeutic agents having been carried out in recent years. There are a number of challenges in designing clinical trials for GA, said Dr Pfau, such as excluding patients with mimicking disease, sub-phenotyping within GA secondary to AMD and the need to define responsive structural and functional clinical endpoints. In terms of differential diagnosis, the DeepMind algorithm at Moorfields Eye Hospital is already capable of multiclass classification for “gross disease categories” such as both forms of AMD (i.e. non-exudative versus exudative AMD), epiretinal membrane, vitreomacular traction and central serous retinopathy, among others. “However, no algorithm has yet been published for recognition of GA-mimicking diseases such as late-onset Stargardt’s disease,” he said. Another issue in GA clinical trials is setting inclusion criteria to select those patients with rapidly progressing lesions. “Patients with non-progressing lesions will not provide much information concerning treatment efficacy. However, taking account of the precise fundus autofluorescence phenotypes and criteria such as minimum atrophy size, as well as lesion size, shape and location may ultimately allow us to build models that explain up to 40% of the variability in future progression rates,” he said. In terms of clinical endpoints, Dr Pfau said that automated quantification using widely available multimodal imaging may prove useful as a functional outcome parameter in the near future. In a recent study, Dr Pfau and co-workers investigated the impact of retinal microstructure on cone and rod function in 43 GA patients, and applied an algorithm to predict functional impairment based on multimodal imaging findings. “We found that local retinal sensitivity can be estimated from retinal structure seen on commonly used clinical multimodal imaging, although again the results need to be validated on an independent data set,” he concluded. Maximilian Pfau: Maximilian.Pfau@ukbonn.de

EUROTIMES | SEPTEMBER 2019

Reach the peak.

www.escrs.org

Belong to something impressive. Join us.

SPECIAL FOCUS: CATARACT & REFRACTIVE

Combined management of cataract & glaucoma Everything you ever wanted to know about the management of co-existing cataract and glaucoma (part 2). Soosan Jacob MD reports

n the second article of this multi-part series on combined management of cataract and glaucoma, we discuss three surgeries. In all three, parts of glaucoma surgery are first performed with a formed globe followed by phacoemulsification before creation of an ostium to allow safe cataract extraction under stable anterior chamber conditions. Finally, the remaining part of glaucoma surgery is completed.

SIGS (STAB-INCISION GLAUCOMA SURGERY): SIGS is a surgical procedure described by the author aimed at minimising conjunctival dissection and obtaining posteriorly directed flow. In the author’s experience, it works well in primary and secondary open-angle glaucomas with adequate virgin conjunctiva. Either 0.2ml of 0.02% Mitomycin-C (MMC) is injected subconjunctivally 20 minutes prior to surgery or an intraoperative application may be done. The speculum is loosened and conjunctiva pushed forwards with nontoothed forceps held flat against the globe to avoid conjunctival and scleral cuts from overlapping. A 2.8mm bevel-up keratome is used to initiate the biplanar SIGS tunnel. The ideal short and shallow tunnel incision starts 1.5mm behind the limbus, avoiding major blood vessels and at 1/3 thickness sclera. This is verified by just seeing the metal keratome through the overlying sclera. The angulation of blade is matched to the scleral curvature to get a uniformly thick tunnel. At the limbus, angulation is increased to match steeper corneal curvature. About 0.5-1mm into the clear cornea, a horizontal entry up to the EUROTIMES | SEPTEMBER 2019

A: Stab-Incision Glaucoma Surgery (SIGS) – A Kelly’s Descemet’s punch is being used to create the SIGS ostium by punching the lower lip of the tunnel

B: Postoperative slit lamp view in SIGS

C: An ExPress shunt is seen post insertion

D: Postoperative slit lamp view with posterior chamber tube placement of an Ahmed Glaucoma Valve combined with phacoemulsification

maximum width of the keratome is made into the anterior chamber (AC) parallel to the iris, avoiding posterior pressure on the tunnel. Taking care not to hit the anterior capsule or the iris, the blade is then quickly withdrawn straight backwards avoiding sideways slicing movements to prevent damage to the side walls of the tunnel. Main and side ports are created as usual on either side of the SIGS tunnel

and phaco is proceeded with. Cataract extraction can be performed with ease and the AC remains stable as the SIGS ostium has not yet been created. After IOL implantation, the SIGS tunnel is intentionally compromised by using a 1mm Kelly’s Descemet’s punch to punch the posterior wall of the tunnel. The posterior wall is punched vertically backwards up to the limbus until it can be just seen on lifting up the conjunctiva and

SPECIAL FOCUS: CATARACT & REFRACTIVE the anterior wall of tunnel. The AC is then shallowed so that the iris moves forward. With the assistant retracting conjunctiva, a non-toothed forceps is used to pull the base of the iris out through the tunnel and a peripheral iridectomy is created using curved Vannas scissors held horizontally. The iris is then pulled back into the AC and viscoelastic washed out. Balanced salt solution (BSS) injected through the side port confirms adequacy of leakage through the SIGS tunnel if free flow of fluid is seen without shallowing of the AC. If the AC deepens and becomes hard, shallow graded nibbling of the posterior lip is further done until such flow is obtained. The conjunctiva is then closed with continuous 10-0 nylon suture. Residual viscoelastic is removed with an I/A probe. Inflation of the bleb during I/A together with a soft, stable and well-formed AC are good signs. Sutures may be applied on phaco main and side ports if required. As in trabeculectomy, releasable sutures may be applied if desired. Advantages of SIGS include simplicity and effectiveness as compared to conventional trabeculectomy as well as cost-effectiveness and greater efficacy compared to many microinvasive glaucoma surgeries. The biplanar tunnel allows posteriorly directed flow and prevents formation of overhanging bleb. It also provides a diffuse area of leakage. SIGS also minimises conjunctival dissection with more virgin conjunctiva available for any future procedures.

EX-PRESS SHUNT This is a 3mm-long non-valved stainless steel, MRI-compatible device with a 50-micron lumen, a spur-like extension that prevents extrusion and a back plate

The silicone model is preferred since it causes less inflammation with less Tenon cyst formation and better control of IOP to prevent erosion. It has a lower risk of hypotony as compared to trabeculectomy. A fornix-based conjunctival flap is created. A half-thickness scleral flap of 3x4mm is dissected to ensure adequate coverage around the Ex-Press shunt and to get adequate resistance with sutures to prevent over-filtration. The flap is dissected slightly forwards into the clear cornea to avoid compression on the shunt. If indicated, MMC is then applied as in trabeculectomy. An entry is made just anterior to the scleral spur in the iris plane using a 27G needle. Using the inserter, the pre-loaded Ex-Press shunt is placed first turned horizontally. Once inside, it is turned 90 degrees to place it vertically. It should be inserted well away from cornea and with the back-plate flush against the scleral bed. The scleral flap is then closed to get a controlled flow and the conjunctiva is also closed. Postoperatively, one of the complications is occlusion of the ostium with fibrin; however this can be cleared with Nd:YAG laser.

AHMED GLAUCOMA VALVE (AGV)

preferred since it causes less inflammation with less Tenon cyst formation and better control of IOP. The author’s personal preference is a posterior chamber placement of the AGV in order to avoid long-term complications such as endothelial decompensation – a complication reported after anterior chamber placement. The FP7 model is generally used in adults. The device is primed by injecting BSS through the tube. The plate is then sutured 8-10mm posterior to the limbus between two recti, most commonly in the superotemporal quadrant. A 5x5mm limbusbased 2/3 thickness scleral flap is created to provide postoperative tube coverage. Phacoemulsification and IOL implantation are proceeded with. A 23G needle is then used to carefully create a sclerotomy about 1-1.5mm posterior to limbus in a plane between the iris and the anterior capsule. The tube is then trimmed and inserted in this retroiridal plane. This is followed by sealing the flap all around the tube in a tight manner with the use of sutures. The conjunctiva is then closed. Phaco incisions may be sutured if leaking.

The AGV is a valved glaucoma drainage device that has an opening pressure of 8mmHg. It is ideal for implantation in refractory glaucomas such as neovascular glaucoma, uveitic glaucoma, post failed trabeculectomy etc. The silicone model is

Dr Soosan Jacob is Director and Chief of Dr Agarwal’s Refractive and Cornea Foundation at Dr Agarwal’s Eye Hospital, Chennai, India and can be reached at dr_soosanj@hotmail.com

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EUROTIMES | SEPTEMBER 2019

SPECIAL FOCUS: CATARACT & REFRACTIVE

French centres adopt ICHOM standards Standards to be tested over four years to evaluate patient outcomes. Dermot McGrath reports

Courtesy of Francois Lignereux MD

ith national health authorities, payers and other stakeholders placing ever-greater emphasis on quality control and value-based healthcare, French cataract surgeons may be forced sooner rather than later to introduce objective benchmarking and quality control measures into their practices, according to Francois Lignereux MD. “Cataract is the most commonly performed surgical procedure in France, with increasing demand from health authorities to quantify the value of the operation to the patient. Certain countries such as Belgium, Sweden and the Netherlands already have a national cataract registry based on patient-reported outcomes, so we can eventually expect to see this evolution as well in France,” he told delegates attending the annual congress of the French Implant and Refractive Surgery Association (SAFIR) in Paris, France. Dr Lignereux said that three French ophthalmic centres – Institut Ophtalmologique Sourdille Atlantique, University Hospital in Nantes and Chénieux Ophtalmologie at Polyclinique de Limoges – have recently adopted the

Cataract is the most commonly performed surgical procedure in France, with increasing demand from health authorities to quantify the value of the operation to the patient Francois Lignereux MD standard set for cataract surgery developed by the International Consortium for Health Outcomes Measurement (ICHOM). Between the three centres, more than 40 practitioners carry out around 15,000 surgeries every year. Medical teams are now able to share and compare patients’ average clinical benefit through a digital platform managed by a non-profit organisation acting as a trusted third party – the Consortium VBHC France – founded by Prof Gregory Katz. On a national level, there is a clear need for more robust outcomes measures and registry data. An estimated 880,000 patients undergo cataract operations in France every year, with a variation of cataract surgeries per capita that nearly doubles depending on French regions.

The ICHOM standard sets are standardised outcomes, measurement tools and time points and risk adjustment factors for a given condition, which were developed to capture the outcomes of care for costly conditions. Dr Lignereux explained that the cataract standard set uses the Catquest-9SF patient questionnaire for patient-reported outcome measures (PROM), which was originally developed by Prof Mats Lundström, founder of the EUREQUO registry developed by ESCRS. The Catquest-9SF measures visual disability on an interval scale and contains nine questions (items); two global items and seven difficulty items. It has been shown to demonstrate robust psychometric properties and has also been selected as the instrument of choice in the European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO) database for the assessment of cataract outcomes. The questionnaire is easily administered and rapidly completed by the patient, said Dr Lignereux. “In the clinic, the secretary attributes a printed QR code to the patient who then goes to the waiting room and uses the QR code to access the questionnaire on a computer tablet. The patient gives consent to participate in the questionnaire and then answers the questions. The responses are automatically recorded in the patient’s electronic medical record,” he said. Overall, the ICHOM methodology should allow surgeons to objectively measure the value of the healthcare they provide to their patients, and is well suited for use in daily clinical practice, he concluded. Francois Lignereux: francois.lignereux@free.fr

EUROTIMES | SEPTEMBER 2019

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Cataract and diabetes Modern-era study finds two-thirds of patients achieve good driving vision. Cheryl Guttman Krader reports

contemporary look at functional outcomes of cataract surgery in patients with diabetes showed that the majority attained good visual acuity (VA), reported researchers at the 2019 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO). To evaluate VA outcomes of patients with type 2 diabetes undergoing cataract surgery in the modern era, the investigators analysed data from 1,136 eyes of 784 participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study and the Follow-On (ACCORDION) Study. They found that postoperative VA of 20/40 or better was achieved by 762 (67.1%) eyes. A logistic regression analysis was also conducted to identify factors associated with postoperative VA ≥20/40. Its results showed that preoperative VA and retinopathy were important predictors of the visual outcome. “Historically, visual outcomes after cataract surgery have been reported as being less favourable in individuals with diabetes. The data we are reporting show that in the current world where patients with diabetes can achieve much better glycaemic control, a good proportion can achieve at least driving vision after cataract surgery. Clearly, however, the presence of diabetic retinopathy seems to be

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associated with poorer VA,” said Emily Y Chew MD, deputy clinical director, National Eye Institute, National Institutes of Health, Bethesda, Maryland, US. Debora H Lee BS, Medical Research Scholar, National Institutes of Health, is lead author of the poster. She noted that compared with the research being presented, previous papers reporting good VA after cataract surgery in patients with diabetes included fewer patients who were operated on over earlier time periods. “Subsequent to publication of these older studies, there have Emily Y Chew MD been a lot of advances in cataract surgery as well as in the management of diabetes and the management of diabetic eye disease. Therefore, we thought it was important to look at VA outcomes after cataract surgery in diabetics using a more recent cohort of patients,” she said. Between 2001 and 2014, the ACCORD and ACCORDION studies followed 10,251 participants with type 2 diabetes at high risk for cardiovascular disease for a median of 9.2 years. Subjects returned for annually and had VA measurements done every two years using ETDRS charts. Cataract surgery was documented at the annual study visits. Eyes were eligible for inclusion in the analysis of cataract surgery functional outcomes if they had VA measurements within two years after surgery. The 784 patients in the study had a mean age of approximately 69 years at the time of cataract surgery, a mean haemoglobin A1C (HbA1C) of 8.3% and a mean diabetes duration of 16.3 years. The logistic regression analysis of potential VA predictors found that in addition to preoperative VA and retinopathy, patient education level and having bilateral surgery were associated with the likelihood of achieving VA ≥20/40. Age at cataract surgery, sex, race, body mass index, smoking history, duration of diabetes, blood pressure, lipid levels and HbA1C level were not predictive factors. “It is interesting to note that the VA outcome was not associated with HbA1C level in the regression analysis. Perhaps it is not the glycaemic control itself but rather the retinopathy as a consequence of poor glycaemic control that influences the potential VA outcome after cataract surgery,” said Ms Lee. The main strength of the study is its size, she said. As a limitation, however, the data set lacked details about certain factors that could also be linked with VA outcomes. “We were able to extract complete data on demographic characteristics, but we lacked detailed data on such factors as the use of medications for controlling inflammation and preventing macular oedema,” she said. “However, more comprehensive ophthalmic data, including fundus photograph gradings of diabetic retinopathy, are available for subjects enrolled in ACCORD-EYE, which is a prospective study of a subset of patients in ACCORD. We are planning to look at that information in more detail in the future.”

...in [a] world where patients can achieve much better glycaemic control, a good proportion can achieve at least driving vision after cataract surgery

A dream come true: breaking the vicious circle of tear dysfunction

0,2% hyaluronic acid - 0,001% hydrocortisone In the last few years, the significant prevalence of ocular surface diseases and the deep knowledge of their pathogenetic mechanisms observed by international scientists and researchers, have attracted the attention of several ophthalmic companies, leading to the development of various innovative drugs. As a matter of fact, these pathologies cause a considerable discomfort for the patient concerning either the symptoms or the visual function. The ocular surface is an “integrated system” with a biological cross-talk that can be altered under pathologic conditions. In this context, the tear film represents the backbone around which the homeostasis, in other words the system balance, must be restored. There is no ocular disease, whether it is of allergic, traumatic, infectious or iatrogenic nature,that does not lead to an alteration of the tear film. If this alteration is recurrent or continued over time, it triggers a vicious cycle and consequently an insidious disease, characterized by tear film instability, an of epithelial alteration and a mild but basically chronic subclinical inflammation, which expresses the “system’s” attempt to restore homeostasis under critical conditions. This inflammation, mainly not clinically manifest, is not responsive to the traditional artificial tears, but supports the pathology, leading the patient to a frantic search for a resolutive therapy. On the other hand, in the case of a subclinical inflammation, the topical use neither of steroidal anti-inflammatory drugs, or of NSAIDs, could be considered appropriate, because

of their poor tolerability. These drugs would determine an excessively powerful and aggressive solution in comparison with the entity of the problem. Alfa Intes, an italian ophthalmological company, is now making available an innovative therapeutic tool to the Ophthalmologist, specifically designed for this pathology. For this purpose, it has indeed developed the formulation of a “Pharmacologically Active Tear Substitute”, which is effective on the prodromes of an evident inflammation of the ocular surface. Thus, Idroflog® was born, together with a new class of tear substitutes, the P.A.T. (Pharmacological Artificial Tears). Idroflog® is an ophthalmic solution, containing 0,2% hyaluronic acid and 0,001% hydrocortisone sodium phosphate. This class III medical device, containing the drug with an accessory function, is an innovative tear substitute. It is effective against all the pathogenetic components of the disease, thanks to its “double soul”, by stabilizing the tear film on one hand, and by having an anti-inflammatory action on the other hand. Idroflog® is a safe eye drop (does not penetrate beyond the cornea) and it is very easy to use. Hyaluronic acid 0,2% stabilizes the tear film, it physiologically favours the repairing processes and dilutes the “toxic tear”, rich in toxic agents and inflammatory proteins. Hydrocortisone 0,001% allows the eye drop to prevent or control subclinical inflammation linked to tear film disfunctions, with a high level of safety.

SPECIAL FOCUS: CATARACT & REFRACTIVE

Corneal inlays Newer corneal inlays show high efficacy but vigilance is needed for unexpected adverse events. Roibeard Ó hÉineacháin reports

he jury is still out on the safety and efficacy of current corneal inlays in the longer term, Ioannis Pallikaris MD, PhD, told a session of the 23rd ESCRS Winter Meeting in Athens. “A variety of surgical options for presbyopia are now available, some are invasive and difficult or impossible to reverse. Corneal inlays, developed in the last decade, are designed to overcome those difficulties,” said Dr Pallikaris, University of Crete, Heraklion, Crete, Greece. The corneal inlays are designed for implantation in the nondominant eye in a pocket in the corneal stroma. The devices have employed a variety of optical approaches, generally aiming for a modified monovision with some degree of multifocality or extended depth of field. Several such devices have come and gone over the years, generally being withdrawn from the market because of biocompatibility issues. Over the past five years, the USFDA has approved two new inlays, the KAMRA (Acufocus) small-aperture inlay in 2015 and the Raindrop – formerly produced by the now defunct company ReVision in 2016. Both inlays showed good initial results but in October 2018 the Raindrop was withdrawn from market after post-marketing surveillance revealed a 43% rate of corneal haze and a 23.3% explantation rate.

AND THEN THERE WERE TWO That leaves only the KAMRA corneal inlay and the Presbia Flexivue Microlens. The USFDA clinical trial with the Flexivue lens has been completed and is expected to receive FDA approval some time in 2019, Dr Pallikaris said. The KAMRA corneal inlay is designed to improve near vision while maintaining distance vision using the pinhole lens concept. The inlay has a diameter of 2.38mm, a thickness of 5.0 microns and is flexible enough to bend to different curvatures without buckling. It is opaque except for a 1.6mm aperture in the centre. It is implanted only in the nondominant eye. Through-focus visual acuity testing in eyes implanted with the devices show that there is considerable enhancement of depth of field compared to preoperative values, with about 2D range around the best focus when measured monocularly. Eyes with the KAMRA inlay need to be near emmetropia preoperatively to achieve the best visual outcomes. Around 90% of eyes with manifest refraction spherical equivalent from -5D to -0.75D achieve 20/20 or better and J3, Dr Pallikaris reported. The disadvantage of the KAMRA inlay’s small Ioannis Pallikaris MD, PhD aperture is that less light

A variety of surgical options for presbyopia are now available, some are invasive and difficult or impossible to reverse

EUROTIMES | SEPTEMBER 2019

Courtesy of Ioannis Pallikaris MD, PhD

A major improvement in near vision is observed for small pupils (ideal for 3.5 mm). The near “add” effect of the Presbia Flexivue Microlens decreases for large pupils (ideal for 6mm – corresponding to far vision)

contributes to the retinal image in one eye, which makes vision more difficult under mesopic or scotopic conditions. Furthermore, reduced retinal illuminance in one eye can also causes a delay in that eye's transmission of the signal to the brain. That can result in a distortion in spatial perception known as the Pulfrich effect.

PULFRICH EFFECT The Pulfrich effect is best known for the way it distorts the apparent path of a swinging pendulum, which will appear to follow an elliptical path as the small pupil sees the object where it was, not where it is. Another potential problem with the KAMRA inlay is a postoperative hyperopisation that occurs in eyes with the device. For example, the Blue Mountains Eye Study showed that eyes with the implant had a hyperopic change equivalent to +0.4D over five years. Other postoperative issues reported for the KAMRA include blurred vision, diminished contrast sensitivity, diplopia, glare and halos. The Presbia Flexivue Microlens is made of hydrophilic acrylic material and has a thickness of 0.015mm and a diameter of 3.2mm. The inlay has a higher refractive index than the corneal stroma. It is designed to provide a near add in the centre of the pupil so that the sharpest near image occurs in indoor lighting conditions. In a study of eyes with the Microlens implant and up to five years of follow-up, the mean uncorrected near VA improved to J1 in 91.3% eyes of eyes and all eyes had an improvement of at least four lines of near vision. Ioannis Pallikaris: pallikar@med.uoc.gr

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SMILE is gaining in popularity, but will it replace LASIK? Roibeard Ó hÉineacháin reports

he relative advantages of small-incision lenticule extraction (SMILE®) over LASIK were brought under scrutiny in a debate held at the 23rd ESCRS Winter Meeting in Athens, Greece. Dimitrios Kyroudis MD took up the cudgel for LASIK, maintaining that its proven track record and only contradictory evidence supporting any superiority of SMILE in terms of visual outcomes or refractive stability, means that LASIK is the laser corneal refractive procedure of choice. SMILE was developed as a way of preserving the cornea’s biomechanical stability in order to prevent keratectasia while at the same time avoiding flap complications, diffuse lamellar keratitis and epithelial ingrowth. However, SMILE has its own, different set of complications, said Dr Kyroudis, Zurich, Switzerland. For example, obstructions to the laser beam on the ocular surface – from meibomian secretions in the tear film to ink used to mark the cornea – can prevent the laser energy from reaching the target stromal layer. The result can be difficult tissue separation, damage to the stromal bed and delayed visual recovery. Other complications can include loss of suction, which can require aborting and restarting the procedure, and retention of lenticule fragments, which can necessitate a second operation, without which the patient will have severe irregular astigmatism. Taking the opposing view, Konstantinos Moschou MD, Thessaloniki, Greece, maintained that there is adequate evidence to support SMILE’s efficacy and its superiority in some respects to LASIK. He noted over the past 10 years or so, more than 1.5 million eyes have undergone SMILE. There are 850 clinics worldwide in 70 countries where 1,700 surgeons can perform the procedure. Furthermore, SMILE was approved by FDA in 2016 and there have been more than 500 peer-reviewed studies published on the technique. He noted that SMILE has an inherent advantage over LASIK in that the femtosecond laser machine is less dependent on environmental conditions than the excimer laser. In addition, SMILE is less demanding than LASIK in terms of centration due to its larger optical zone than any excimer ablation profile. This results in less spherical aberrations. He added that whereas PRK and LASIK remove the shallower, stronger anterior stroma, SMILE removes deeper, weaker posterior stroma. That protects the eye from the development of ectasia. There are only four case-reports of ectasia published and, of those, three had infraclinical preoperative keratoconus. “In conclusion, with SMILE we have better biomechanical stability, fewer higherorder aberrations and less dry eye symptoms,” Dr Moschou said. Dimitrios Kyroudis: dkyroudis@gmail.com

SMILE has an inherent advantage over LASIK in that the femtosecond laser machine is less dependent on environmental conditions than the excimer laser Konstantinos Moschou MD

SPECIAL FOCUS: CATARACT & REFRACTIVE

Improving alignment New pendular marker improves toric intraocular lens placement accuracy. Dermot McGrath reports

n innovative pendulum marker offers eye surgeons a fast and accurate means of accurately aligning toric intraocular lenses (IOLs), offering some clear advantages over traditional ink marking methods, according to Guillaume Boutillier MD, speaking at the French Implant and Refractive Surgery Association (SAFIR) annual meeting in Paris. “We all know the importance of accurate toric IOL alignment in correcting astigmatism and limiting postoperative refractive errors. This new system works well, is easy to use and resulted in a statistically significant difference in the accuracy of corneal marking,” he said. Dr Boutillier said that the study, which he co-auhored with Marc Muraine MD, PhD, and Joel Mehech, resident of ophthalmology, was inspired by the fact that his clinic at Rouen University Hospital does not have access to recent guidance tools such as Callisto Eye (Carl Zeiss Meditec) or Verion Image Guided system (Alcon Laboratories Inc.). “We were using the bubble marker approach in combination with a Mendez ring, a system which leaves a lot to be desired

in terms of the precision of marking the cornea. We thought it would be interesting to see how this new marker might potentially improve marking of the axis for correct positioning of the toric lens in order to limit postoperative refractive error,” he said. Developed in the United States by Surgilum and retailed by Cristalens in France, the RoboMarker uses a gravitybased pendular weight system to ensure that the ring dial maintains the chosen axis. The system uses pre-inked, sterile, disposable tips allowing a one-step marking process with the patient in a sitting position. When applied to the cornea, the marker produces marks that last up to two hours. Dr Boutillier’s study included 100 eyes of 50 patients scheduled for toric IOL implantation. The right eye of each patient was marked using the RoboMarker and the left with a standard bubble marker and Mendez Ring combination. Following the marking, a photo was taken immediately afterwards, with special software then used to measure the axis alignment and to compare it to the targeted axis of alignment. The resulted showed a mean error of axis alignment of 3.2 degrees (±2.7 degrees) for

On the end of the Robomarker, there is a light in the centre that serves as a fixing point for the patient during the tracking. It is clear that the ends are thin, which makes it possible to make clear marks on the limbus

EUROTIMES | SEPTEMBER 2019

Courtesy of Guillaume Boutillier MD

Top: The Robomarker device. Above: The patient follows the light to the centre as the surgeon approaches the eye. The pendulum head must then be locked at the last moment with the index finger to avoid any rotation at the time of registration

the RoboMarker eyes and 6.2 degrees (± 2.9 degrees) for the bubble marker eyes. “This was statistically significant and while a 3-degree difference may not seem a lot it actually makes a big difference for toric IOL placement. In terms of astigmatism, it equates to about 10% of uncorrected astigmatism for the RoboMarker eyes and 20% for the bubble marker eyes. The other advantage is that the axis marking was finer, ie more precise and therefore easier to identify during the intervention,” he said. Dr Boutillier said that the study was limited by the fact that it only focused on one potential source of toric IOL alignment and did not take account of alignment errors induced by intraoperative positioning of the lens and postoperative rotation. “Nevertheless, our clinical experience was that the RoboMarker seems to be precise, rapid and efficient. However, at a cost of around €2,000 it represents a considerable investment,” he concluded. Guillaume Boutillier: guillaume.boutillier@chu-rouen.fr

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How to avoid dosing errors Study documents a need for greater dosing precision. Cheryl Guttman Krader reports

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Hill-RBF 2.0 The new version of RBF is based on a bigger dataset consisting over 3x the amount of data compared to the previous version. This leads to an impressive outcome of 94.8% within ±0.5 D in all eyes*. In addition the Hill-RBF was complemented with the well-established Abulafia -Koch algorithm for torical applications. * n = 288 / Clinical Study: Sperical Equivalent Results, Steven V. Scoper, Satelite Symposium, ASCRS 2017

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ntracameral injection of cefuroxime at the end of the case has become standard practice in the UK for preventing endophthalmitis after cataract surgery, but dosing errors are relatively common, according to a study presented at the 2019 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Vancouver, Canada. The recommended dose of cefuroxime for prophylaxis of postoperative endophthalmitis after cataract surgery is 1mg/0.1mL. In the study, the actual dose administered was determined in a series of 26 patients by comparing the preand post-injection volumes in the syringe. Two surgeons at Moorfields Eye Centre, Bedford Hospital, Bedford, UK, performed all of the operations, and a 1mL insulin syringe was used for the intracameral injection in all cases. In the study, the mean pre-injection volume was 0.36±0.11mL, the mean post-injection volume was 0.24±0.11mL and the mean injected volume was 0.12±0.02ml, exceeding the standard dose by 20%. Dosing errors occurred in six cases (23%), reported Simrun Singh Virdee MBBS. “The occurrence of dosing errors with intracameral cefuroxime should not be disregarded because underdosing might increase susceptibility to postoperative infection, while overdosing can increase the risk of drug-related toxicity,” said Dr Virdee. “Because the intracameral injection is performed without direct visualisation of the syringe, we recommend that surgeons check the syringe pre- and post-injection to ensure that the correct dose was administered. Although it seems to be an obvious step, we believe it is something that it is not being done routinely.” Dosing errors included three cases of overdosing and three cases of initial underdosing. In the cases of overdosing, there was accidental loss of the antibiotic prior to injection that necessitated repriming the syringe and led to excess injection. In the cases of underdosing, the error was identified when the post-injection volume was measured, allowing immediate correction. Dr Virdee noted that the average 20% excess administered dose of cefuroxime recorded in the Simrun Singh Virdee MBBS study is below the toxic range. He reported that no cefuroxime-related toxicity was observed in the series. Nevertheless, concern about safety in cases of overdosing is justified considering that even a standard dose has been reported to cause retinal toxicity, Dr Virdee said. He suggested that a graduated pre-made syringe providing tactile feedback could help overcome the potential for cefuroxime dosing errors that can occur with current preparation methods that involve loading the syringe with exactly 0.1mL or with extra volume to allow for accidental loss.

Although it seems to be an obvious step, we believe it is something that it is not being done routinely

Simrun Singh Virdee: simvirdee@aol.com EUROTIMES | SEPTEMBER 2019

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Precision pulse capsulotomy Effective and quick automated capsulotomy device offers advantages over femtolaser. Dermot McGrath reports

new automated capsulotomy system is effective at providing consistent, circular capsulotomies and reduces the risks of certain complications associated with cataract surgery, according to Matteo Piovella MD. “There is an initial learning curve associated with it, but once the technology has been mastered it enables the surgeon to create a precise and repeatable circular anterior capsulotomy while reducing the risk of capsular tears,” Dr Piovella told delegates attending the European Society of Ophthalmology (SOE) meeting in Nice, France. Dr Piovella explained that the Zepto capsulotomy system (Mynosys Cellular Devices) is a disposable, automated device consisting of a disposable handpiece with a silicone suction cup and a nitinol ring made of a nickel-titanium alloy. The application of suction forces the ring against the capsule, with a short pulse of energy causing the ring to generate a hole in the capsule, creating a circular, centred capsulotomy in just 4 milliseconds. The device integrates seamlessly into the routine steps of cataract surgery with phacoemulsification, noted Dr Piovella, and there is no need for the surgeon to alter his or her normal routine. Instead of using a capsulorhexis forceps or a cystotome, the surgeon uses the automated ring instead. The current version of Zepto produces a mean capsulotomy diameter of 5.2mm, with the possibility of a paediatric capsulotomy device being developed at a later stage. For pupils smaller than 5.5mm, Zepto can be slid under the iris before suction is engaged and there is no danger of iris tissue being captured by the suction, advised Dr Piovella.

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For pupils larger than 6.5mm, the iris tissue will not be in close proximity to the suction cup and will not be captured by the suction. This approach confers a number of clinical benefits, said Dr Piovella, who presented the results of a study using Zepto in 187 eyes of 107 cataract patients. “It is very quick and provides consistent, high-quality circular capsulotomies with a greater margin of safety compared to a capsulorhexis. The device is also less expensive than femtosecond laser-assisted cataract surgery and provides continuous technical improvements,” he said. Another benefit of the device is that because the silicone suction cup is transparent it allows the surgeon to preserve visual axis information during the procedure. In Dr Piovella’s study the mean endothelial cell count at six months was 2,181 compared to 2,249 preoperatively, with under 4% loss of cells over the follow-up period. There were eight anterior radial tears in the first 25 cases, directly related to the learning curve with the device, he said. Although Zepto works well for routine cataract cases, it may also prove particularly beneficial in more complex cases such as zonular disorders, retinitis pigmentosa and white cataracts, with the only limitation being an anterior chamber depth of at least 1.8 millimetres. Matteo Piovella: piovella@piovella.com

EUROTIMES | SEPTEMBER 2019

SPECIAL FOCUS: CATARACT & REFRACTIVE

THOMAS KOHNEN European Editor of JCRS

JCRS HIGHLIGHTS VOL: 45 ISSUE: 7 MONTH: JULY 2019

CATARACT COST-EFFICACY Cataract surgery is cost-effective and is becoming even more so, a large insurance study suggests. US researchers looked at data from public and private health insurance records. They performed costutility analysis with Value-Based Medicine standardisation of input and output variables. The overall analyses indicated that cataract surgery is highly cost-effective, whether for first-eye surgery, secondeye surgery or bilateral surgery. Interestingly, both the perceived value to patients and cost-efficacy showed significant increases between 2012 and 2018. For example, the cost-utility ratio of $1,001/quality-adjusted life years for first-eye surgery was 41.8% more cost-effective than in 2012 and 73.7% more cost-effective than in the year 2000. GC Brown et al., “Cost-utility analysis of cataract surgery in the United States for the year 2018”, Vol.45, Issue 7, 927-938.

PUPIL EFFECTS WITH NEWER ICLS Researchers conducted a prospective study to compare pupillometry characteristics before and after implantation of the older model V4 ICL and the newer V4c lens (Staar). The Visian V4c ICL includes a 360μm central hole to allow aqueous humour to flow without the requirement for an iridotomy. The study followed 50 patients who received ICLs for three months after the surgery. ICL implantation had a miotic effect under certain illumination conditions, resulting in decreases in pupil contraction amplitude and velocity in light reflexes. Regarding the pupil light reflex, contraction amplitude and velocity declined after surgery, whereas other dynamic parameters remained unchanged. The static and dynamic pupillary characteristics were similar between the V4 and V4c ICL groups. These investigators concluded that the central hole and aqueous humour hydrodynamic difference had little influence on iris motility. Y Zhu, “Static and dynamic pupillary characteristics in high myopic eyes with two implantable collamer lenses”, Vol.45, Issue 7, 946-951.

ANGLE KAPPA IN HYPEROPIC ASTIGMATISM Angle κ, defined as the angle between the visual axis and the pupillary axis, is generally larger in hyperopic patients, and is considered as a drawback when planning excimer laser vision correction. A retrospective multi-centre study of 170 hyperopic eyes of 112 patients looked at the prevalence of preoperative, intraoperative and postoperative angle κ in hyperopic eyes and its effect on the refractive outcomes. The study found statistically significant differences between the preoperative and real-time intraoperative angle κ in eyes with a preoperative angle κ of 0.25mm or more. The preoperative magnitude of angle κ did not predict the safety, efficacy or predictability of hyperopic excimer laser vision correction. The study notes that using the preoperative larger angle κ as an intraoperative offset might cause a too nasally centred ablation zone. A Frings et al. “Analysis of excimer laser treatment outcomes and corresponding angle κ in hyperopic astigmatism”, Vol.45, Issue 7, 952-958.

JCRS SYMPOSIUM

CONTROVERSIES in Cataract and Refractive Surgery

Sunday 15 September | 14.00 – 16.00 During the 37th Congress of the ESCRS, Paris, France

Chairpersons: T. Kohnen GERMANY (EUROPEAN EDITOR) W.J. Dupps USA (U.S ASSOCIATE EDITOR)

IOL calculations 14.00

D. Gatinel FRANCE Artificial intelligence

14.15

G. Barrett AUSTRALIA Modern IOL calculations

14.30

Discussion

Presbyopia-correcting IOLs 14.40

R. Mencucci ITALY EDOF

14.55

J. Alfonso SPAIN Trifocal

15.10

Discussion

Intraoperative antibiotics 15.20

A. Behndig SWEDEN Yes

15.35

A. Brezin FRANCE No

15.50

Discussion

16.00

End of session

JCRS is the official journal of ESCRS and ASCRS

EUROTIMES | SEPTEMBER 2019

CORNEA

CXL – Epi-on or off? Debate continues as corneal cross-linking tech advances. Howard Larkin reports

here’s no question corneal collagen cross-linking (CXL) stiffens the cornea and is an effective treatment for keratoconus and corneal ectasia. But does CXL’s future lie with the epithelium-off approach developed for the canonical Dresden protocol two decades ago? Or are more recent epithelium-on approaches using various methods to help riboflavin, oxygen and UV radiation penetrate the intact epithelium more promising? Two eminent clinicians debated the question at the 2019 ASCRS ASOA Annual Meeting in San Diego, USA.

FOR EPI-ON Arguing for epi-on, Roy Rubinfeld MD, MA, of MedStar Georgetown University Hospital, Washington DC, and Medical Director of Re:Vision, Chevy Chase, Maryland and Fairfax, Virginia, USA, challenged the entire debate premise. Given the pain and potential complications of removing the epithelium, he believes the real question should be “why isn’t all standalone cross-linking epi-on?” The answer goes back to Theo Seiler MD, PhD, and colleagues who invented the procedure in Dresden, Germany, in 1998. “They did not have a formulation that would go through the epithelium so they just took it off,” Dr Rubinfeld said. Major potential complications of epi-off CXL include corneal oedema, sterile infiltrates, infectious keratitis, delayed epithelial healing, corneal haze, persistent ocular surface issues as well as stromal scars in nearly 3% of cases – and these are all related to removal of the protective epithelium (Koller et al. JCRS 2009;35:1358). “We prefer not to have any of these,” Dr Rubinfeld emphasised. After numerous attempts and failures, one epi-on approach using a novel riboflavin formulation and system has had notable success in multiple studies,

Dr Rubinfeld said. This epi-on CXL stabilising the cornea through stiffening; technology was tested in 592 eyes including low risk of sight-threatening complications; 49 paediatric cases with keratoconus and comfortable for patients; and cost-effective postoperative ectasia. Progression was and sustainable in practice. arrested in all eyes including a consistent “So why are we even interested in epicohort over a full two years of follow-up on? Which of these characteristics could in the consistent cohort (Stulting D et. al. be improved?” Dr Dupps asked. JCRS 2018;44:1363-1370). He allowed that epi-on CXL In published animal research, might lower the procedure’s risk this sodium iodide riboflavin profile and improve patient formulation known as comfort, but added that the RiboStat™, CXLO, LLC case must be made based (Encinitas, California, USA), on all relevant criteria. adequately penetrated corneal He further cautioned that epithelium and loaded corneal various epi-on approaches, stroma in rabbit eye studies such as varying riboflavin Dr Rubinfeld and colleagues concentrations, admixing conducted (Quantitative analysis Roy Rubinfeld MD, MA various ingredients, mechanical of corneal stromal riboflavin augmentation and iontophoresis concentration without epithelial to increase stromal penetration removal. Roy Rubinfeld, MD, R. Doyle of riboflavin, are very different and must Stulting, MD, Glenwood Gum, PhD, be evaluated individually. Jonathan Talamo, MD. J Cataract Refract Regarding effectiveness, epi-off may be Surg. 2018 Feb;44(2):237-242. Erratum in: J more reliable and predictable, Dr Dupps Cataract Refract Surg. 2018 Apr;44(4):523. said. Removing the epithelial barrier https://www.jcrsjournal.org/article/S0886helps ensure penetration of riboflavin, 3350(18)30100-7/fulltext) and the sodium oxygen and UV radiation, and reduces iodide protected the riboflavin in the the risk of reduced stromal reaction, thus stroma from UV photodegradation (Gum, maximising the magnitude of stiffening. Rubinfeld, Parsons. ARVO 2019). It also may reduce the variability CXLO, in which Dr Rubinfeld has a of stiffening, which is essential for financial interest, is finishing a large phase developing titratable procedures for safely II clinical trial with interim results on treating thinner corneas and enhancing 1,195 keratoconus and 190 post-surgical reproducibility for future refractive ectasia cases are largely consistent with Dr applications of CXL. Several studies also Stulting’s findings. suggest that epi-on CXL induces less Visual recovery and clear corneas one clinical flattening, greater late loss of day after surgery make epi-on the future flattening effect and shallower stiffening choice for CXL, Dr Rubinfeld concluded. depth than epi-off. “The trend in surgery is toward less Regarding avoiding sight-threatening invasive procedures.” complications and patient comfort, Dr Dupps pointed out that epithelial disruption can still occur with epi-on FOR EPI-OFF CXL, and reduced effectiveness could In support of epi-off CXL, William J require retreatment. Dupps Jr MD, PhD, of the Cleveland Epi-on techniques ideally should be Clinic, Cleveland, Ohio, USA, reviewed equivalent in terms of long-term stability, criteria for the ideal CXL. In descending or show sufficient safety advantages order of importance, they are: effective in that repeat treatment is as safe and effective, as epi-off treatment, Dr Dupps concluded. “Comparative trials large enough to compare complication rates and patientreported outcomes are needed.”

So why are we even interested in epi-on? Which of these characteristics could be improved?

Roy Rubinfeld: rrubinfeld@cxlophthalmics.com

William J Dupps Jr MD, PhD

William J Dupps Jr: duppsw@ccf.org

EUROTIMES | SEPTEMBER 2019

CORNEA

Pre-stripped and pre-loaded DMEK Is pre-cut tissue the future of endothelial surgery? Dermot McGrath reports

sing pre-stripped and pre-loaded tissue for Descemet’s membrane endothelial keratoplasty (DMEK) procedures results in more efficient surgery and may help to cut down on tissue wastage, according to William Barry Lee MD, FACS. “DMEK is rising in popularity in the United States and elsewhere and initial studies indicate that pre-stripped, pre-stamped, pre-stained, pre-cut and pre-loaded (PPPPP) DMEK outcomes appear equivalent to surgeon-prepared tissue in the operating room. This approach improves surgeon efficiency, eliminates surgeon tissue wastage and reduces equipment costs,” he told delegates attending the European Society of Ophthalmology (SOE) meeting in Nice, France. A recent literature review by Deng et al. found that with respect to visual recovery time, visual outcomes, and rejection rates, DMEK seems to be superior to Descemet’s stripping endothelial keratoplasty (DSEK) and seems to induce less refractive error with similar surgical risks and endothelial cell loss, noted Dr Lee. “So the question now is how can we help surgeons in the OR perform DMEK surgery and make it easier? Using preloaded tissue enables surgeons to focus on the patient, increase their surgical efficiency and not worry about the risks of damaging endothelial tissue. It also enables surgical centres to avoid having to pay for expensive equipment such as trypan blue, trephine blades or anterior chamber equipment,” he said. Dr Lee said that a growing number of eye banks in the United States are now able to provide pre-loaded DMEK tissue for transplantation. “In Georgia we do over 2,000 corneal transplants a year and so our eye bank provider has become very accomplished at preparing these preloaded tissues. They also can prestamp the tissue for you, which is very useful as it is sometimes tricky in the OR to know if the tissue is upside down or reversed. Pre-marking it with a letter can help significantly and reduces the risk of a potential source of error in the surgery,” he said. Clinical results with preloaded DMEK tissue are comparable to other DMEK techniques, said Dr Lee. The Devers Eye Institute group in Portland, Oregon, reported a re-bubble rate of 14.4%, no primary graft failures and endothelial cell loss of 30% in 111 eyes over six months. Dr Lee’s own group in Georgia had a re-bubble rate of 23%, primary graft failure in 4% and endothelial cell loss of 34% after six months. For surgeons starting off DMEK with pre-prepared tissue, Dr Lee advised selecting cases with a good view and avoiding those with severe corneal oedema. For pseudophakic patients, avoid those with blebs and tube shunts and avoid high myopes. “Try to make the surgery as close to cataract surgery as you can, use a peripheral iridotomy inferiorally to help with pupillary block and use SF6 gas to decrease graft dislocations,” he concluded.

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William Barry Lee: wblee@mac.com EUROTIMES | SEPTEMBER 2019

CORNEA

NEW DRUGS & DEVICES for dry eyes More comparative studies needed for latest dry eye treatments. Dermot McGrath reports

phthalmologists now have a wide range of potential treatments to treat dry eye, many new and largely unproven in randomised, controlled studies, but the success of any treatment will always depend upon a correct diagnosis and appreciation of the underlying aetiology, according to Stephen C. Kaufman MD, PhD. “We have a lot of new devices and drops to treat dry eye and there are more in the pipeline. While we await large-scale comparative studies for these, the correct underlying diagnosis of the cause of the dry eye is essential, and the underlying disease must be treated or you will not have success in the long term,” he told delegates attending the European Society of Ophthalmology (SOE) meeting in Nice, France. Dr Kaufman, Professor and Vice Chairman of Ophthalmology at the University of Minnesota, Minneapolis, USA, noted that a number of new treatments over the past year have focused on meibomian gland disease. Many work on the same principle as LipiFlow (Johnson & Johnson Vision), which has been on the market for a number of years, said Dr Kaufman. The LipiFlow device works by combining heat with physical massage to liquefy and express the meibomian gland contents in order to try to return the lipid layer of the ocular surface back to normal functioning. Recent alternatives to LipiFlow include iLux (Alcon), a handheld device that

directly targets the blocked meibomian glands through the application of light-based heat and compression, and TearCare (Sight Sciences), wearable eyelid technology that provides targeted and adjustable thermal energy to the meibomian glands. “All of these devices are FDA approved and have been shown to improve ocular surface disease index (OSDI) scores. However, there are no large-scale studies and no comparative studies against other devices or treatments. We advise using meibography to document the initial condition of the glands and to track any improvement with treatment, but bear in mind that patients may improve symptomatically without any significant change in the glands, so this is an indication that treatment is effective,” he said. Other recent experimental approaches to dry eye include radio frequency and intense pulsed light therapy (IPL), said Dr Kaufman. “These are interesting approaches although we need more studies to establish their safety and efficacy over the long term,” he said. The importance of ruling out Demodex mite lid infestation as a possible underlying cause of meibomian gland disease was also emphasised by Dr Kaufman. “There are specific treatments available to treat Demodex infestation such as Cliradex (Bio-Tissue), a concentrated tea tree oil derivative. We also have some alternative tea tree oil formulations now available, which are available in the United States without a prescription and which are

less expensive than Cliradex,” he said. Over the counter (OTC) artificial tears historically have been the first line of treatment for dry eye syndrome and dry eye‐ related conditions, and more are coming on the market every year, said Dr Kaufman. “There are multiple new artificial tear formulations which are usually designed to target at least one tear film layer, as well as those which provide vitamin A and omega-3 fatty acids. Again, comparative studies are lacking for many of these new products so understanding the primary deficiency of your patient’s tear film should help guide the treatment strategy,” he said. Another potentially interesting treatment in the pipeline is amniotic membrane-derived eyedrop formulations, although none are currently FDA approved, said Dr Kaufman. Those interested in dry eye treatments should also have a look at TrueTear (Allergan), a neurostimulator that stimulates nasal nerves which increases tearing through a central pathway. Two FDA studies of the device have been conducted, said Dr Kaufman, with all patients using TrueTear showing increased tear production based on Schirmer scores. “We have used it in our clinic and it seems to work well. It is expensive, however, and we are not sure if the tears produced are the same as basal tears produced by the accessory lacrimal glands, so more studies are needed on this device as well,” he concluded. Stephen C. Kaufman: SCK@UMN.edu

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CORNEA

The eye and the immune system Insights on mechanisms and benefits of ocular immune privilege and its loss. Cheryl Guttman Krader reports

S president John F Kennedy once said: “When written in Chinese, the word ‘crisis’ is composed of two characters – one represents danger and the other represents opportunity.” Jerry Y Niederkorn PhD referenced the famous quote in his delivery of the Proctor Lecture at the 2019 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Vancouver, Canada, drawing an analogy with the eye and the immune system. He provided a detailed review of research showing how the same concept describes the consequences of sympathetic loss of immune privilege (SLIP), a phenomenon in which perturbation of the ocular surface in one eye leads to termination of immune privilege in the opposite eye. Dr Niederkorn is Professor and Vice Chair of Research, University of Texas Southwestern Medical School, Dallas, USA. In his talk, “The eye sees eye to eye with the immune system”, Dr Niederkorn explained that ocular immune privilege is a beneficial adaptation for preserving vision. He went on to describe how its termination can also be beneficial because it serves to protect the host from potentially lifethreatening infections, albeit at the risk of blindness.

UNDERSTANDING IMMUNE PRIVILEGE Providing a contemporary definition of immune privilege, Dr Niederkorn said that it describes a compromise between the eye and the immune apparatus to minimise immunemediated inflammation and injury to ocular tissues that have limited or no regenerative capacity. “Immune privilege of the ocular surface allows the ocular surface to tolerate daily exposure to nominal noninfectious agents. It is an adaptation to silence an immune-mediated inflammatory response and protect the EUROTIMES | SEPTEMBER 2019

In its wisdom, the immune system anticipates that an ocular infection in one eye will be followed by infection in the fellow eye Jerry Y Niederkorn PhD

ocular tissues from irreparable injury in order to preserve vision.” Ocular immune privilege also explains the extremely low rejection rate (~10%) of first corneal transplants that occurs in the absence of histocompatibility matching or use of systemic immunosuppressive medications. “I know of no other type of transplant that can survive at that rate under those conditions. Subsequent corneal allografts in the second eye in humans have a two- to three-fold increased incidence of rejection. Mouse studies suggest that this increased risk for rejection in humans is due to SLIP,” noted Dr Niederkorn .

RESPONDING TO CRISIS – MECHANISMS EXPLAINED The dichotomous effects of loss of ocular immune privilege were demonstrated by the findings of an animal experiment that investigated the inflammatory response to herpes simplex virus (HSV) corneal inoculation. The research showed that while T-celldeficient animals developed infection and died, their corneas remained clear. In contrast, the normal mice that were able to generate an immune response developed necrotising keratitis, but the animals survived because their intact immune response protected against virus dissemination. “This experiment tells us that the immune response to HSV infection, not the virus, is responsible for damaging the cornea, and that the outcome of being unable to mount an immune response is death as opposed to blindness,” Dr Niederkorn said.

He explained that the mechanism for immune privilege involves anterior chamber-associated immune deviation (ACAID), a phenomenon in which antigens introduced into the eye reach the spleen where they induce formation of T regulatory cells that suppress the immune response in the eye. SLIP occurs when the T regulatory cells become disabled through a pathway that is regulated by corneal nerves and mediated by release of the neuropeptide, substance P. Research conducted by Dr Niederkorn and colleagues provided understanding of these mechanisms and showed that in the setting of a first corneal transplant, the severing of corneal nerves by trephination is responsible for inducing secretion of substance P. Similarly, the release of substance P explains SLIP in HSV keratitis. Substance P is released in response to infection as the dense network of corneal sensory nerves acts to alert the immune system of infectious agents that produce tissue damage but that are also a threat to host survival, Dr Niederkorn explained. “In its wisdom, the immune system anticipates that an ocular infection in one eye will be followed by infection in the fellow eye. The eye has a dialogue with the immune system, and in an adaptation to preserve life, the dialogue leads to termination of immune privilege, even if it means blinding the eyes, because some of those infections can take the life of the host.” Jerry Y Niederkorn: Jerry.Niederkorn@utsouthwestern.edu

CORNEA

New approaches to target dry eye Novel diagnostic and treatment methods can help treat tear instability. Howard Larkin reports

ear instability is a major cause of ocular discomfort, visual disturbances and dissatisfaction with vision-correcting surgery. Identifying and targeting the underlying causes is essential for successful treatment, Stephen C Pflugfelder MD said in his Binkhorst Lecture to the 2019 ASCRS ASOA Annual Meeting in San Diego, USA. A stable tear film consists of two layers: a hydrated mucous gel consisting of mucin secreted by conjunctival goblet cells mixed with proteins and electrolytes from the lacrimal glands, anchored to the epithelium by glycocalyx mucin and covered by a polar and non-polar lipid layer produced by the meibomian glands. Instability can result from disruption of any of the systems producing these components as well as environmental and anatomic factors that inhibit tear flow. The quest for tear stability starts with the integrated lachrymal functional unit, said Dr Pflugfelder, of Baylor College of Medicine, Houston, USA. Cooling and increased osmolarity at sites of tear break-up activate TRPM8 signalling channels in corneal nociceptors, initiating the neural reflex that drives tearing and blinking. Lacrimal factors including epidermal growth factor and vitamin A support tear-stabilising mucin production by conjunctival goblet cells, which also suppress antigen presenting cells leading to immune tolerance on the ocular surface. Aqueous deficiency leads to goblet cell loss, further destabilising tear film and promoting immune inflammation, stimulating cytokines, chemokines and proteases including MMP-9 that damage apical epithelial cells and decrease surface wetability, leading to irritation, blurred vision and corneal epitheliopathy. By contrast, meibomian gland dysfunction is linked to increased goblet cell density, which may explain the greater severity often seen in cases caused by tear deficiency, Dr Pflugfelder said.

DIAGNOSIS AND TREATMENT Four fluorescein break-up patterns have been identified that can help identify the root causes of tear instability, Dr Pflugfelder noted (Yokoi N, Georgiev GA. IOVS 2018). Noninvasive assessment of Placido ring patterns provide a kinetic record of tear break-up patterns that helps spot corneal and surface pathologies promoting instability, such as nodular degeneration or epithelial membrane dystrophy, he added. Conjunctivochalasis is a common age-related cause. Onethird or more of patients over age 50 could benefit from surgery, Dr Pflugfelder said (Mimura et al. AJO 2009). To stabilise tear film, Dr Pflugfelder recommended increasing humidity and minimising air drafts, and correcting any lid and conjunctival abnormalities. A wide range of therapies targeting specific causes are also available, including thermal meibomian gland expression and essential fatty acid for lipid problems, retinoids, serum plasma and plugs for hydrated mucin gel, and doxycycline and steroids for the epithelium. “It’s important to target therapies to the underlying causes of tear dysfunction,” Dr Pflugfelder concluded. Stephen Pflugfelder: stevenp@bcm.edu

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CORNEA

A vicious cycle of inflammation

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opical administration of nanoparticleencapsulated micro-RNA (miR) inhibitors may provide a new approach to the treatment of Sjögren’s syndrome, according to Emily Greenan MD, Royal College of Surgeons in Ireland, Dublin, Ireland. “Our research has identified miR-dysregulation in Sjögren’s syndrome patients that may play a role in mediating ocular inflammation. We have also formulated and characterised suitable non-immunogenic particles to deliver miR-modulating compounds to the ocular surface,” said Dr Greenan at the Irish College of Ophthalmologists Annual Conference 2019 in Galway, Ireland. In Sjögren’s syndrome patients, dry eye results from a vicious circle of inflammation. It starts with the initial inflammation of the lacrimal gland, which, in turn, decreases the aqueous flow. The resulting tear film hyperosmolarity damages epithelial cells, leading in turn to the release of inflammatory cytokines, propelling the cycle further, Dr Greenan explained. In recent years, miR dysregulation has been identified as a potential biomarker for inflammation in Sjögren’s syndrome patients. She noted that miR molecules are fragments of RNA containing 18-to-23 nucleotides that have a function in the post-transcriptional regulation of gene expression.

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DME – there’s an app for that New digital platform to manage DME patients. Dermot McGrath reports

novel digital platform designed to promote better communication and interaction between patients and doctors in the context of diabetic macular oedema (DME) is currently being trialled in Italy, Spain and the United Kingdom, with other countries set to follow in the near future. Vision Coach, an initiative financed and supported by Bayer AG in association with Healthforge, a UK-based startup specialising in healthcare software, aims to improve treatment adherence and visual outcomes for patients and clinic efficiency and capacity management for clinicians. The development of the Vision Coach platform was inspired by the DR Barometer study conducted in 41 countries with more than 7,000 participants to identify gaps in vision care for people with diabetes, which is now a multidisciplinary network of thought leaders and organisations working together to address these (www.drbarometer.com). “The idea is to give patients access to key data and educational resources required for greater engagement, persistence and improved outcomes. For clinicians, the benefit is to have access to novel tools to promote patient activation and ultimately, we hope, improved persistence and outcomes,” said Bill Aylward FRCOphth, Clinical Director of Healthforge. The platform consists of three components: a patient application (available on iOS and Android), a web application for physicians and a patient website. The potential demand for such an app is enormous, points out Dr Aylward. DME is the leading cause of vision loss in the working age population, affecting an estimated 21 million globally in 2010 and is set to grow significantly in future, driven in part by growth in the underlying diabetes population. The standard of care for most patients with DME is anti-VEGF therapy. However, a large number of DME patients who are treated with anti-VEGFs fail to adhere to therapy, contributing to suboptimal visual outcomes.

of patient activity between appointments. Dr Aylward said that the pilot programme will be trialled in about two-to-three centres in each participating country. “We’re aiming to recruit around 500 patients this year and the pilot will last for 2019. From that we’ll study the quantitative key performance indicators (KPIs) around user numbers, utilisation, and early data on persistence, and qualitative KPIs on usability and pain points to mass adoption,” he said.

TECH PENETRATION

Vision Coach aims provides patients with access to important sight score data to facilitate more active management of their disease

Vision Coach aims to improve adherence by providing patients with access to important sight score data to facilitate more active management of their disease. It helps them to set meaningful goals targeting health-promoting behaviours, and tracking progress against them. The app also provides accessible educational content to help increase patient selfconfidence and take charge of their DME. On the clinician side, the app enables workflow support for patient and appointment management, treatment plan creation, and recording encounters and sight scores. A dual data entry model allows patients to enter sight score data and clinicians to modify this data if it is incorrect. It also gives the physician a view

While an older population group might not seem the ideal target for a mobile app, Dr Aylward believes that tech penetration is on the rise in this demographic. “A decent proportion of DME patients are of working age, in their 50s, and smart phone penetration is higher in this group. The median age of patients in the aflibercept phase III studies, for example, was early 60s, which is 10 years younger than patients in the wet AMD studies,” he said. The app marks something of a new departure for Bayer into broader areas of patient-clinician interaction and education. “Vision Coach is an innovative platform designed to engage, empower and educate patients with DME, with the ultimate aim of improving patient outcomes” said Dr Rafiq Hasan, VP & Global Head of Ophthalmology at Bayer. Although DME is the initial focus of Vision Coach, Dr Hasan said that other ocular diseases might also benefit from the platform. “DME was where we happened to choose to start. However, age-related macular degeneration and retinal vein occlusion are diseases where there may also be utility. Based on experience in the pilot, and strategic priorities for Bayer, we will decide on which to extend to next,” he concluded. https://healthforge.io/en EUROTIMES | SEPTEMBER 2019

RETINA

Expanding the application of AI Researchers describe first machine learning OCT-A-based AMD classification. Cheryl Guttman Krader reports

nitial evaluation of a machine learning algorithm for the automated interpretation of optical coherence tomography angiography scans shows that it has promising diagnostic potential for agerelated macular degeneration (AMD). The project, which was a collaboration between researchers from Moorfields Eye Hospital, London, UK, and the School of Computer Science, University of Manchester, Manchester, UK, included approximately 200 scans from patients with AMD and 100 scans from healthy controls. As reported at the 2019 annual meeting of the Association for Research in Vision and Ophthalmology (ARVO) in Vancouver, Canada, the classifier demonstrated good performance and resilience in distinguishing eyes with wet AMD both from normal controls and from eyes with dry AMD. “This work is a promising step towards the development of machine learning support systems for the interpretation

The inner retinal layers are not where we would expect to see changes indicative of wet AMD Konstantinos Balaskas, MD

of OCT-A scans in the diagnosis and classification of AMD,” said Konstantinos Balaskas MD, Director of the Ophthalmic Imaging Reading Centre, Moorfields Eye Hospital. “Our future plans include enriching the dataset with more scans, An OCT Angiogram showing a typical Choroidal Neovascular network in the outer retina and conducting additional choriocapillaris slabs (the inner retinal slabs appear unaffected) validation exercises with other datasets and developing OCT-A-based classifiers for other pathologies.” Looking ahead, Dr Balaskas also noted the The algorithm was based on a hybrid potential of combining OCT-A diagnostic approach that decreases the chance of having algorithms for AMD with other artificial multiple correlated features and redundant intelligence decision support systems to features. Two classifiers were tested, and for develop tools for use in clinical practice. both the algorithm for AMD demonstrated “Artificial intelligence support systems high sensitivity and specificity when have been developed for interpreting colour combining information from all of the retinal fundus images from eyes with diabetic vascular layers or when focusing on individual retinopathy and OCT scans from eyes with layers, including the inner retinal layers. AMD. Combining output from machine “The inner retinal layers are not where learning algorithms that interpret different we would expect to see changes indicative but complementary imaging modalities of wet AMD; although we do not yet know (such as OCT and OCT-A) could provide what pattern the classifier was identifying, an additional layer of certainty for diagnostic this is quite an intriguing finding. There is systems and support their adoption,” he said. the potential, to be confirmed by further work, that the algorithm is able to pick https://readingcentre.org/ up differences that are not identified by Konstantinos Balaskas, MD clinicians,” Dr Balaskas told EuroTimes. k.balaskas@nhs.net

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Learning from retinal implants Experience with discontinued implant provides important insights. Cheryl Guttman Krader reports

aking into account reimbursement obstacles and outcomes that fall short of today’s patients’ expectations, Retina Implant AG shareholders recently resolved to dissolve the company. Therefore, production of Retina Implant Alpha AMS, the company’s subretinal visual implant, has been discontinued. Looking back, however, valuable information can be gleaned from experience with the electronic subretinal prosthesis RETINA IMPLANT Alpha AMS and its earlier generation version (RETINA IMPLANT Alpha IMS), said Katarina Stingl MD, at the Annual Meeting of the Association for Research in Vision and Ophthalmology in Vancouver, Canada. Dr Stingl, University of Tübingen, Tübingen, Germany, has 12 years of clinical experience with the subretinal visual implants involving patients implanted in clinical trials and post-commercialisation. Highlighting four issues, she said that the experience provided proof of concept that the subretinal implant approach could restore vision to patients with complete blindness from photoreceptor degeneration. The approach, however, had limitations.

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VISUAL ACUITY “Visual acuity (decimal) will never be better than 0.1, the visual field is only a square of 10º to 15º, and there is no colour vision and no automatic adaptation to light levels,” said Dr Stingl. As another caveat, which was Dr Stingl’s second point, it was seen that outcomes vary individually. Approximately one-half of patients could recognise shapes and rough details. Of the rest, about one-half were able to localise objects, but the remaining patients perceived no useful visual information from the implant in their daily life. “Although all patients who received the implant were selected based on the same inclusion and exclusion criteria, not everyone benefited in the same way. The individual differences in outcomes were sometimes explainable, but sometimes were a black box for us,” she explained.

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FOVEAL ECCENTRICITY Not surprisingly, implant location was one factor that made a difference. Dr Stingl’s third point was that foveal eccentricity matters. Higher visual functions – location perception, grating acuity, motion perception, and ability to read letters – were almost only possible in patients whose implant was in a subfoveal versus a parafoveal location, she said. Lastly, Dr Stingl noted that the subretinal implant approach had a good safety profile. Surgery-related adverse events included cases of haemorrhage and IOP increase, but they resolved within days to a few weeks after implantation. Over 12 years of clinical experience, the implant showed good long-term biocompatibility and there were no cases of endophthalmitis or inflammation. Retinal thickness measured by OCT for six months after surgery remained unchanged.

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Katarina Stingl: Katarina.Stingl@med.uni-tuebingen.de EUROTIMES | SEPTEMBER 2019

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Use of FLIO in retinal disease The older your grow, the more you glow – tracking retinal disease with FLIO imaging. Dermot McGrath reports

luorescence lifetime imaging ophthalmoscopy (FLIO) is a new, non-invasive imaging technique capable of capturing highly reproducible measurements in the retina and revealing valuable information on a wide range of retinal diseases, according to FLIO image of a healthy left eye. Martin Zinkernagel MD, PhD. “I think this has a lot of potential going forward as the measurements obtained by the device are very reproducible. It can provide information about outcomes measures for macular pigment even in the presence of macular atrophy in diseases such as age-related macular degeneration (AMD) or geographic atrophy (GA). We can also identify disease-specific patterns and it may provide additional parameters for outcomes in diseases such as Stargardt or choroideremia,” he told delegates attending the European Society of Ophthalmology (SOE) meeting in Nice, France. Unlike conventional fundus autofluorescence imaging, which measures the intensity of endogenous fluorophores, and primarily lipofuscin, in retinal tissue, FLIO measures the average amount of time a fluorophore remains in the excited state before emitting a photon to return to the ground state. “We use a laser to excite the fluorophore, which then releases photons to get back to the ground state. This time can be calculated and assessed, as fluorescence lifetimes are specific for individual fluorophores and depend on the metabolic environment,” he said. FLIO is based on a Spectralis HRA system (Heidelberg Engineering), which uses a picosecond-pulsed diode laser at 473nm wavelength and 80MHz repetition rate to excite the retinal fluorophores. Fluorescence decay times are then measured in both a short (498-560nm) and long (560720nm) spectral channel by time-correlated single photon counting. The detection of emitted single fluorophores over time results in a fluorescence decay curve for every pixel within the field of registration, explained Dr Zinkernagel. “The lifetimes are represented in topographic colourcoded imaged scales, with short lifetimes in red and long lifetimes in blue,” he said. Studying the FLIO maps in healthy individuals established the high reproducibility and repeatability of the lifetime values, and also showed a correlation of fluorescence lifetimes with age, said Dr Zinkernagel. “Basically, the older you grow, the longer you glow. Older individuals exhibit longer fluorescence lifetimes, possibly due to progressive accumulation of visual cycle end products within the retina,” he added. Potential applications of FLIO include tracking and monitoring a broad range of retinal diseases such as AMD, GA, central serous chorioretinopathy and inherited retinal diseases such as Stargardt’s disease. It may also help to identify potential biomarkers in certain diseases and to monitor patients’ responses to therapies, including novel and innovative therapeutic strategies, he concluded. Martin Zinkernagel: m.zinkernagel@gmail.com EUROTIMES | SEPTEMBER 2019

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Biomarkers for macular disease

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Novel biomarkers are proving useful in the treatment and management of DME. Dermot McGrath reports

ngoing research is helping to identify and validate a wide range of traditional and novel biomarkers that can prove useful in monitoring disease activity and response to treatment in diabetic macular oedema (DME), according to Anat Loewenstein MD. “Biomarkers can help us to answer some fundamental questions relating to our treatment strategies. It can shed light on why a patient responds to one specific steroid or antiVEGF agent and not another and what the level of response might be,” she told delegates attending the European Society of Ophthalmology (SOE) meeting in Nice, France. Dr Loewenstein defined a biologic biomarker as a characteristic that is objectively measured and evaluated as an indicator of normal biological occurrence, pathologic processes or pharmacological response to a therapeutic intervention. She noted that there are multiple assessments possible with current biomarkers, many of which lack validation in controlled trials. She cited functional tests such as ETDRS, microperimetry and contrast sensitivity, biological samples of aqueous or vitreous to target specific cytokines or molecules such as VEGF or imaging tests such as optical coherence tomography (OCT), fundus photography and fundus autofluorescence. Focusing on the biomarkers that may have the greatest utility in tracking DME, Dr Loewenstein cited baseline visual acuity, lens status, as well as a variety of specific OCT biomarkers as potentially valuable. The value of baseline visual acuity as a biomarker has been shown over the years in landmark studies such as Protocol I and II and others, she said. “We learnt from Protocol I, for instance, that baseline visual acuity was a valuable prognostic predictive biomarker not to treat with laser photocoagulation too quickly. It was actually shown to do more harm than good for those patients with better visual acuity at baseline,” she said.

LENS STATUS Lens status has also proven a useful biomarker in some recent studies, with pseudophakic eyes tending to respond better to triamcinolone in Protocol I, for instance, and also in the BEVORDEX trial where phakic eyes responded less well to both triamcinolone and bevacizumab, she said. In terms of OCT, Dr Loewenstein said that her colleagues at Tel Aviv University had recently identified some interesting biomarker candidates for DME treated by intravitreal dexamethasone (DEX) implant. Among eyes with DME, those with submacular fluid, no hyper-reflective foci and a continuous inner segment-outer segment layer responded better to DEX implants than those without these features. Two other biomarkers of interest as possible predictors of functional or anatomical improvement in anti-VEGF treatments include the disorganisation of retinal inner layers (DRIL) and the height of intraretinal cystoid fluid at baseline, concluded Dr Loewenstein. Anat Loewenstein: anatl@tlvmc.gov.il

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Surgical technique for macular holes Inverted ILM peeling effective at closing larger macular holes. Dermot McGrath reports

n inverted internal limiting membrane flap technique for the treatment of large macular holes offered a higher incidence of anatomical closure compared with the standard internal limiting membrane peel, according to a study presented at the 9th EURETINA Winter Meeting in Prague. “While we found similar closure rates and visual acuity outcomes with smaller holes, larger macular holes over 400 microns achieved a better closure rate with the inverted flap technique. The visual acuity outcomes depend on the diameter of the macular hole and on the preoperative visual acuity,” said Eva Klofacova MD, Charles University and General University Hospital in Prague, Czech Republic. Her retrospective study included 50 eyes with idiopathic macular holes that were randomly assigned into two groups. Group 1 patients underwent standard internal limiting membrane (ILM) peel, and group 2 patients underwent inverted ILM flap technique. The researchers evaluated visual acuity and postoperative macular hole closure as the primary outcome measures. In smaller holes of less than 400 microns, a closure rate of 100% was achieved in both groups with very similar visual acuity outcomes, said Dr Klofacova. In macular holes larger than 400 microns, a closure rate of 100% was achieved with the inverted flap approach compared to 95% for standard ILM peeling. Macular hole surgery has evolved greatly from the initial studies of Wendel in 1991 when closure rates were in the region of 73%, noted Dr Klofacova. “Since 1996, ILM peeling has greatly improved the anatomical success rate of the surgery up to around 90%. In some instances, however, this standard procedure does not work so well, including cases of macular holes of large diameter, longstanding macular holes and macular holes secondary to ocular trauma, high myopia Eva Klofacova, MD and uveitis. Until recently, there was no efficient surgical procedure for these cases,” she said. Further advances in idiopathic macular hole surgery came with the inverted ILM flap technique by Zofia Michalewska and colleagues in 2010, which involved covering the macular hole with an inverted remnant of ILM that is left attached to the margins of the macular hole after ILM peeling. “The ILM functions as a scaffold for proliferation and migration of Müller cells, which can induce gliosis and contribute to closure of the hole. The ILM flap may also provide an environment in which photoreceptors can assume new positions in direct proximity to the fovea and improves postoperative visual acuity,” she concluded.

Since 1996, ILM peeling has greatly improved the anatomical success rate of the surgery up to around 90%

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GLAUCOMA

Advances in glaucoma

ew glaucoma medications with new targets and new mechanisms of actions, and new modes of delivery may extend the range of medical IOP control, reports Cédric Schweitzer MD, Bordeaux University Hospital, France. “There is a need for additional medical treatment alternatives because current drugs can lead to various systemic or local adverse events in some patients. There are also those patients who do not respond to current medications or do not comply to the treatment recommended by the ophthalmologist,” Dr Schweitzer told the 23rd ESCRS Winter meeting in Athens, Greece.

NEW RHO KINASE INHIBITORS Some recent developments to that end include the Rho kinase (ROCK) inhibitors, which target the trabecular meshwork. ROCK inhibitors achieve their IOP-lowering effect through a downregulation of cytoskeleton function that causes disruption of the actin bundles and retraction of cell bodies in the trabecular meshwork, decreasing resistance to outflow. Peer-reviewed studies indicate that the new ROCK inhibitor ripasudil (Rhopressa, Aerie Pharmaceuticals) reduces IOP by 2.2-to-3.7mmHg. Regarding adverse events, in a monotherapy trial involving 173 patients, conjunctival hyperaemia occurred in 75.7% of patients, but was mild in all but 1.7%, in whom it was moderate. In addition, blepharitis occurred in 25.4% of patients, in 20.2% it was mild

There is a need for additional medical treatment alternatives because current drugs can lead to various systemic or local adverse events in some patients Cédric Schweitzer MD

and in 5.2% it was moderate. Another new type of agent in clinical trials are the adenosine receptor agonists. One of the new agents, trabodenoson (Inotek), is a highly selective agonist to the A1 receptors of the trabecular meshwork. It increases the production of matrix metalloproteinase 2 (MMP-2), which results in the increased removal of collagen 4, which, in turn, increases the outflow of aqueous through the trabecular meshwork. Sustained-release delivery drug system placed in the iridocorneal angle In a phase II randomised controlled trial, trabodenoson lowered IOP by a mean of 4.1mmHg in eyes with ocular hypertension Among these new products is the ocular or primary open-angle glaucoma. The surface sustained-release ring, which is main adverse event was conjunctival placed beneath the eyelids. In a phase II hyperaemia, which was mild in most cases randomised controlled trial, eyes receiving and occurred in only 17.6%. a ring containing bimatoprost had IOP reductions of 3.2-to-6.4mmHg, compared to reductions of 4.2-to-6.4mmHg with topical GENE INHIBITION timolol. However, conjunctival hyperaemia Another approach is gene inhibition with and punctate keratitis were more frequent small interfering RNA (siRNA). Bamosiran with the ring. (Sylentis) is a siRNA targeting the beta2There are also new biodegradable implants adenoreceptor and is designed to decrease designed for insertion into the anterior IOP by decreasing the ciliary body’s aqueous chamber. In a phase II randomised trial the humour production. In a phase I clinical bimatoprost SR implant reduced mean IOP trial, it appeared to lower IOP by 20%. by 8.1-to-9.5 mmHg, which was roughly The main adverse event was conjunctival equivalent to the reduction achieved in eyes hyperaemia, Dr Schweitzer said. receiving topical bimatoprost. Another new medication is the prostanoid Another strategy entering clinical trials receptor agonist, which has a similar mode is the use of a subconjunctival injection of of action to prostaglandin analogues. A medication encapsulated within liposomes. compound combining an agonist to the F2 In a phase II trial where patients received alpha prostanoid receptor with nitric oxide a preparation of liposome-encapsulated latanoprostene bunod (Vyzulta, Bausch latanoprost and dorzolamide IOP was reduced + Lomb) is designed to improve both the by 30% over a period of three months. uveoscleral and trabecular outflow. Phase III Also in clinical trials are new punctum randomised controlled trials have shown that plug sustained-release devices designed to be it lowers IOP by around 7.0-to-9.0mmHg. embedded in the canaliculus. In a feasibility Adverse events have included mild-tostudy, a punctum plug containing travoprost moderate hyperaemia. produced IOP reductions of 20-to-24% over the 30-day follow-up. The main adverse event NEW DELIVERY MODES was excessive tearing, which occurred in less Several companies are developing sustainedthan 5% of patients. release devices that deliver drug concentrations to ocular target tissues for periods of weeks or Cédric Schweitzer: months without having to rely on patients’ cedric.schweitzer@chu-bordeaux.fr adherence to their regimen. EUROTIMES | SEPTEMBER 2019

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New types of IOP-lowering agents and delivery modes bring hope of more effective medical treatment of glaucoma. Roibeard Ó hÉineacháin reports

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Studies find benefit of implant persisting at one and two years. Cheryl Guttman Krader reports

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n investigational intracameral sustainedrelease bimatoprost implant (Bimatoprost SR, Allergan) appears to provide very durable IOP control, premarketing clinical trials suggest. The research, which was presented at the 2019 annual meeting of the American Society of Cataract and Refractive Surgery, showed that in a large percentage of patients, the IOP-lowering benefit persisted far longer than the anticipated four-to-six months and was maintained even when the biodegradable pellet was no longer visible in the eye. E Randy Craven MD is Associate Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, USA, and a Bimatoprost SR study investigator. He told EuroTimes: “BimSR is potentially a very long-term solution to the problem of adherence to glaucoma medications that could be moving us toward drop-free therapy.” The longevity of the IOP-lowering effect of the Bimatoprost SR implant was analysed using data from the phase I/II APOLLO study and the phase III ARTEMIS program. APOLLO was a 24-month, paired-eye comparison study that included 75 patients with openangle glaucoma who received one of four dose strengths of bimatoprost SR in the study eye – 6, 10, 15 and 20μg. Its results showed that IOP control was maintained without need for retreatment with the implant or rescue with a topical IOPlowering medication in 68% of patients at six months, 40% of patients at 12 E Randy Craven, MD months and 28% of patients at 24 months. Patients randomised to Bimatoprost SR treatment in ARTEMIS received implants containing 10μg or 15μg at day one, week 16 and week 32. By Kaplan-Meier analysis, the Bimatoprost SR-treated patients had an 83% probability of surviving 360 days without need for rescue treatment. Among patients in APOLLO who received a Bimatoprost SR 10 or 15µg implant as a one-time procedure, the probability of surviving 360 days without need for rescue or retreatment was 36%. The researchers postulated that the sustained benefit of IOP lowering after the implant was no longer visible may be explained by bimatoprost-induced remodelling of aqueous outflow pathways that is mediated by its ability to increase matrix metalloproteinase release from ciliary smooth muscle cells. E Randy Craven: erandycraven@gmail.com

GLAUCOMA

Combination therapy Intravitreal dexamethasone combined with systemic immunosuppressive therapy is an effective approach to the treatment of uveitis. Roibeard Ó hÉineacháin reports

he combination of intravitreal dexamethasone (Ozurdex®, Allergan) to induce control of intraocular inflammation and immunosuppressive therapy to maintain disease quiescence appears to be an effective approach to managing uveitis affecting the posterior segment, suggest the results of a study presented by Dr Christine Goodchild at the Annual Conference of the Irish College of Ophthalmologists in Galway, Ireland. “Our study showed similar outcomes when compared to other international studies including the HURON study. However, our study had a much higher number of immunosuppressed patients,” said Dr Goodchild, Royal Victoria Eye and Ear Hospital, Dublin. The non-comparative, retrospective study included 43 eyes of 37 patients with noninfectious uveitis who were treated with

Ozurdex from October 2013 to March 2018 under the care of Prof C. Murphy and Mr D. Kilmartin. The types of uveitic conditions included panuveitis in 52% of cases, posterior uveitis in 22% and intermediate in 21%. Dr Goodchild noted that 94% of patients were receiving systemic immunotherapy at the time of intravitreal dexamethasone injection. They included 9% who were receiving oral corticosteroids only, 76% who were receiving oral steroids and steroid-sparing immunosuppressant and 9% who were receiving steroid-sparing immunosuppressant alone. During the four-and-a-half-year study period, the patients received a total of 79 inserts, equivalent to a mean of 2.14 injections. The mean interval between the first and second Ozurdex insert was 11.5 months and median of 6.7 months. Fifty-six per cent of patients received only one insert, 26% received two, 9% received three and 9% received more than three.

The mean logMAR BCVA improved significantly, from a baseline value of 0.65 to 0.47 at one month and 0.42 at three months (p<0.05). Mean central foveal thickness also improved significantly, decreasing from a baseline value of 474.5µm to 392.2µm at nine months (p<0.05). BIO scores also improved significantly from 1.81 at baseline to 0.68 at three months (p<0.00) and was significantly sustained to nine months at 1.15. Dr Goodchild noted that the adverse event profile following Ozurdex implantation was similar to that reported in randomised controlled trials. There was a transient rise in IOP in the first month, and 15% of additional patients needed IOP-lowering drops. In addition, 18.60% of patients became newly pseudophakic during the study, 11.63% of patients developed a new cataract and 13.95% had worsening of their cataract post-implant. Christine Goodchild: cgoodchild@rcsi.com

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GLAUCOMA

Future of glaucoma medications Long-term glaucoma drug delivery platforms near market, but challenges remain. Howard Larkin reports

ithin 10 years, a range of extended-release platforms that deliver glaucoma drugs to the eye for three-to-six months or more are likely to be available for clinical use, James D Brandt MD told the Glaucoma Subspecialty Day at the 2018 American Academy of Ophthalmology Annual Meeting in Chicago, USA. These may include intracameral and conjunctival implants, and drug-eluting punctal plugs and conjunctival rings, several of which are in or approaching phase III clinical trials. However, while such devices may improve intraocular pressure (IOP) control, they are not likely to eliminate eye drops for many patients, and some may not be suitable for treating early disease, said Dr Brandt, of the University of California, Davis, USA. Variable effectiveness among patients, delivering multiple medications and addressing potential complications are among issues that will take years of clinical experience to completely address, he added.

develop cystoid macular oedema or other complications, and the potential long-term effects of anterior chamber placement on the corneal endothelium. External devices may address some safety and reversibility issues. These include punctal plugs, such as the OTX-TP (Ocular Therapeutix), which supplies travoprost for up to 90 days and is in phase III trials, and Evolute (Mati Therapeutics), which delivers latanoprost and is in phase II trials. Dr Brandt has conducted extensive trials of the Bimatoprost Ring (Allergan), which is a periocular ring installed in the conjunctival cul-de-sac, releasing the drug for six months or more. In a phase II study followed by a 13-month open-label extension, the ring was effective in reducing IOP for 19 months with three insertions and was retained by 95% of patients over the last 13 months with a safety profile similar or better than topical treatment.

ANTERIOR CHAMBER IMPLANTS

However, while sustained-release glaucoma devices are on the horizon, for many patients they are not likely to completely meet their intended goal of eliminating eye drop use any time soon, Dr Brandt noted. In part that’s because about half of patients require more than one medication to adequately control IOP. Combining multiple drugs in a single device may be a solution. But developing these will take time and may be challenging due to differing pharmacokinetic properties of different medications possibly affecting their availability. Variations in length of time a device maintains therapeutic drug levels across populations will also need to be assessed and monitored closely to ensure patients do not run out prematurely. The risk of some devices, particularly implants, must be balanced against the benefits of topical medications, and the trade-off may favour drops for early-stage patients. Long-term observation under real-world conditions will be needed to evaluate these risks and this will take time, Dr Brandt said. “We need to be careful not to over-promise” that patients will never need drops again, he emphasised.

Closest to market is the Bimatoprost SR (Allergan), a biodegradable implant injected into the anterior chamber designed to release medication for four months or more. Three-month data released in January from two 20-month phase III clinical studies now in progress suggest that the device reached its 12-week primary efficacy goal of non-inferiority to timolol drops for reducing IOP, and is as effective as topical prostaglandins. The studies also suggest the device may be effective for 12 months or more in most patients, according to an Allergan release. Travoprost XR-ENV 515 (Envisia Therapeutics) is a biodegradable implant delivering Travoprost over extended periods nearing the end of a phase IIa trial. Also in phase III trials is iDose (Glaukos), a non-biodegradable titanium anterior chamber implant anchored in the trabecular meshwork that releases travoprost for six months or more, and can be replaced periodically. In phase II trials it, too, showed similar efficacy to topical timolol and prostaglandins, reducing IOP by about 30% in open-angle glaucoma patients. Promising as these implants appear, the need for surgical implantation presents challenges, Dr Brandt noted. These include the need for a second surgery to remove them should the patient

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GLAUCOMA

Innovation in aqueous filtration New device may control IOP by shunting aqueous directly to the ocular surface. Howard Larkin reports

urrent glaucoma devices and procedures shunt aqueous to one of three places – the subconjunctival space, conventional outflow channels or the suprachoroidal space. Yet each has its drawbacks in terms of limited IOP reduction or complication risks. A fourth option, a device shunting aqueous directly to the conjunctival surface, may be on the horizon, Patrick Riedel MD told the innovators session at the ASCRS ASOA 2019 Annual Meeting in San Diego, USA. Early patient studies suggest the Beacon Aqueous Microshunt may provide consistent, long-lasting IOP reduction on par with filtration surgery with a much lower complication profile – with improved tear volume as a bonus.

PREVENTING INFECTION Conceived 20 years ago by Minneapolis, USA, MIGS pioneer J David Brown MD, MicroOptx was formed in 2014 to develop the device. It is implanted through the conjunctiva, slightly posterior to the limbus through a paracentesis-type incision, with one end in the anterior chamber over the iris and the other on the ocular surface. The arrowhead-shaped device is 3.1mm long and 0.19mm thick with a 1.7mm wide external flange. Aqueous exits the anterior chamber through a central channel measuring 30x48 microns. The shell is composed of two layers of thermoplastic polyurethane to resist impact, while the channel is embedded into a layer of polyethylene glycol (PEG) to resist biofouling. Beacon went through extensive development to mitigate the obvious risk of retrograde pathogens causing endophthalmitis, Dr Riedel said. Laminar flow from the anterior chamber to the ocular surface is fast enough to prevent backwash and pathogen attachment, while hydrophilic PEG also prevents adherence of bacteria and protein. “Pathogens simply cannot gain a foothold,” said Dr Riedel, also of Minneapolis.

IOP LOWERING In porcine studies of 105 animals followed up to six months, the Beacon produced significant and persistent IOP lowering with no infections – even in eight animals that were challenged with bacteria on the surface for 10 days. “When we tried to infect these eyes we were unable to get endophthalmitis,” Dr Riedel said. More importantly, implants in 15 patients in the USA and Europe showed a mean IOP reduction from 27mmHg to 13mmHg, and greater than 20% reduction in 13 from baseline to the last visit, mostly at six months post-surgery. Similarly, 14 of 15 patients required no meds to control IOP, with a mean reduction from 2.5 to 0.08 per patient. Two patients reported mild discomfort, while six devices experienced blockages with one explanted for persistent blockage due to pseudoexfoliation. All patients were at least somewhat satisfied. A study involving 90 patients at 15 sites is planned. Roy Martin: rmartin@microoptx.com EUROTIMES | SEPTEMBER 2019

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PAEDIATRIC OPHTHALMOLOGY

Easing anxiety in difficult patients Oral sedation makes examinations easier for special needs children. Roibeard Ó hÉineacháin reports

dministration of oral midazolam can increase the speed and efficiency of measuring refraction and performing fundus examination in children with behavioural difficulties, according to Geraldine Comer MD, University Hospital Galway, Galway, Ireland. “This new service delivered by the medical ophthalmologist reduces the need for valuable theatre slots, in-patient bed use and consultant ophthalmic surgeon time. In addition, non-theatre examination reduces general anaesthesia risks and is cost-effective overall,” Dr Comer told the Annual Conference of the Irish College of Ophthalmologists in Galway, Ireland. Dr Comer and her associates reviewed the clinical notes of 12 children aged between three and eight years (mean age five years, three months) who underwent examination under sedation between December 2017 and March 2019. All children were also under the care of a paediatrician for developmental Geraldine Comer MD delay. Five children had autism. The patients received oral midazolam (0.5mg/kg), in either blackcurrant or apple juice, 30 minutes prior to instillation of cyclopentolate 1% and one hour prior to examination and refraction in the paediatric day ward. The maximum dosage is 15mg, as agreed in the 2018 protocol between ophthalmology and paediatrics departments. Three children who weighed more than 30kg were administered the maximum dose, 15mg. “We have noted that there is an increasing number of children with severe special needs, particularly autism, who were being seen in the paediatric orthoptic clinic and it was impossible to do an examination and incredibly distressing for the child, the parent and myself. Therefore, we wrote the protocol in conjunction with the paediatric department,” Dr Comer explained.

ADEQUATE OCULAR EXAMINATION She noted that the onset of sedation was rapid and permitted adequate ocular examination in all cases. All children were admitted and discharged from the hospital within five hours. Furthermore, in two cases general systemic examination and blood tests were facilitated on the same day as the eye examination while the child was still under the effects of midazolam. No local or general adverse reaction was experienced by any of the 12 children. Moreover, none of the children required flumazenil to reverse the effects of the midazolam. “This non-invasive method of sedation has been successfully used by our ophthalmology department for children who would otherwise require general anaesthesia. The environment of the out-patient paediatrics treatment room is a calm, child-friendly and well-equipped space for children with special needs requiring an ophthalmology assessment,” Dr Comer concluded.

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PAEDIATRIC OPHTHALMOLOGY

Retinopathy of prematurity Increasing rates of ROP and new treatments call for new guidelines. Roibeard Ó hÉineacháin reports

s care of pre-term infants The current guidelines predate the improves the incidence of evidence-based use of bevacizumab and retinopathy of prematurity other anti-VEGF agents and therefore do (ROP) is rising, and as new not include it in their protocol. They treatments become available recommend transpupillary diode laser new guidelines are necessary, said Claire therapy as first-line therapy and argon Hartnett MD, Temple Street Children’s laser as second-line therapy. University Hospital, Dublin, Ireland. Introduced in the 1990s, laser treatment “ROP is a potentially blinding condition. provides a predictable regression pattern Worldwide, in 2010 an estimated 53,000 and in almost all eyes treatment will either infants required ROP treatment and succeed or fail within nine weeks. Failure 20,000 infants became blind or severely rates are especially low in specialised sight-impaired because of the disease. treatment centres. However, laser treatment Two-thirds of those infants suffering sight is difficult to apply in eyes with media loss live in middle-income countries,” Dr opacities. It also requires the co-ordination Hartnett told the Annual Conference of of a multi-disciplinary team. Moreover, the Irish College of Ophthalmologists in the treatment causes permanent loss of the Galway Ireland. peripheral visual field and often induces She noted that in high-income countries, clinically significant myopia. the incidence of blindness from ROP is 3-to-13%. The rate is rising because ADVENT OF ANTI-VEGF more infants are surviving when Since the Royal College of born at gestational ages as low Ophthalmology published as 23 weeks, with birth weights their guidelines in 2008, the as low as 600g. Infants born results of the BEAT-ROP at that age are more likely to study have demonstrated develop posterior ROP and a that intravitreal injection more aggressive disease. of bevacizumab produced Meanwhile, in middlesignificantly better outcomes income countries, increased in eyes with stage 3 ROP disease survival of profoundly premature in zone 1 but not zone II. However, infants has led to high rates of ROP Claire Hartnett MD there was a 4% risk of delayed because the neonatal intensive care recurrence at a mean 16 weeks’ follow-up units (NICUs) in those regions often lack (Mintz-Hittner et al N Engl J Med 2011; sophisticated technology for monitoring 364:603-615), Dr Hartnett said. oxygen delivery. Intravitreal anti-VEGF agents have

WHEN TO TREAT, HOW TO TREAT The Royal College of Ophthalmology established guidelines in 2008 regarding when treatment should be considered and when it is unequivocally indicated. They advise that treatment is indicated in any ROP in zone I with plus disease, stage 3 ROP in zone I with or without plus disease and in zone II stage 3 with plus disease. Treatment should be considered in eyes with stage 2 ROP in zone II, although studies have shown that around half of eyes in this category of ROP will go on to show regression of the condition without any treatment. EUROTIMES | SEPTEMBER 2019

several practical advantages over laser treatment, she noted. They do not require intubation, they are easy to administer and the agents are readily available. In addition, they provide a rapid regression of neovascularisation. They also allow for further non-pathological retinal vascularisation, thereby preserving the peripheral visual field. Anti-VEGF treatment can be a better option than laser treatment in eyes with ROP in a number of circumstances, Dr Hartnett said. First, there are eyes with stage 3 zone I disease. Other indications include eyes where poor fundus visualisation

ROP is a potentially blinding condition. Worldwide, in 2010 an estimated 53,000 infants required ROP treatment and 20,000 infants became blind or severely sightimpaired because of the disease Claire Hartnett MD

precludes laser treatment and cases where an infant is unstable and the anaesthetic risk is too high. However, anti-VEGF may be contraindicated in infants whose parents will be unlikely to return for the frequent follow-up visits required because of the risk of early and late reactivation. Other potential anti-VEGF sequelae include persistent vascular abnormalities. They, in turn, can lead to contraction of the retinal fibrovascular membrane resulting in circumferential and prepapillary types of retinal detachment. An unanswered question is the effect of systemic exposure of anti-VEGF agents in pre-term infants. The agents persist systemically for several weeks with demonstrable VEGF inhibition. She noted that VEGF is important in organogenesis and microvascular maintenance. In foetal development it plays a critical role in lung maturation, cardiac, renal and pancreatic development, bone growth and neurogenesis. Claire Hartnett: drchartnett@gmail.com

OCULAR

Raising IRD awareness A collaborative programme aims to keep inherited retinal disease patients up to date on their condition. Roibeard Ó hÉineacháin reports

roviding inherited retinal disease (IRD) patients with the most up-to-date knowledge on their condition and their own disease status can enable them to make fully informed decisions on which style of management will suit them best, according to Ms Aoife Mary Long, Retina Research Group, Mater University Hospital, Dublin, Ireland on behalf of Target 5000 (Fighting Blindness). “There is often a lack of awareness amongst IRD patients and professionals of all the resources, supports and therapies available to them. Modern clinical management involves patients in decisionmaking and a collaborative method of communicating available options must be considered,” Ms Long told the Annual Conference of the Irish College of Ophthalmologists in Galway, Ireland. Ms Long and her associates in the IRD clinics at the Mater have created care-plan templates to optimise communication between healthcare teams and patients affected by IRDs. The format provides patients with information on their condition as well as any relevant treatments and information on services available for low vision. “Our aim is to create a care plan template that can be individualised, along with a database of general and genespecific IRD clinical trials and clinical trials on interventions for associated comorbidities,” Ms Long said.

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To create the care-plan formats, Ms Long and associates recruited patients with Stargardt’s Disease, USH1B and X-Linked retinoschisis from participants in Target 5000, the Irish National IRD registry. They determined their phenotypes using clinical history, ophthalmic exam, colour photography fundus autofluorescence OCT and functional testing. The patients were genotyped using nextgeneration sequencing at the School of Genetics, Trinity College, and accredited testing was performed at the Manchester Centre for Genomic Medicine, Manchester, UK. Results were relayed to patients via the Mater’s Target 5000 Genetic Counselling service. Ms Long and associates then conducted literature reviews on the condition including research into its history, as well as current information on clinical trials and established therapies and therapeutic possibilities. The draft was subject to further review and discussion by a focus group including patients, patients’ relatives, advocates, geneticists, genetic counsellors, clinicians and scientists. “This format can attempt to provide transparent information in an era of overwhelming and often conflicting data. It should help manage patient expectations in a clear, unambiguous manner while informing on the hope for upcoming therapies,” Ms Long added. Aoife Mary Long: aoifemarylong@rcsi.ie

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OCULAR

Greater HazMat awareness needed

Preparedness for hazardous material incidents are often inadequate. Roibeard Ó hÉineacháin reports

n many countries, hazardous material (HazMat) emergencies like the Sarin attack in Tokyo may seem a very far-off possibility, but the location of such events can be surprising and unpredictable, and a strategy for dealing with them, including their ophthalmological aspects, should be in place even where the risk seems only moderate, said Conor Malone MD, Sligo University Hospital, Sligo, Ireland. “Hazardous material incidents range from chemical plant accidents to biological warfare and terrorism. The 2018 Salisbury Novichok nerve agent attack in the UK highlighted the small but significant risk of chemical weapons,” Dr Malone told the Irish College of Ophthalmologists Annual Conference in Galway, Ireland. He noted that hazardous material incidents frequently involve ocular injury with early effects that include eye complaints such as miosis, epiphora, conjunctival irritation, photophobia, eye pain and blepharospasm. Late effects include severe dry eye, corneal ulceration and corneal scarring. The Irish Government's Department of Defence 2017 National Risk Assessment Conor Malone MD noted a moderate likelihood of high-impact HazMat incidents. To assess the awareness of HazMat among ophthalmologists in Ireland and to gauge their interest in formal HazMat training, Dr Malone sent an anonymous questionnaire to all clinicians registered with the Irish College of Ophthalmologists, Ireland’s national ophthalmology training body.

ABSTRACT SUBMISSION OPENS AUGUST 1!

PERSONAL PROTECTIVE EQUIPMENT Among the 51 physicians who responded to the survey, 81% worked at units providing emergency eye care. A majority, 88%, had never treated a HazMat victim, and 82% rated themselves as not at all confident when treating such patients. In addition, 68% were unfamiliar with the four levels of personal protective equipment involved in HazMat care delivery. However, although only 4% had received HazMat training, 40% were interested or very interested in pursuing a formal HazMat course. Moreover, 83% felt that every ophthalmologist should have, at the very least, received online basic training, like the Basic HazMat Life Support course, Dr Malone said. “The results of this national survey suggest that there is a gap in ophthalmology training, which could expose clinicians to contamination and could hinder clinical care of HazMat victims,” Dr Malone said. Dr Malone therefore recommended that every hospital have a copy of their local HazMat emergency plan. Physicians and other healthcare personnel should familiarise themselves with the protective equipment necessary when contaminated patients present to casualty units. Furthermore, all emergency centres should have a clinician who has taken the online basic HazMat training course, he said. Conor Malone: conmalone@gmail.com

www.icowoc.org EUROTIMES | SEPTEMBER 2019

J IN US

MAY 13 – MAY 19 2020 ASCRS Annual Meeting May 15 – May 19 Boston, MA Coinciding with World Cornea Congress VIII May 13 – 15 Featuring ASCRS Subspecialty Day (Refractive, Glaucoma) May 15

Hear what others have to say about their recent ASCRS Annual Meeting experiences: “The 2019 ASCRS meeting was the highlight of my work year. I came home energized by so many great ideas on how to better treat patients and how to strengthen my practice,” Dr. John Hovanesian

“I truly believe a significant value derived from the meeting this year is how many different avenues for education of new techniques/technologies were at the 2019 meeting. From lectures, wet labs, peer to peer opportunities; so many other creative ways so that each attendee can learn the way they do best,” Dr. Zaina Al-Mohtaseb

“There’s new technology and new advancements in surgery presented every year,” Dr. Deborah Ristvedt

“With so many educational options to choose from, I’m overcome with “FOMO” at the ASCRS Annual Meeting,” Dr. David Chang

HOSPITAL DIARY

Take off your mask

Leigh Spielberg MD reflects on the momentary blindness he experienced during a scuba diving lesson

Illustration by Eoin Coveney

nderwater you through my nose, I felt a tiny sliver can’t really hear of the relief that patients must anything. Sound experience after successful surgery is muffled and for serious bilateral disease. communication Some bilateral disease is between people occurs via very relatively straightforward to treat. basic underwater sign language. Consider the occasional patient Vision is everything. It’s the who comes to your office with only one of the five senses that cataracts that have reduced vision matters. Taste is reduced to a to counting fingers in both eyes. Or mélange of salt of the sea and the less fortunate but still perfectly the rubber of the breathing hose. treatable patients with Fuchs’ Smell is impossible. The only endothelial dystrophy. Bilateral thing you can feel is the motion macular holes pose a more difficult of the water and the contours of challenge; operating on both eyes your scuba gear. quickly can leave the patient with “Take off your mask,” my bilateral gas tamponade, which instructor signed to me. greatly inhibits their ability to We were 13 metres below function, but waiting too long to the surface, where the water treat the second eye can lead to pressure is more than twice that suboptimal results. of the air on land, and I was Others, however, are vastly being instructed to take off my more challenging: although diving mask and expose my eyes severe diabetic retinopathy has to the underwater elements. I become much less common, would be “blinded” until I could patients still occasionally reposition the mask on my face present with bilateral vitreous and clear the water out with haemorrhage or, even worse, my breath. I don’t even like tractional retinal detachments opening my eyes underwater due to proliferative disease. in a swimming pool. I knew For some, however, there is no that the pressurised, salty water cure yet, such as the unlucky souls ...We were 13 metres below the surface, would sting my eyes and rush with degenerative genetic disease where the water pressure is more than into my nose and then my of the optic nerve or retina. throat, producing a choking, I was very happy to regain my twice that of the air on land, and I was drowning sensation. vision as soon as I had cleared being instructed to take off my diving But I had to do it. This the salty water from inside the crazy manoeuvre was just mask. But my eyes continued to mask and expose my eyes to the one of those required for sting, and I wondered how long underwater elements the open-water scuba diving it would take for them to recover. certification course in which Seeing my diving buddies we had enrolled. I pulled the mask off quickly, holding it tight struggling with the same problem made me feel better, and, so I wouldn’t lose it before I could put it back on, clear the having finished the other required tasks, like simulating the loss of water and reopen my eyes. the breathing tube and sharing a spare tube with a buddy whose I was diving with three friends and a scuba instructor in the tank has run out, we swam off to enjoy a few minutes of freedom Red Sea, where we had arrived in a shiny red speedboat earlier before we had to surface to get ready for the next training session. that morning. The moment we dove in, four curious dolphins As I circled a spectacular coral reef, I wondered whether scuba had come to investigate. They were close enough to reach out and diving might be something that the visually impaired might enjoy. touch, and they lingered long enough for us to make eye contact Although I am a wildlife enthusiast and have probably seen every before they went on their smiling, merry way. nature video that the naturalist David Attenborough has ever Scuba diving was our backup plan. We had come to Egypt made, I don’t dive for the excitement of coming eye-to-eye with to kite surf in the shallow, wind-swept lagoons close to shore. a dolphin or watching tuna dart past me at what seems like the Kite surfing is a high-speed sport that harnesses the wind to speed of light. These are simply enjoyable extras. let you glide across the surface of the water like a racing yacht. Instead, I dive to experience the sensation of lightness and Its quick movements and exposure to the sun, surf, sand and the feeling of serenity, for the complete peace of mind that only shore, with loud wind in your ears, constitute a sort of sensory tropical fish seem able to enjoy. I dive for the silence and the flow overload that might be considered addictive. But there was no and the freedom of movement that weightlessness affords. And so wind for a few days, so we entered the alternate, silent, slowI closed my eyes and swam. motion world of scuba instead. Without vision, a scuba diver is completely handicapped, and Dr Leigh Spielberg is a vitreoretinal and cataract surgeon at as I replaced my mask and forced the water out by blowing air Ghent University, Belgium EUROTIMES | SEPTEMBER 2019

Capturing the best conversations at meetings Watch experts discuss the hottest topics from the 2019 ASCRS ASOA Annual Meeting, and be sure to subscribe today to catch live interviews from future meetings!

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BOOK REVIEWS

PUBLICATION OPHTHALMOLOGY REVIEW: A CASE-STUDY APPROACH

LEIGH SPIELBERG MD Books Editor

BOOK

EDITOR TARAPRASAD DAS

A re-evaluation of a constant threat

The risk of endophthalmitis was, until relatively recently, on every cataract surgeon’s mind during and after every single procedure. Although this perpetual fear has been significantly reduced by the introduction and general acceptance of intracameral antibiotics, we still need to remain alert. Endophthalmitis: A Guide to Diagnosis and Management (Springer), edited by Taraprasad Das, is a re-evaluation of the threat in this new phaco-prophylactic era. But cataract surgery is of course not the only context in which endophthalmitis can occur. Intravitreal injections have not yet benefited from the same prophylactic measures as cataract surgery. This 400-page book is divided in to seven parts. ‘Part I: General Features’ strives to define endophthalmitis and differentiate it from differential diagnoses such as TASS. ‘Part II: Specific Endophthalmitis’ deals with each cause of this complication, such as blebs, trauma, endogenous infection and keratoplasty, among many others. ‘Part III: Pharmacology’ tackles the science of endophthalmitis treatment, whereas ‘Part IV: Microbiology’ informs the reader about the best methods to collect ocular specimens and interpret the results, including molecular diagnostic methods. ‘Part V’ takes it one step further, describing the pathology of endophthalmitis. Most interesting to the clinician might be ‘Part IV: Prophylaxis and Prevention’, including “Guidelines for Safe Surgery”, whereas anyone involved in research will appreciate ‘Part VII: Clinical Trials in Endophthalmitis’. I found Chapter 5 to be particularly interesting for my own clinical practice. Entitled “Epidemiology of Endophthalmitis and Treatment Trend in Europe”, this chapter reviews the development of the current guidelines, which were largely coordinated by the ESCRS. And, as a cataract and vitreoretinal surgeon who also administers a significant number of intravitreal anti-VEGF injections, the specific chapters on endophthalmitis occurring after each of these three drew my attention. How best to manage endophthalmitis once it occurs is also of great importance to me, as it often involves close collaboration with the microbiologist and occasionally the pharmacist, interactions that I otherwise am not frequently required to do. This book is useful not only for ophthalmic surgeons, but for any ophthalmologist, whether in training or in practice, who might encounter a patient with endophthalmitis.

PUBLISHED BY SPRINGER

DELVING DEEPER INTO REFRACTIVE SURGERY

PUBLICATION TITLE EDITORS NAME PUBLICATION MANAGEMENT OF PUBLISHED BY XXX COMPLICATIONS IN REFRACTIVE SURGERY: SECOND EDITION

EUROTIMES EDITORS | MONTH YEAR JORGE ALIÓ AND DIMITRI AZAR PUBLISHED BY SPRINGER

PUBLISHED BY THIEME

A WIDE ARRAY OF CONDITIONS

Reviews PUBLICATION ENDOPHTHALMITIS: A GUIDE TO DIAGNOSIS AND MANAGEMENT

EDITORS KULDEV SINGH, WILLIAM E. SMIDDY AND ANDREW G. LEE

Refractive surgery is, for the most part, spectacularly successful and proceeds complication-free. However, when problems occur, the ophthalmologist can find him- or herself in the uncomfortable situation of having caused a problem in a previously healthy eye undergoing purely elective surgery. Management of Complications in Refractive Surgery: Second Edition (Springer), edited by Jorge Alió and Dimitri Azar, is a 400-page textbook that covers everything from button-hole flaps to melting. It includes a great amount of magnified slit-lamp photography, showing problems such as flap micro- and macrostriae, as well as corneal topography demonstrating ectasia and other undesirable outcomes. Any ophthalmologist considering adding refractive surgery to the practice’s offerings, or seeking to delve deeper into the subspecialty, might consider this text.

There are several ways to learn. Some, like multiple-choice questions or bulleted outlines, offer only snippets of information. Ophthalmology Review: A Case-Study Approach (Thieme), by Kuldev Singh, William E. Smiddy and Andrew G. Lee, offers a different approach. This study guide is a practical, case-based reference covering a wide array of common-to-serious ophthalmic conditions encountered in daily practice. Nearly 100 real-world patient management cases are carefully described in three pages each, utilising a typical clinical scenario to present and discuss the history and examination findings of a particular pathology. From ocular hypertension to retinitis pigmentosa and from childhood esotropia to the white dot syndromes, this book is intended to help both trainees and general ophthalmologists develop an effective methodology of patient treatment.

PUBLICATION PSEUDOPHAKIC MONOVISION: A CLINICAL GUIDE EDITORS FUXIANG ZHANG, ALAN SUGAR AND GRAHAM D. BARRETT PUBLISHED BY THIEME

ACHIEVING SUCCESS WITH MONOFOCAL IOLS Pseudophakic Monovision: A Clinical Guide (Thieme) is a 90-page book on how to successfully achieve intraocular lens monovision using monofocal IOLs. Achieving patient satisfaction in monovision requires the correct assessment of various factors, including patients’ personalities and expectations. The section entitled “Who Should Be My First Few IOL Monovision Patients and How Should I Start My First Case?” thus caught my interest. “Avoid demanding personalities… select preoperative hyperopic patients with easygoing personalities… start with mini- or modest monovision with an anisometropic level of about 1.00D to -1.50D…” This book is for any ophthalmologist who does enough cataract surgery to be able to offer monovision with confidence. If you have a book you would like to have reviewed please send it to: EuroTimes, Temple House, Temple Road, Blackrock, Co Dublin, Ireland

EUROTIMES | SEPTEMBER 2019

OUTLOOK ON INDUSTRY

Aerie in Europe

Addressing unmet needs in glaucoma is just the beginning for ophthalmic pharma innovator. Howard Larkin reports

ith US Food and Drug Administration approval of its first product in December 2017, newcomer Aerie Pharmaceuticals made history. The company’s proprietary Rho kinase (ROCK) inhibitor eye drop, Rhopressa (netarsudil ophthalmic solution) 0.02%, represented the first new drug class approved in the US for reducing intraocular pressure (IOP) in open-angle glaucoma and ocular hypertension since the prostaglandin class was introduced with latanoprost in 1996. This milestone also meant the company had achieved the objective it was founded to pursue – discovering a drug that targeted the underlying pathological process in glaucoma. After clearance and successful introduction in the USA, Aerie’s ROCK inhibitor is now under review by the European Medicines Agency. Aerie Chairman and CEO Vicente Anido, Jr, PhD, anticipates a decision by the end of this year. The company is currently planning for potential product introductions, a

The impact of factors including dosing complexity and tolerability on adherence to medical therapy and clinical outcomes is well established Vicente Anido, Jr, PhD EUROTIMES | SEPTEMBER 2019

Aerie’s recently completed state-of-the-art sterile fill facility in Athlone, Ireland

process spearheaded by Aerie’s new chief commercial officer for Europe. Aerie’s lead molecule is also being studied in Japan, where enrolment in a phase II study was recently completed months ahead of schedule. Next up for regulatory submission in the EU, once the original molecule is approved, will be the investigational fixed dose combination of the ROCK inhibitor and latanoprost. This once-a-day eye drop treatment was approved by the FDA this year and launched in the US in May as Rocklatan (netarsudil and latanaprost ophthalmic solution) 0.02%/0.005%. In two completed pivotal phase III studies in the USA, the fixed-dose combination proved statistically significantly more effective in reducing IOP than both of its components alone, at all measured time points. In Europe,

it is being compared to a leading fixed-dose combination drop in a phase III clinical trial under way in 11 countries. Both of these drugs were developed to overcome some of the trade-offs associated with conventional glaucoma therapeutics, Dr Anido notes. “The impact of factors including dosing complexity and tolerability on adherence to medical therapy and clinical outcomes is well established. In designing our glaucoma products to improve conventional outflow facility, we also knew they had to provide once-daily dosing, minimal systemic adverse events and manageable topical adverse events.” With a growing pipeline and active drug discovery effort, Aerie plans to be a major player in ophthalmic pharma. The firm’s initial focus on glaucoma was driven by

OUTLOOK ON INDUSTRY

Vicente Anido, Jr, PhD, Aerie Chairman and CEO

the research and vision of its founder, the late David Epstein MD, chairman of ophthalmology at Duke University, into the underlying pathology of openangle glaucoma, which is the stiffening of the trabecular meshwork. His insight that cytoskeletal changes in conventional outflow pathways could be chemically altered to reduce outflow resistance ultimately led to the company’s search for molecules that block Rho kinase, which was known to regulate stress fiber formation and tissue contraction.

GROWING LIBRARY

Since these initial discoveries, refinement of small-molecule kinase inhibitors by Aerie scientists has produced a growing library that now encompasses more than 4,000 proprietary molecules, including the firm’s first product candidates. Recognising that many applications of these small molecules in the eye would require sustained delivery, the Aerie team acquired access to a bioerodible polymer from Netherlands-based DSM for developing implants that steadily release drug for up to six months. It also obtained ophthalmic rights to a scalable platform for producing these

No two patients respond the same way. Glaucoma physicians have multiple drug classes they can use, alone or in combination, to find the best treatment regimen for each patient Casey C Kopczynski PhD

sustained-release implants from Envisia in the USA. Aerie is using these enabling technologies to develop treatments for a broad range of ophthalmic conditions, says Chief Scientific Officer Casey C Kopczynski PhD. Furthest along is an investigational steroid intravitreal implant for treating macular oedema due to retinal vein occlusion, now in a phase II clinical trial. Since small molecules penetrate the retina and are cleared much more quickly than large proteins used in anti-VEGF therapy, sustained release is thought to be critical to reduce injection frequency and avoid dosage spikes that might be toxic, particularly with steroids, Dr Kopczynski says. “With a controlled release, we have the opportunity to enhance both efficacy and safety. Our clinical studies have just started and we are hopeful we can demonstrate efficacy and a favorable adverse event profile over the sixmonth treatment duration.” An intravitreal implant that releases an active metabolite of Aerie’s first molecule, inhibiting both Rho kinase and protein kinase C (a promoter of smooth muscle contraction and vasoconstriction), is also entering the clinic as an investigational treatment for neovascular age-related macular degeneration (AMD) and diabetic macular oedema (DME). New therapies are needed in these significant indications because about 40% of DME patients do not respond to anti-VEGF, and many AMD patients become resistant to treatment over time. “No two patients respond the same way. Glaucoma physicians have multiple drug classes they can use, alone or in combination, to find the best treatment regimen for each patient. We want to give retinal physicians a similar range of treatment choice to better individualise therapy,” Dr Kopczynski says. Rho kinase inhibitors are good candidates to investigate for retinal diseases because they have anti-inflammatory, antineovascular and anti-fibrotic properties. Along with other selective kinase inhibitors they may be useful for treating other ocular conditions involving longterm inflammation, possibly including geographic atrophy and dry eye. A longacting IOP-lowering implant placed in the anterior chamber and delivering Rho kinase inhibitors for months is also in pre-clinical development. Rho kinase inhibitors may also have neuroprotective properties that are being explored.

DIRECT TO OPHTHALMOLOGISTS

As Aerie enters major segments of the ophthalmic market, beginning with glaucoma, the company is determined to control its own destiny, says Dr Anido. He previously served as Allergan’s president for the Americas and led another public ophthalmic pharmaceutical firm before joining Aerie in 2013. This independent

Casey C Kopczynski PhD, Aerie co-founder and Chief Scientific Officer

strategy gives Aerie the ability to be more agile in addressing physician and patient need, he believes. For example, rather than find a distribution partner, Aerie built its own sales organisation in the USA and will do the same in Europe. “We realised that we can serve the majority of glaucoma prescribers in the US with about 100 sales representatives. The retina community is even more compact. If our own people identify, develop, and commercialise our products, Aerie retains global rights to its discoveries while the entire organisation is 100% focused on delivering these innovations to clinicians and patients. There is no dilution of effort or limitation on activity as there might be if we licensed these assets,” Dr Anido says.

‘GO IT ALONE’ APPROACH

While waiting for its first EU approval, Aerie is assessing markets for launch and making the rounds of clinical meetings to develop relationships with the treatment community and better understand how to support clinicians’ efforts to improve patient quality of life, Dr Anido says. Consistent with its “go it alone” approach, the firm has completed its own state-ofthe-art sterile fill production facility in Athlone, Ireland, to support global product supply. The plant will come on line in early 2020 and already boasts the company’s largest concentration of employees in the EU to date. The Athlone facility complements an implant production lab in the USA. “We are committed to bringing new drugs with new mechanisms of action to the market for different eye diseases, and therefore are continuing to invest in and expand our development pipeline. We very much value our relationships with physicians and our increasing engagement with the European eye care community will help guide our innovations and shape our offerings for the future,” he concludes. https://aeriepharma.com/ EUROTIMES | SEPTEMBER 2019

INDUSTRY NEWS

Join

the EUREQUO Platform

Track

your Surgical Results

Convenient

Web-Based Registry

Cataract, Refractive and Patient Reported Outcomes in One Platform The patient-reported outcome

INDUSTRY

NEWS

OPTIONAL SOFTWARE

NIDEK CO., LTD., has launched the LPM optional software, a low-power mode for the YLC-500 Vixi laser photocoagulator. “LPM delivers a therapeutic effect to the retina by decreasing the laser power during photocoagulation. During treatment, the standard laser power is decreased by a specified ratio, achieving minimally invasive photocoagulation to the macular region,” said a company spokesman. According to NIDEK, notable features of this laser include an auto forward function and arcade grid scan pattern for laser delivery. “As there are no visible signs of photocoagulation during LPM treatment, these features are included to provide feedback during laser emission,” said the spokesman. www.nidek-intl.com

is linked to clinical data in EUREQUO. This enables better knowledge of indications for surgery and offers a tool for clinical improvement work based on the patients’ outcome.

EUREQUO is free of charge for all ESCRS members

www.eurequo.org

SOFTWARE UPDATE

IMAGING SYSTEM

OD-OS has released a new software update for its Navilas 577s. “With a new, multimodal export wizard, retina specialists can flexibly generate highresolution images of their treatments in different configurations,” said a company spokeswoman. The Navilas 577s Laser System enables physicians to digitally pre-plan the entire laser therapy on fundus images as well as on third-party diagnostic images, and to precisely execute this therapy plan with the help of computerised image guidance.Dr Winfried Teiwes, Managing Director at OD-OS said: “The Navilas 577s system was also designed with teaching the next generation of laser surgeons in mind. Thanks to the digital pre-planning functionality, supervisors can review laser plans of their residents prior to treatment and monitor treatments on a computer screen in real-time.” www.od-os.com

ZEISS has announced that it has received 510(K) clearance from the FDA for the CLARUS® 700, High-Definition, UltraWidefield Imaging system for advanced care specialists. “CLARUS 700 is the first high-resolution ultra-widefield imaging with True colour and a complete range of fundus imaging modalities, including fluorescein angiography (FA),” said a ZEISS spokesman “Ultra-widefield fluorescein angiography helps eye care specialists identify earlier more severe forms of diabetic retinopathy like neovascularisation and retinal diseases such as uveitis, choroidal masses, retinal tears, detachments and peripheral ischemia. “The high-resolution and high-contrast images of the FA from the CLARUS 700 allow clinicians to capture the smallest details from the macula in early phase to the periphery in late phase of FA,” according to ZEISS. www.zeiss.com/meditec

EUROTIMES | MONTH YEAR EUROTIMES | SEPTEMBER 2019

CALENDAR

The 24th ESCRS Winter Meeting will take place in Marrakech, Morocco

↙

LAST CALL

SEPTEMBER 2019

MEACO 19

5–8 September Greater Amman, Jordan https://meacojordan.com/home.html 5–8 September Palais des congrès Paris, France www.euretina.org

10th EuCornea Congress 13–14 September Paris Expo Porte de Versailles Paris, France www.eucornea.org

WSPOS Subspecialty Day 13 September Paris Expo Porte de Versailles Paris, France www.wspos.org

37th Congress of the ESCRS 14–18 September Paris Expo Porte de Versailles Paris, France www.escrs.org

Advances in Glaucoma Research and Clinical Science Meeting 2019 26–28 September Amsterdam, The Netherlands www.glaucomacongress.com

3–5 October Kyoto, Japan apacrs2019.org

↙

19th Euretina Congress

OCTOBER 32nd APACRS Annual Meeting

Ophthalmic Imaging: from Theory to Current Practice

4 October Paris, France https://www.vuexplorer.com/en/congres

AAO Annual Meeting

2020

EVER 2019

NEW All India Ophthalmology Conference 2020

12–15 October San Francisco, USA www.aao.org

17–19 October Nice, France www.ever2019.org

NOVEMBER NEW 33rd European Ophthalmology Congress 14–15 November Madrid, Spain https://ophthalmologycongress. ophthalmologyconferences.com/

DECEMBER NEW World Eye and Vision Congress 5–6 December Abu Dhabi, UAE https://eye.conferenceseries.com/

FEBRUARY 13–16 February Gurugram, India https://aios.org/aioc2020.php

6th Annual Congress on Controversies in Ophthalmology Asia-Australia (COPHy AA) 14–15 February Bangkok, Thailand http://cophyaa.comtecmed.com/

24th ESCRS Winter Meeting Marrakech 21–23 February Marrakech, Morocco www.escrs.org

MARCH NEW 10th EURETINA Winter Meeting 20–21 March Vilnius, Lithuania http://www.euretina.org/vilnius2020/

11th Annual Congress on Controversies in Ophthalmology: Europe (COPHy EU) 26–28 March Lisbon, Portugal http://cophy.comtecmed.com/

EUROTIMES | SEPTEMBER 2019

CALENDAR

MAY

The World Ophthalmology Congress (WOC) will take place in Cape Town, South Africa

NEW SFO 2020 Congress

9–12 May Paris, France https://www.sfo.asso.fr/

NEW World Cornea Congress VIII 13–15 May Boston, USA www.corneasociety.org

ASCRS•ASOA Symposium and Congress 15–19 May Boston, USA www.ascrs.org

18th SOI International Congress 27–30 May Milan, Italy https://www.congressisoi.com

NEW EyeAdvance 2020

29–31 May Mumbai, India https://www.eyeadvance.org/

NEW 14th EGS Congress

May 30–June 2 Brussels, Belgium https://www.eugs.org/eng/default.asp

JUNE

JULY

OCTOBER

20th EVRS Meeting 2020

ASRS 2020

38th Congress of the ESCRS

June 11–14, Stockholm, Sweeden http://www.evrs.eu

World Ophthalmology Congress (WOC) 26–29 June Cape Town, South Africa http://woc2020.icoph.org

23–28 July Seattle, USA www.asrs.org

OCTOBER 20th Euretina Congress 1– 4 October Amsterdam, The Netherlands www.euretina.org

11th EuCornea Congress 2–3 October Amsterdam, The Netherlands www.eucornea.org

WCPOS V 5th World Congress of Paediatric Ophthalmology and Strabismus 2– 4 October Amsterdam, The Netherlands www.wspos.org

See into the future of eye surgery and patient care. Belong to something inspiring. Join us.

www.escrs.org EUROTIMES | SEPTEMBER 2019

3–7 October Amsterdam, The Netherlands www.escrs.org

NOVEMBER AAO Annual Meeting 2020 14–17 November Las Vegas, USA www.aao.org

100th SOI National Congress 25–28 November Rome, Italy https://www.congressisoi.com

SPECIAL FOCUS CATARACT & REFRACTIVE

September 2019 | Vol 24 Issue 9

ARTIFICIAL INTELLIGENCE in Ophthalmology CORNEA | RETINA | GLAUCOMA PAEDIATRIC OPHTHALMOLOGY | OCULAR

Faros MAKING THE DIFFERENCE WITH LEADING INNOVATION ™

How do you make something great even better?

NEW

with active infusion (GFI) available soon

EYE SURGERY. SWISS MADE .

24th ESCRS Winter Meeting

M arrakech

In conjunction with SAMIR (Moroccan Society of Implant & Refractive Surgery)

21 – 23 February 2020 Mövenpick Hotel Mansour Eddahbi & Palais des Congrès, Marrakech, Morocco

Abstract Submission Deadline 31 October 2019

www.escrs.org

Minimally Invasive Cataract Surgery by Alcon Chondroitin Sulfate OVDs - cornea endothelium protection1-3 Balanced tip - reassurance of better thermal profile on the incision, maximum stroke at the phaco tip to lead to higher surgical efficiency4-6

Pre-phaco

Active Fluidics & Torsional - starting from safety in terms of low infusion settings and lower Endothelial Cell Loss respectively, to higher surgical efficiency7

INTREPID I/A portfolio - capsule friendly8, comfort to get higher surgical efficiency

Phaco

UltraSert featuring depth guard - lower incision wound stretch, better preservation of wound architecture9-13

Irrigation / Aspiration

IOL delivery OVDs

The Cataract Refractive Suite

BY ALCON

1- Glasser DB, Katz HR, Boyd JE, Shobe SL, Sniffer RL. Protective effects of viscous solutions in declassification and traumatic lens implantation. Arch Ophthalmol. 1989;107(7):1047BY ALCONusing in vivo confocal microscopy. J.Cataract Refract. Surg. 1051. 2- Petroll WM, Jafari M, Lane SS, Jester JV, Cavanagh HD. Quantitative assessment of ophthalmic viscosurgical retention 2005;31(12):2363-2368. 3- Lindstorm RL, Ong M. Protective effect of OVDs against hydrogen peroxide-induced oxidative damage to corneal endothelial cells: in vitro model. Presented at ASCRS; 26 Mar 2011; San Diego, CA. 4- Sudarshan Khokhar, MD, Neelima Aron, MD, Sagnik Sen, MB BS, Ganesh Pillay, MD, Esha Agarwal, MD, “Effect of balanced phacoemulsificationDisCoVi tip on the outcomes of torsional phacoemulsification using an active-fluidics system” J Cataract Refract Surg 2017; 43:22–28. 5- Santaro Noguchi, MD, Shunsuke Nakakura, MD, PhD,OPHTHALMIC VISC Nobuyuki Tokuoka, BS, Hitoshi Tabuchi, MD, PhD, Naoyuki Maeda, MD, PhD, Kohji Nishida, MD, PhD “Difference in torsional phacoemulsification oscillation between a balanced tip Verion ™ IOL Family and a mini tip using an ultra-highspeed video camera”, J Cataract Refract Surg 2016; 42:1511–1517. 6- Demircan, Süleyman et al. AcrySof “Comparison®IQ of 45-Degree Kelman and 45-Degree IMAGE GUIDED SYSTEM Balanced Phaco Tip Designs in Torsional Microcoaxial Phacoemulsification.” International Journal of Ophthalmology 8.6 (2015): 1168–1172. 7- Kerry D. Solomon, MD, Ramon Lorente, MD, Doug Fanney, MBA, Robert J. Cionni, MD, “Clinical study using a new phacoemulsification system with surgical intraocular pressure control”, J Cataract Refract Surg 2016;DuoVisc 42:542–549 Q 2016 ASCRS and ESCRS 8- Decrease in complications during cataract surgery with the use of a silicone-tipped irrigation/aspiration instrument Preston H. Blomquist,VISCOELASTIC SYS MD, Anne C. Pluenneke, MD. 9- AcrySof® IQ UltraSert® Pre-loaded Delivery System DirectionsLenSx for Use. 10Alcon Data on File, available on request. CR-ILN296-P001 (November 29, AcrySof ® IQ ® 2016). 11- Mendicute J, Amzallag T, Martinez A. Multicenter clinical assesment of 3 IOL preloaded at ASCRS ASPHERIC IOL Congress; May 5-9, 2017; Los Angeles, LASER delivery system. Paper presented CA. 12- Amzallag T, Mendicute J, Martinez A. Multicenter Clinical Assessment of a Pre-loaded IOL Delivery System. Paper presented at ASCRS Congress; May 5-9, 2017; Los Angeles, CA.ProVisc® 13- Alcon data on file, available on request. TDOC-0053373 (March 7, 2017). OPHTHALMIC VISC

LuxOR

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OPHTHALMIC MICROSCOPE

The Cataract Refractive Suite

OVDs UltraSert

AcrySof IQ Toric ®

ASTIGMATISM-CORRECTING IOL

AdvancingUltraSert Advancing Centurion UltraSert AcrySof IQ ReSTORAdvancingDiagnos

CATARACT REFR

®® CATARACT SURGERY

® ® CATARACT SURGERY PRE-LOADED DELIVERY SYSTEM PRESBYOPIA-CORRECTING

VISION SYSTEM PRE-LOADED DELIVERY SYSTEM

PRE-LOADED DELIVERYBY SYSTEM ALCON

IOL

® CATARACT SURGERY

BY ALCON

™

DisCoVisc

ORA System

OPHTHALMIC VISCOSURGICAL DEVICE WITH VERIFEYE+™

AcrySof IQ ReSTOR Toric ®

P RESBYO P IA - CORRECTIN G IOL