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ASIA-PACIFIC’S FIRST MAGAZINE ON THE POSTERIOR SEGMENT

10 THE RACING ISSUE June/July 2019 www.piemagazine.org

magazine posterior segment • innovation • enlightenment

Cover Story

In the

Fast Lane Winning Posterior Segment Outcomes

Page 16 Next Generation Supplements

Robots Are Upon Us:

Are micronutrients the missing link to ocular health? Page

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Diagnosing Diabetic Retinopathy with AI Technology Page

THE WORLD’S FIRST FUNKY OPHTHALMOLOGY MAGAZINE

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Inside this issue...

Posterior Segment Matt Young

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CEO & Publisher

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Next Generation Supplements Are micronutrients the missing link to ocular health?

Robert Anderson Media Director

Hannah Nguyen

Production & Circulation Manager

Gloria D. Gamat

08 12 14

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WANTED: AMD Screening Solutions that won’t ‘Break the Bank’

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The Perfect Shot in Retinal Imaging

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SubLiminal Laser Therapy: A Ray of Light for Retina Diseases and Glaucoma Patients

Chief Editor

Brooke Herron Associate Editor

Ruchi Mahajan Ranga Project Manager

Alex Young

Publications & Digital Manager Graphic Designers

COVER STORY Racing for Positive Patient Outcomes in the Posterior Segment

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Winson Chua Patalina Chua Writers

April Ingram Gerardo Sison Hazlin Hassan Joanna Lee Olawale Salami Tan Sher Lynn www.piemagazine.org

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Innovation page

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Published by

Media MICE Pte. Ltd.

6001 Beach Road, #19-06 Golden Mile Tower, Singapore 199589 Tel: +65 8186 7677 Fax: +65 6298 6316 Email: enquiry@mediamice.com www.mediaMICE.com

Society Friends

Asia-Pacific Academy of Ophthalmology

DEX OF ALL TRADES: Dexamethasone Implants in Treatment-naïve Diabetic Macular Edema Eyes

page

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Robots Are Upon Us: Diagnosing Diabetic Retinopathy with AI Technology

Enlightenment page

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Fighting Blindness in Asia

page

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For the Love of the Retina

Conference Highlights page

Asia-Pacific Vitreo-retina Society

page

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Oculoplastic Conditions and Current Strategies in Practice

page

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Highlights of Retina Posters at ASCRS 2019 San Diego

Anti-VEGF Battle Royale: SCORE2 and LEAVO Results Reveal the Winners

Ophthalmology Innovation Summit

Vitreo Retina Society of India

We are looking for eye docs who can contribute articles to PIE magazine. Interested? Let's talk! Send us an email at enquiry@mediamice.com.

To place an advertisement, advertorial, symposium highlight, video, email blast, or other promotion in PIE magazine contact CEO Matt Young at matt@mediamice.com.


PIE MAGAZINE LETTER TO READERS

Dear Reader, Coming at you live and straight from Vietnam: Team Media MICE has returned to the good ‘ol U.S. of A.!

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t Media MICE, we have a diverse pit crew. With team members hailing from North America, Asia and Europe – and a company headquarters in Singapore – we’re scattered about . . . well, like mice. A few of the American team members (myself included) reside in Da Nang, Vietnam – a place often associated with the war in its past, however, today the region continues to develop into a vibrant locale and tourist destination. The area’s growth, coupled with its unparalleled beauty, has attracted expatriates from the world over – many of whom are ‘creative types’ like us. We’re not doctors . . . rather, we’re idea generators and content creators who have found a great place to live – and who also happen to be passionate about ophthalmology. Our location in Asia provides an ideal home base as we race to cover and commentate on the ophthalmic leaderboard from around the world. This racing-themed issue of PIE Magazine, our vehicle for the posterior segment, brings us to Chicago, Illinois, USA, for the annual meeting of the American Society of Retina Specialists (ASRS). Insights from congresses like ASRS, along with doctor input, drive much of the content for PIE, as well as our online video series PIE Talks. However, don’t wave the checkered flag just yet . . . because we then add our own special ingredient: a little bit of funkiness. In the ophthalmic industry, our style is one-of-a-kind (we checked) – and it’s this creativity that makes Media MICE stand out in the crowd (congress costumes aside). Clearly, we’re not your average ophthalmology magazine – and nothing revs our engines like the posterior segment (although we do like our fair share of CAKE [Cataract Anterior Segment - Kudos - Enlightenment] Magazine, too). This creativity, along with our worldwide presence and approach, puts Media MICE in a whole different lane . . . and in a unique position to spread news and awareness of the hottest topics in vitreo-retina. In this issue – and in an expanded cover section – the race is on with the “Posterior Segment Triple Crown.” In the first match-up, we breakdown the overall scores in the ‘grand prix’ of imaging: Will SD-OCT or SS-OCT take home the trophy? Then, we shift gears to antiVEGF agents and treatment regimens, where we ask: Which fuel do you use, and how often do you fill the tank? Laser is the final contender in the race for positive outcomes – where does it fall in the pack? You’ll have to read more (beginning on page 16) to find out. Driven by innovation and research, the race for positive patient outcomes from sight threatening conditions is certainly on! And if you’re cruising around ASRS 2019, stop by Booth #104 for more PIE Magazine metaphorical wizardry. I hear they have an on-site ‘racing’ team...

Sincerely, Brooke Herron Associate Editor PIE & CAKE Magazines

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PIE MAGAZINE ADVISORY BOARD MEMBERS Dr. Gemmy Cheung, MBBS(Lond), FRCOphth(UK) Dr. Cheung currently serves as deputy head and senior consultant of the medial retina service for Singapore National Eye Centre (SNEC), as well as senior clinician investigator for the Singapore Eye Research Institute (SERI). Her research interests include the study of risk factors and clinical features of macular diseases that may be unique in Asian populations. Dr. Cheung has published more than 150 articles, mostly regarding age-related macular degeneration, including polypoidal choroidal vasculopathy, and conducted several clinical trials in anti-vascular endothelial growth factor therapies. Dr. Cheung has also been actively involved in training and education, and has served as an instructor on Asia-Pacific Academy of Ophthalmology (APAO) and American Academy of Ophthalmology (AAO) courses and many other educational programmes. In addition, she is also a volunteer faculty member for the ORBIS Flying Eye Hospital Programme. Dr. Cheung has received a number of prestigious awards, including the Macula Society Young Investigator Award (2017), APAO achievement award (2017), APAO Nakajima Award (2014), APAO Outstanding Service in Prevention of Blindness Award (2013), the Bayer Global Ophthalmology Research Award (2012), the Roper-Hall Medal (2005) and the Elizabeth Hunt Medal (Royal College of Ophthalmologists, UK). [Email: gemmy.cheung.c.m@singhealth.com.sg]

Prof. Mark Gillies, M.D., Ph.D. Dr. Gillies presently holds a number of positions including: director of research and director of the Macula Research Group for the Save Sight Institute; foundation fellow for the Sydney Medical School; professor in the Department of Clinical Ophthalmology at the University of Sydney; head of the Medical Retina Unit at the Sydney Eye Hospital; deputy chair for the Ophthalmic Research Institute of Australia; and director of Eye Associates in Sydney. Dr. Gillies has served as a principal investigator or associate investigator in more than 70 clinical trials, and his research regarding macular degeneration and drug safety and efficacy has been published in 188 journals. He has also received a number of grants to study treatments for age-related macular degeneration, retinal disease and Muller cell dysfunction – among other treatments and studies. Dr. Gillies has also appeared in national media on numerous occasions, including the evening news of all major networks, on ABC radio as a local expert, as well as in print media. His dedication and research has resulted in multiple awards. Most recently, he received Gerard Crock trophies for the best papers at the Royal Australian and New Zealand College of Ophthalmologists (RANZCO) Annual Scientific Meeting (2013 and 2015), an achievement award from the Asia-Pacific Academy of Ophthalmology (APAO) in 2014, and an achievement award from the American Academy of Ophthalmology (AAO) in 2015. [Email: mark.gillies@sydney.edu.au]

Dr. Vishali Gupta, M.D. Dr. Gupta currently serves as a professor of ophthalmology at Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh in India. Throughout her career, she has completed original work in the fields of intraocular tuberculosis, optical coherence tomography, diabetic retinopathy, and fungal endophthalmitis. In addition, she is actively studying vitreoretina and uveitis diseases. She has been published in 65 per-reviewed journals, and has authored 17 book chapters and four complete books. Dr. Gupta also holds a US patent for the development of multiplex PCR for uveitis. In addition, she is a sought after speaker, and has made more than 350 presentations in various national and international meetings. Dr. Gupta has received several awards for her work, including the first JN Pahwa award from the Vitreo Retinal Society of India, the first NA Rao Award from the Uveitis Society of India, and the first NA Rao award from All India Ophthalmological Society (AIOS). [Email: vishalisara@yahoo.co.in]

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POSTERIOR SEGMENT EYE HEALTH

Next Generation Supplements Are micronutrients the missing link to ocular health?

by April Ingram

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atients faced with looming vision loss are motivated – and oftentimes desperate – to prevent disease progression and preserve their remaining visual acuity. As a result, millions have been spent on supplements for eye health and vision preservation. Store shelves and internet ads promote products, some with vague claims of “protecting” or “maintaining” eye health. Therefore, as physicians, its vital to have knowledge of these supplements (along with the supporting science) to help patients avoid the often ineffective, sometimes dangerous, act of self-medication.

Looking back at AREDS Two studies AREDS (Age-Related Eye Disease Study) and AREDS2, found that an antioxidant supplement could limit free radical cell damage in agerelated macular degeneration (AMD) in certain patients. In AREDS, a high-dose combination of vitamins C and E, beta carotene and zinc oxide, with a dash of copper, was shown to effectively reduce the risk of worsening macular degeneration and severe vision loss by 25% over a period of six years.1-2 The AREDS2 formulation was just as

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effective, but the low zinc replaced the beta carotene (which increased lung cancer rates in smokers), with lutein and zeaxanthin.3 However, the AREDS formulations did not demonstrate benefits for all patients across all stages of AMD – it only slowed progression for those with intermediate AMD, or with the advanced form in only one eye. In addition, the AREDS formulations do not prevent AMD, and they’re not a cure . . . these things are rarely noted on package labels. Therefore, it’s important to counsel patients.

Backing benefits with science Supplying micronutrients to the aging eye is often hampered because of altered microcirculation and problems at the blood-retina-barrier. To investigate this issue, US-ophthalmologist Craig Brown and Swiss chemist Martin Ulmann reviewed all the available – yet somewhat fragmented – knowledge regarding dietary supplements. They also brought a team together of leading experts from varying fields. From this, Mr. Ulmann’s startup company Aprofol AG was created; and OCUFOLIN® forte, an FSMP (food for special medical purposes), was

optimized for the European- and Asian market. OCUFOLIN® uses the highest quality forms of each ingredient, at doses based on current best practices, all within a lipophilic matrix. In a recent pilot study, OCUFOLIN® demonstrated effectiveness in lowering homocysteine, a known risk factor for vascular retinal disease. Additionally, the study showed a strong trend toward an increase in retinal blood flow and surprisingly, a significant decrease in intraocular pressure.4 “In patients with chronic ocular diseases like age-related macular degeneration or diabetic retinopathy, reduced microcirculation and elevated homocysteine levels are common,” explained Mr. Ulmann. Therefore, eliminating local micronutrient deficiencies would have tremendous potential as a safe way to delay or stop progression of serious eye diseases, such as diabetic retinopathy (DR) or AMD. One micronutrient family in particular was singled out by Mr. Ulmann: folates. There are more than 100 naturally occurring folate compounds found in various foods and circulating through the body; its synthetic form, folic acid, is used in


many dietary supplements and in food fortification. The universal natural form of folate is L-methylfolate, the only form able to cross the blood-brainbarrier and the blood-retina-barrier. As a chemist, he recognized the highly variable properties of various forms of folate in the lab, and was intrigued to uncover the different behaviors of each of the folate forms in the body – and more specifically, in the eye. Mr. Ulmann’s investigations were supported by recent work from Stover et al., which confirms the need for supplementation in disease-induced micronutrient deficiency.5 The study reports that it “often cannot be addressed by nutrient intakes derived from a whole food-based diet alone.” Low folate status may be caused by low dietary intake, poor absorption of ingested folate, and alteration of folate metabolism due to genetic defects or drug interactions. Similar effects are also recognized for vitamins B12 and D. According to Mr. Ulmann, his product OCUFOLIN® shows sciencebacked benefits: “It is a science-based FSMP developed by, and under the guidance of, ophthalmologists and chemists. It’s specifically designed for the dietary management of patients with a metabolic disorder and underlying retinal and choroidal ischemia, resulting in microvascular alterations.” As Singh et al.6, noted: “We know that both AMD and DR patient types have elevated levels of homocysteine, but also low folate or vitamin B12 levels. We know that elevated homocysteine levels, along with oxidative stress, have been associated in the etiology of several vascular diseases that can lead to the development of choroidal neovascular membranes (CNV) in AMD.” Mr. Ulmann explained further: “Elevated homocysteine levels and oxidative stress indicate a metabolic imbalance. A deficiency in L-methylfolate is inversely correlated to elevated homocysteine levels. Oxidative stress impairs the enzymatic homocysteine metabolism. As a consequence of elevated

homocysteine levels, micro vessels are impaired in exchanging nutrients and metabolites, leading to deposits . . . and consequently inflammation in the eye.” Referencing the 2013 work by Fonseca et al.7, he added: “The formulation is based on the AREDS formulation, B-vitamins of the Metanx study and complemented with vitamin D, as well as intracellular antioxidants.” OCUFOLIN® forte is a specific formulation that supplies individuals (suffering from a deficit, or an impaired metabolic capacity, in forming L-methylfolate) with the necessary co-factors in the respective dosage to maintain a normal level of L-methylfolate. In addition, the reduction of homocysteine is supported by zinc and intracellular antioxidants to optimize the biochemical cascade. In the pilot study at the University of Vienna4, 24 diabetic subjects (type I and II) took one capsule of OCUFOLIN®

forte each day over a period of 12 weeks. During the study period, homocysteine-levels decreased from 14.2 to 9.6 µmol/L (32%), which is greater than the mean 25% reduction reported by the HLT (Homocysteine Lowering Trialists). In addition, there was a trend toward an increase in total retinal blood flow and it was found to significantly reduce intraocular pressure. Ready to go the extra mile, Mr. Ulmann said: “We want to confirm the results of the Vienna pilot study in a larger placebo-controlled study and improve our understanding of the mechanisms of the microcirculation in the eye. In view of the still limited possibilities for patients with early or intermediate AMD and DR, we want to eliminate underlying deficiencies known as risk factors. OCUFOLIN® is a safe, premium food product now available for patients with harmful eye diseases.”

References: Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for Age-Related Macular Degeneration and Vision Loss: AREDS Report No. 8. Arch Ophthalmol. 2001;119(10):1417-1436. 2 Age-Related Eye Disease Study Research Group. A Randomized, Placebo-Controlled, Clinical Trial of High-Dose Supplementation With Vitamins C and E, Beta Carotene, and Zinc for AgeRelated Cataract and Vision Loss: AREDS Report No. 9. Arch Ophthalmol. 2001;119(10):14391452. 3 AREDS2 Research Group, Chew EY, Clemons T, et al. The Age-Related Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1). Ophthalmology. 2012;119(11):2282-2289. 4 Homocysteine Lowering Trialists’ Collaboration. Dose-dependent effects of folic acid on blood concentrations of homocysteine: a meta-analysis of the randomized trials. Am J Clin Nutr. 2005;82(4):806-812. 5 Stover PJ, Durga J, Field MS. Folate nutrition and blood-brain barrier dysfunction. Curr Opin Biotechnol. 2017;44:146-152. 6 Singh M, Tyagi S. Hyperhomocysteinemia and Age-related Macular Degeneration: Role of Inflammatory Mediators and Pyroptosis; A Proposal. Medical Hypotheses. 2017 (105): 17-21. 7 Fonseca VA, Lavery LA, Thethi TK, et al. Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. Am J Med. 2013;126(2):141-149. 1

About the Contributor Martin Ulmann is the founder and CEO of Aprofol AG, a Swiss startup company. He is a chemist and a veteran with some 40 years experience in the folate-field. In his former positions at a Merck KGaAsite, Martin was responsible for the development, manufacturing and marketing of reduced folates (Leucovorin, Levoleucovorin, Metafolin®) and over the years gained a lot of knowledge on the in-vitro and in-vivo properties of the different forms of folate. Together with well-known experts from different fields his company is developing science-based folate-containing products for the prevention and treatment of chronic diseases. Aprofol’s first products OCUFOLIN® forte and prevent were launched 2018 in Switzerland, Germany and Austria, and soon in other countries. [Email: martin.ulmann@aprofol.com]

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POSTERIOR SEGMENT SCREENING TOOLS

Wanted

AMD Screening Solutions that won’t ‘Break the Bank’ by Joanna Lee

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hen diagnosing age-related macular degeneration (AMD), it’s accepted that the earlier the intervention or treatment, the better the patient’s outcome. However, the cost to screen patients – and provide that early treatment – can be prohibitive. For example, a study in Japan determined that screening helped 41 percent of patients avoid blindness. And while this exercise was deemed highly effective, the actual screening itself proved not to be cost-effective.1

Searching for a lower-cost model Clearly, cost is an issue. This, along with a lack of scientific data on the topic, inspired a team of researchers from Korea to investigate the costs of using various screening strategies to find a more cost-effective solution. Ideally, these results could be replicated in different countries. Using the Markov model, they compared the cost-effectiveness of four AMD screening methods: opportunistic examination (when a patient sees an ophthalmologist annually and undergoes screening); opportunistic treatment (when a patient sees an ophthalmologist because they are actively experiencing symptoms of AMD); systematic photography (where the entire population is screened annually using fundus photography);

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and systematic examination (where the entire population undergoes an annual examination by an ophthalmologist). These would be compared against the status quo of no screening. Using a hypothetical cohort of 100,000 males and females aged 40 with and without AMD at baseline, they measured the results with quality-adjusted life-years (QALY) and each strategy’s incremental cost-effectiveness ratio (ICER). They would then project the model from age 40 to until when a patient dies or reaches 100 years to come up with an estimation of AMD healthcare costs in the patients’ lifetime. The researchers also made several assumptions in their model regarding disease prevalence and progression rate, treatment effectiveness, complications, test characteristics (sensitivity and specificity) for fundus photography, and costs (in terms of direct and indirect healthcare costs related to the treatment and management of AMD).

The authors found that opportunistic examination was the least effective, providing fewer QALYs at a higher cost. Both opportunistic treatment and systematic examination were found to be weakly dominated by systematic photography – the most cost-effective method. This led the researchers to conclude that “providing AMD screening through systematic photography can potentially mitigate the future disease burden and cost of AMD among South Korean population.” The study team also advised that these findings should be tested in prospective studies to determine if the results are validated – and therefore, could potentially be incorporated into policy changes. According to consultant ophthalmologist Dr. Manoharan Shunmugam, this study not only showed a need, but also presented a challenge, regarding launching effective screening protocols for AMD.


There is no doubt that screening can identify AMD at an earlier stage – and if treated early, visual preservation is not only more likely, but also easier and less expensive (as the treatment may be given for a shorter duration).

“There have been many other studies in the past, many of which have employed varied screening strategies,” he said, noting the Cochrane Systematic Review of community screening for visual impairment in older people3, which concluded that there was little benefit for visual screening as it did not make a difference to the visual outcomes of the community as a whole. He says that outcome [from the Cochrane Review] is likely due to the screening processes employed by many of the analyzed studies: “The majority of studies use self-reported screening as both the screening tool and the outcome measure.” “This study, however, employed a more objective method [fundus photography] as its tool,” added Dr. Shunmugam. “Therefore, this demonstrates the critical importance of employing a screening method that isn’t just clinically effective, but that’s also objective, reproducible and costeffective.”

Are we at home with selfmonitoring? There is no doubt that screening can identify AMD at an earlier stage – and if treated early, visual preservation is not only more likely, but also easier and less expensive (as the treatment may be given for a shorter duration). So, what if patients could screen and monitor themselves from home? It’s certainly an option to consider – especially, if a home screening device could produce results comparable to a formal microperimetry. There’s a great opportunity for this type of “in the home” monitoring – not only does it save patients’ physical access time to clinics, but quicker intervention could also be made with ongoing monitoring. Dr. Mae-Lynn Catherine Bastion, who treats patients in her private practice and at a public hospital, cites the practical challenges of elderly patients accessing clinics as one of the reasons that home-monitoring could be investigated as an alternative.

“I have a population of patients that I’m not able to monitor because they rely on their children to bring them,” she explained. “And children, even like me, are so busy . . . most seniors don’t complain because they don’t want to disturb their caregivers. So, most of them present late.” This is problematic as advanced stages of AMD can occur undetected if not monitored. Taking a modern approach to this issue, Adams and colleagues recently published a study to determine the feasibility of using a home-based tablet device to monitor retinal sensitivity in intermediate agerelated macular degeneration (iAMD) and assessed the benefits of weekly SMS reminders. The authors then compared their findings with clinicbased (MAIA microperimetry) results.4 Thirty-eight participants with iAMD were enrolled and underwent thorough ophthalmic testing (MAIA, retinal imaging and SD-OCT tests). They were also taught how to use the specially designed home monitoring application (PsyPad) on an iPad 2. Participants were then randomized into two groups: one received weekly SMS reminders to take their iPad test, and the other did not. At two months, 21 participants remained in the study (10 with SMS; 11 without). The 17 inactive participants (7 with SMS; 10 without) dropped out for a variety of reasons, including: inability to download and activate the app (7); other technical challenges (6); and family or medical reasons (2). One patient did not find the test useful and dropped out. Overall, the study found good agreement between retinal sensitivity measured at home versus at a formal, clinic-based microperimetry, making the concept a feasible one. They also found that weekly SMS reminders were helpful for improved compliance.

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POSTERIOR SEGMENT SCREENING TOOLS While the authors were disappointed with the high level of inactivity, they acknowledged that this was largely due to technical issues, rather than with the test itself. In the future, the authors suggest that technical support is vital to improve long-term activity, as well as providing immediate feedback and positive reinforcement. And this technical support will likely be critical to a successful home monitoring program. Dr. Bastion says that most senior patients are not technologically savvy . . . in fact, they’re technophobic. “There’s a need to train the elderly on digital literacy – that’s where the community can come in,” she added, proposing that mobile phone companies could work together with communities to help educate senior citizens. “This is important because a number of treatments can be delivered over the internet. I think this is where home-monitoring can have a role,” said Dr. Bastion.

Targeted solutions may reduce costs (overall) According to Dr. Shunmugam, the health economics of screening are complex: “It [might] require more targeted screening or employ a multipronged screening strategy that could suit different demographics.” So, perhaps there might be multiple solutions for these different populations. “For example, nursing home or immobile patients may warrant mobile eye screening in the form of tele-ophthalmology, while the independent ambulate community would be able to go to community screening centers,” explained Dr. Shunmugam. “This would not only make screenings more efficient, but also improve QALY (quality-associated life years).” Detecting vision problems before they advance in severity can also save healthcare costs in other areas. For example, patients with wet AMD are more likely to have problems performing daily activities like making

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There’s a need to train the elderly on digital literacy ... This is important because a number of treatments can be delivered over the internet. I think this is where home-monitoring can have a role. – Dr. Mae-Lynn Catherine Bastion phone calls, shopping, cooking and caring for themselves. Dr. Shunmugam adds: “Sixty-three percent of people with low vision reported falls that resulted in injury – the healthcare coasts of preventing this alone would be a significant savings, as well as preserve the patient’s QALY.” Not only would preventative screening have the potential to save sight – it can help the elderly maintain

their quality of life. Noting this, Dr. Shunmugam concludes: “The impact of effective preservation of vision has a greater cascade effect than we may be able to quantify.” Editor’s Note: Drs. Shunmugam and Bastion were not part of the studies mentioned but were generous enough to share their thoughts regarding the matter.

References: Tamura H, Goto R, Akune Y, et al. The Clinical Effectiveness and Cost-Effectiveness of Screening for Age-Related Macular Degeneration in Japan: A Markov Modeling Study. PLoS One. 2015;10(7):e0133628 2 Ra H, Song LD, Choi JA, Jee D. The cost-effectiveness of systematic screening for age-related macular degeneration in South Korea. PLoS One. 2018; 13(12): e0209521. 3 Community screening for visual impairment in older people. Cochrane Review website. Available here: https://www.cochrane.org/CD001054/EYES_community-screening-visual-impairment-olderpeople 4 Adams M, Ho CYD, Baglin E, et al. Home Monitoring of Retinal Sensitivity on a Tablet Device in Intermediate Age-Related Macular Degeneration. Transl Vis Sci Technol. 2018; 7(5): 32. 1

About the Contributing Doctors Dr. Manoharan Shunmugam is a consultant ophthalmologist, adult and pediatric vitreoretinal surgeon who trained in the UK and returned to Malaysia in 2012. He has a keen interest in research with publications in a wide-range of high-impact journals and has been invited to many international conferences as a speaker. He is also a contributing author of 2 book chapters in vitreoretinal reference textbooks. He graduated in Scotland and subsequently undertook his Ophthalmic Specialist Training and VR Fellowship in London. En route, he further honed his skills with a pediatric VR fellowship at L.V. Prasad Eye Institute, Hyderabad, India – making him one of the few pediatric VR surgeons serving the Asia-Pacific region. He continues to serve at Hospital Kuala Lumpur, Pantai KL & Assunta Hospital. He is also the Hon. Secretary of the Malaysian Society of Ophthalmology, and is a member of the Asia-Pacific Vitreoretinal Society (APVRS) & American Society of Retinal Specialists. [Email: manoshun@gmail.com} Dr. Mae-Lynn Catherine Bastion received her medical degree from the University of Sydney, Australia with First Class Honours in 1999. In 2003 she received fellowship with the Royal College of Surgeons and Physicians of Glasgow, UK and in 2004 completed her Doctor of Ophthalmology postgraduate studies in Ophthalmology with UKM (National University of Malaysia). Appointed as a member of the Academy of Medicine of Malaysia (AMM) in 2006, she received the AMM Fellowship in 2016. In 2007, she completed her clinical fellowship in vitreoretinal surgery under Associate Professor Dr Lim Tock Han and 3 other vitreoretinal surgeons at The Eye Institute, Tan Tock Seng Hospital, Singapore. Following that, she returned to UKM and served as Head of Vitreoretinal services. She was appointed a Professor of Ophthalmology (Vitreoretina) at UKM in 2014 and continues to mentor and teach postgraduates and undergraduates while maintaining a private practice at the UKM Specialist Centre. She is also chairperson of the CPD Subcommittee, College of Ophthalmologists, Academy of Medicine Malaysia, elected council member of Malaysian Society of Ophthalmology and member of the National Professors Council. [Email: maelynnbdr7@gmail.com}


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The Perfect Shot in W

Retinal Imaging

hile retinal diagnoses can be improved with high-quality imaging, many available systems don’t quite cut it. Compared to newer technology, traditional fundus cameras can be awkward to use and inaccurate in certain imaging contexts like media opacities and small pupils. Now, however, the cameras are being overtaken by a relatively new system. Deemed the first, fully-automated retinal imaging system, the EIDON TrueColor Confocal Scanner (CenterVue, Padova, Italy) is FDA cleared for retinal disease management and diagnosis. By combining enhanced confocal imaging with true color capabilities, the device provides greater contrast and sharper image quality. While it has several innovations, how does it stack up with real world applications?

First-Hand Look at the EIDON

TrueColor Imaging

The EIDON has a 14-megapixel sensor that produces detail-rich images of the highest resolution (15 μm). This allows for closer analysis and easier detection of various pathologies such as diabetic retinopathy, vein occlusion and macular degeneration. Dr. K. Bailey Freund, retinal specialist, author of The Retinal Atlas and clinical professor of ophthalmology at the NYU School of Medicine, has fully integrated the EIDON into his practice. “One of the reasons I like the EIDON is that it takes high-resolution images, especially in eyes that don’t have the clearest ocular media,” said Dr. Freund. “This has been useful in examining patients with cataracts.” The advanced confocal technology reduces backscattered and reflected light effects from areas outside the focal plane for a refined retinal image.

What makes the EIDON unique is the combination of its advanced confocal technology with true color capabilities. The system uses a white light LED source to illuminate the eye and mirror – what you’d normally see if you were to directly observe the eye. In this way, it reflects the actual appearance of the fundus. These details greatly surpass those that can be achieved with an SLO pseudo-color imaging system. “With a white light source, the image is quite sharp,” Dr. Freund explained. “As opposed to other devices that use scanning laser illumination, this full-spectrum light source allows the EIDON to collect essential details that would otherwise be overlooked by other imaging systems. The exposure is consistent and there is no doubling of vessels.” The EIDON also provides multiple imaging modalities to further examine the different layers of the retina. In addition to TrueColor imaging, these modalities include red-free filtering as well as infrared to highlight the vasculature of the eye or explore deeper into the retina. “Sometimes it’s important to have different modalities when one is trying to understand the underlying histologic changes producing what we’re looking at – to have a very crisp detailed fundus image,” explained Dr. Freund. “I find these images very useful when creating figures and presentations.”

Panoramic Views, Image Flickering

The EIDON FA is the latest, top class model in the EIDON family.

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With its wide-field views, the EIDON achieves superior imaging of the central retina and the periphery. The EIDON can produce images with 60-degree wide views which can assist


Color montage image showing characteristic retinal findings of pseudoxanthoma elasticum (angiod streaks and peau d’orange).

with viewing the midperiphery of the retina. “You can also program it to take multiple fields,” said Dr. Freund. “You can then montage the images together automatically for a 110-degree mosaic.” Another valuable feature of the EIDON is the ability to flicker between two images. “The software precisely aligns two images which enables detection of minor changes from different visits,” added Dr. Freund. “Not only is it helpful for small changes, but it is also quite useful as a demonstration for patients who are on anti-VEGF treatments. You can see the resolution of the disease by comparing prior images to what it looks like three months later.”

Fluorescein Angiography The EIDON FA (the latest, top class model in the EIDON family) incorporates fully automated video capabilities for an otherwise complex process: fluorescein angiography (FA). The imaging system is able to take, in addition to high definition FA images, complete videos of retinal blood flow (FA video resolution: 1840 x 1644 pixels). “The EIDON FA produces very fine vascular details in a real-time movie,” said Dr. Freund. “This way you can examine and monitor retinal blood flow from a dynamic perspective.”

60-degree color image showing finding of severe nonproliferation diabetic retinopathy.

Effects on Workflow Retinal examinations can sometimes be a laborious task not only for the patient, but for the operator as well. With this in mind, the question inevitably arises: How is the EIDON used in practice? The EIDON eases the imaging process by automatically aligning with the pupil, auto focusing, and capturing images of the retina – all with minimal operator intervention. It can also be operated with a multi-touch, color display tablet. “You could do it yourself, push a few buttons and it aligns and takes a picture,” explained Dr. Freund. “Sometimes I’m with my research fellows and something of interest comes up. There can sometimes be a long wait in our photography

department. But this camera allows for convenient imaging with minimal training.” With its image quality and practical usage in clinical settings, it’s hard to miss the benefits of using the EIDON over a traditional fundus camera. Between the different iterations of the scanner – the EIDON and the EIDON FA – the standard of imaging remains consistent whether a specialist is examining the nerve fiber layer, the deep retina, or just a general overview of the retina. The TrueColor Confocal Scanner produces details that are essential for proper diagnosis and management. For this reason, it might just be the go-to imaging system for years to come.

About the Contributing Doctor Dr. K. Bailey Freund is a retinal expert in diseases such as diabetic retinopathy and macular degeneration, among other inflammatory disorders. He is based in New York, where he is a clinical professor of ophthalmology at the New York University School of Medicine and an attending surgeon at the Manhattan Eye, Ear and Throat Hospital and New York Presbyterian Hospital. Dr. Freund is acclaimed for his contributions to the field both within the U.S. and internationally as a founding member and trustee of the International Retinal Imaging Society (IntRIS). He has been a principal investigator for various treatments for retinal disorders and a leader in using the latest technologies for diagnosis and imaging. Dr. Freund is an editor for the journal Retina and has contributed to over 400 scientific manuscripts. He has accepted several awards such as the Senior Achievement award from the American Academy of Ophthalmology and the Young Investigator Award from the Macula Society. [Email: kbfreund@gmail.com]

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SubLiminal Laser Therapy ®

A Ray of Light for Retina Diseases and Glaucoma Patients

S

ubLiminal® laser therapy can provide better treatment with lower risks for patients with retinal diseases and glaucoma, experts told delegates at a Quantel Medical Sponsored Symposium on SubLiminal® Laser Therapy, from Glaucoma to Retina Treatment at the recently held Asia-Pacific Academy of Ophthalmology Congress (APAO 2019) in Bangkok, Thailand. “In the last 10 years, this area of subthreshold laser treatment has grown exponentially,” said Dr. Kenneth Fong, retinal surgeon, Sunway Medical Center, Malaysia. From treating retinal disorders, it can now also be used on glaucoma patients, added Dr. Fong, who has used a SubLiminal® retina laser for ten years. Compared to conventional laser photocoagulation, the SubLiminal® subthreshold laser therapy by Quantel Medical (Cournon d’auvergne, France), does not use a continuous-wave laser beam and is non-thermal. Instead, it uses extremely short microsecond laser pulses followed by cooling time periods. This allows a high level of control over the thermal effect on targeted tissue. By using short enough laser pulses and long enough cooling times, the tissue can cool in between laser pulses, preventing damage and avoiding scarring while treating the retina. Using laser can reduce the burden of antiVEGF injections in patients. “Around the world, specifically in the Asia Pacific region, many countries cannot afford the continuous intravitreal injections. Patients can’t take it, and the governments and insurance companies can’t afford the cost of all the drugs you have to inject every few months, or every month or so into your patients’ eyes. So I believe that laser has a strong

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role in treating CSCR (central serous chorioretinopathy) and DME (diabetic macular edema),” explained Dr. Fong. Subthreshold laser works by changing the microenvironment through retinal pigment epithelium (RPE) cells. There is no need to kill the RPE cells, but just enough energy is used to elicit a response. Subthreshold laser stimulation of the RPE leads to repair of the inner blood retinal barrier. Sublethal photothermal stimulation induces heat shock protein expression in RPE cells without cellular damage. Subthreshold means that visible changes cannot be seen during the procedure; and changes cannot be seen using current imaging technology. With subthreshold laser, it is important not to undertreat patients, cautioned Dr. Fong. “There is a high risk of undertreatment in early cases,” he noted, adding that DME cases are often treated late with laser after failure with anti-VEGF and steroids. “Many times, patients with DME are referred to me after they have had many months of anti-VEGF or steroid treatment and a very chronic cystoid macular edema,” he explained. However, to date, there have been no randomized controlled trials comparing subthreshold laser versus anti-VEGF yet.

SubCyclo® Laser: A New Way to Treat Glaucoma As a leading cause of irreversible blindness worldwide, glaucoma affects around 60.5 million people globally. Traditional glaucoma surgery carries risks, prompting doctors to wait until it is necessary to perform glaucoma surgery but in the meantime the patients’ vision then deteriorates. Dr. Nassima Benhatchi, Glaucoma Institute, Saint Joseph Hospital, Paris,

France, talked about the interest of the SubLiminal® laser technology in enhancing cyclophotocoagulation procedures (SubCyclo®) for the treatment of advanced and endstage glaucoma. Traditional cyclodestruction TSCPC (transscleral cyclophotocoagulation) employs a continuous wave with no cooling time, and tissue temperature builds up, causing damage in targeted and adjacent tissue, and sometimes results in severe complications. Side effects include initial high IOP (10%), uveitis (15-30%), chronic hypotony (1-15%), phthisis bulbi (0.5%-5%), and vision loss (30%), highlighted Dr. Benhatchi. “Recently, another diode laser delivery mode has been used to treat glaucoma efficiently with more selective targeting tissue and less tissue damage,” she explained. The SubCyclo® laser therapy for intraocular pressure (IOP) reduction is a significant alternative in the treatment of glaucoma. It uses laser technologies that are not new, but new in its usage to treat glaucoma cases, especially in cyclophotocoagulation (CPC) therapy. The SubCyclo® laser procedure for glaucoma is a non-thermal treatment for open-angle glaucoma and angle-closure


glaucoma. It lowers IOP by stimulating the ciliary body and the uveoscleral pathway, without damaging effects. Using extremely short microsecond pulses, this cyclophotocoagulation procedure lets surgeons precisely manage the thermal effect, while preserving the ciliary body structures. The use of ultrashort and repetitive pulses with rest periods, allows for tissue cooling times, as well as minimizes adjacent tissue damage. The ability to lower IOP safely, with the added advantages of speed and ease for patients and surgeons, makes this an exciting advancement in the treatment of glaucoma. It could offer benefits to patients, as surgeons often have to balance noncompliance with drugs versus invasive surgery. “The daily treatment of glaucoma with drugs produces problems with compliance versus laser and surgery,” said. Dr. Benhatchi. A study was carried out from January to December 2017 to evaluate the efficacy, tolerability, side effects, and anatomical effects of SubCyclo® subthreshold cyclophotocoagulation comparing 25% and 31.3% duty cycles. It included all types of glaucoma, primary or secondary, advanced or moderate stage, as well as after failure of other therapeutics and high risk of surgery. Indications for SubCyclo® laser included advanced stage of glaucoma after failure of other therapeutics, moderate stage of glaucoma, if filtration surgery presented too high a risk, intolerance to medication, palliative treatment or surgery failure, and in preparation for another surgery requiring an urgent IOP reduction such as cataract surgery. Topical prednisolone acetate 1% was prescribed 4 times a day for 1-2 weeks post-laser. The study showed that in both groups treated by SubCyclo® laser, IOP reduction was statistically significant, at more than 20%, with no serious complications. In conclusion, the use of SubCyclo® is found to have few complications, and no tissue damage, with a low rate of vision loss over time.

Efficacy of the procedure was proven through clinical studies and practical experience. The treatment is fast, easy and repeatable if necessary. “My SubCyclo® experience is that it can be used in different stages of glaucoma and with different IOP levels,” Dr. Benhatchi said, adding that the 31.3% duty cycle is more efficient.

SubLiminal® Laser also Works on DME A meta-analysis of the subthreshold laser for DME on 613 eyes from 11 studies, with 7 studies having a control group of 195 eyes treated with conventional laser, showed that no laser scar formation was seen with less than a 15% duty cycle, reported Dr. Kenneth Fong. Overall, there was an increase in best corrected visual acuity (BCVA) and reduction in central retinal thickness (CRT) compared with conventional laser. Types of DME suitable for SubLiminal® laser include those with clinically significant extrafoveal edema, and fovea-involving mild edema with good vision. In summary, SubLiminal® laser for DME works but doctors and patients must exercise patience as a perfectly performed laser takes from 6 to 12 weeks to show its effect.

Treating CSCR with SubLiminal® Laser Conventional laser is effective for central serous chorioretinopathy (CSCR) but may damage the RPE and outer retina, said Professor Xiaoling Liu, Department of Retina, Wenzhou Medical University Eye Hospital, China. SubLiminal® laser subthreshold treatment was a novel therapy for CSCR, she noted. A study was conducted to assess the efficacy and safety of 577nm SubLiminal® laser subthreshold treatment versus conventional laser treatment in CSCR. It concluded that SubLiminal® laser subthreshold treatment promotes the absorption of SRF effectively and improves visual acuity, she noted. It was non-inferior to conventional laser for improving BCVA at 12 weeks and has been found safer than conventional treatment.

Image courtesy of Alejandro Filloy Rius, MD, PhD or Tarragona, Spain

Most published results show better visual acuity (VA) gains compared to a traditional style laser, noted Dr. Fong. Advanced targeting software allows accurate placement of burns. It is a cost-effective option and should not only be considered in rescue situations when anti-VEGF and steroids have failed.

Editor’s Note: The APAO 2019 Congress was held in Bangkok, Thailand, on March 6-9, 2019. Reporting for this story also took place at APAO 2019. Media MICE Pte Ltd, PIE Magazine’s parent company, was the official media partner at APAO 2019.

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COVER STORY

Racing for Positive Patient

in the Poster Poste

by Brooke Herron

T

hree prestigious races comprise the Triple Crown of Motorsport: the Indy 500, the 24 hours of Le Mans and the Monaco Grand Prix. Winning all three during a driver’s career is considered an unofficial racing achievement – and it’s only happened once (Fun fact: Graham Hill is the driver that won all three). Each of the three Triple Crown

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courses varies widely. Winding through the streets of Monaco, the Grand Prix is a slower race (average speed 97mph or 156km/h) with a lot of twists and turns (19 to be exact); the Indy 500 is much faster (average speed 227mph or 365km/h) with only four turns; and the 24 hours of Le Mans has been called the ‘Grand Prix of Endurance and Efficiency’ – where racers must

balance the demand for speed while maintaining the car’s ability to run for 24 hours without mechanical failure. Certainly, this is a lot of information about car racing for an ophthalmology magazine. However, here at PIE Magazine, we’re always keen to take a deeper (or perhaps a more metaphorical) look ‘under the hood’ – and as it turns out, car racing and


Outcomes

rior Segment erior Imaging: The Grand Prix of diagnosis and management Held on a narrow course on the streets of Monaco, the Grand Prix has many elevation changes, tight corners and a tunnel – making it one of the most demanding tracks in Formula One.

ophthalmology might have more in common than meets the eye . . . In fact, we think the posterior segment has a ‘triple crown’ of its own: imaging for diagnosis and management, and laser and anti-VEGF for therapy. Together, these create the ‘triple crown’ of treatment in the posterior segment, leading to championship wins by improving outcomes for patients.

The anatomy of the posterior segment has some similarities with the Monaco Grand Prix: With all its twists and turns, it provides a complicated course for surgeons to navigate. Without accurate roadmaps – or images – finding the correct course would be impossible. Thankfully today, surgeons have access to the ultimate in eye ‘roadmapping’. Since its introduction, spectral domain optical coherence tomography (SD-OCT) has led the pack in imaging and diagnostics, due to its low cost and high-resolution imaging. But now, there is a new car in the race: swept-source OCT (SS-OCT). With faster scanning speeds and longer wavelengths for deeper imaging, is SSOCT gearing up to overtake SD-OCT? Is a new champion to be crowned? According to Dr. Judy Kim, a tenured professor at the Department of Ophthalmology and Visual Sciences, Medical College of Wisconsin (USA), there are different factors to consider – and for each, a different winner. Here’s how she says the SD-OCT vs. SS-OCT races breakdown: For vitreoretinal interface and showing intra- and subretinal fluid: It’s a tie. “Both SS-OCT and SD-OCT are excellent at showing intra- and subretinal fluid as well as vitreoretinal

interface,” said Dr. Kim. “Since much of our treatment decisions for retinovascular diseases are based on the presence or absence of fluid, and surgical decisions for vitreoretinal interface disorders are assisted by OCT, both OCTs are incredibly helpful in our daily management of patients . . . and the race may be a tie.” On speed: SS-OCT wins. Dr. Kim says if the race was purely based on speed, there is no question that SS-OCT would win – simply because it’s faster. She explained: “The faster scanning speed of SS-OCT allows for denser scanning and a wider scanning area for a given image acquisition time compared to SD-OCT.” On imaging deeper structures: SS-OCT wins. Compared to SD-OCT, SS-OCT has a longer wavelength and reduced sensitivity roll-off. “These characteristics of SS-OCT allow better imaging of deeper structures and better penetration through RPE (retinal pigment epithelium),” explained Dr. Kim. “As a result, one area that SS-OCT excels over SD-OCT is in OCT Angiography (OCTA). There are studies that show better detection and delineation of type 1 choroidal neovascularization (CNV) with SS-OCTA compared to SD-OCTA.”

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COVER STORY

One such study was published in 2017 by Miller et al.1 There, the investigators found that “SS-OCTA imaging provided a more accurate representation of the CNV compared with SD-OCTA imaging, in particular the SS-OCTA measurements are more consistent across the different scan sizes”. Overall: Cost wins for SD-OCT. Like in the Monaco Grand Prix – where the race is won at much lower speeds – faster doesn’t always win in imaging. And despite the benefits of SS-OCTA, Dr. Kim currently believes that SD-OCT is way ahead in the race. “While SS-OCT is fast, it has a huge problem that drags and slows down its adaptation by the masses and that’s the cost,” she explained. “It is highly expensive compared to SD-OCT and, until the cost comes down – or its limited drivers who race with SS-OCT can demonstrate that it significantly improves our patient outcomes compared to what we can achieve currently with SD-OCT – I believe that most retina specialists will continue to drive with SD-OCT.” So, what navigation system does Dr. Kim use in her practice? They use SD-OCT. “Being at an academic setting, we try to get the latest and best . . . however, the definition of ‘best’ also includes ‘most cost-effective’,” she said, noting that SD-OCT allows them to care for patients well without the significant downsides posed by cost. “[With SD-OCT] we do not have to worry about added costs of buying more expensive imaging equipment that may not add further to management of our patients, we believe SD-OCT is an excellent choice,” continued Dr. Kim, adding that she has systems from Carl Zeiss Meditec (Jena, Germany) and Heidelberg Engineering (Heidelberg, Germany), but most of the time, she uses the latter.

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While SS-OCT is fast, it has a huge problem that drags and slows down its adaptation by the masses and that’s the cost. It is highly expensive compared to SD-OCT and, until the cost comes down – or its limited drivers who race with SS-OCT can demonstrate that it significantly improves our patient outcomes compared to what we can achieve currently with SD-OCT. – Dr. Judy Kim

She says the Heidelberg system’s image averaging, eye tracking and image registration provides excellent images from visit to visit: “I appreciate that I can get a widefield B-scan OCT with a special lens in this system, which I often use to study the vitreoretinal interface,” she said, noting that it also has other features, including autofluorescence which helps to follow geographic atrophy; and ICG (indocyanine green) angiography, which is useful in detection of various diseases such as polypoidal choroidopathy and central serous choroidopathy. On the side of SD-OCT, Dr. Kim continued that in clinical practice, qualitative data (such as the presence or absence and relative growth of CNV compared to previous visits) is often used – rather than exact measurements of CNV size, which is needed in research. Given its imaging capabilities, Dr. Kim says she would love to have SSOCT in her clinic, but cost remains a huge limiting factor. “Until we can solve that issue, and also demonstrate that SS-OCT can significantly alter the care of our patients relative to how we are doing currently, SD-OCT should suffice for now,” she said. “However, algorithms and instrumentation are continually changing in this imaging field; I eagerly await its every day clinical utility over SD-OCT.”

Final Score: While SS-OCT provides faster and deeper images, it remains too cost-prohibitive for widespread clinical use. Therefore, the current victor remains SD-OCT. But how long will it remain in the lead? Only time will tell . . .

Anti-VEGF: A race of ‘endurance and efficiency’ Like the 24 Hours of Le Mans, those using anti-VEGF are in for the theoretical (and literal) long-haul – and like the race, finding the agent and treatment regimen that balances ‘endurance’ and ‘efficiency’ continues to challenge doctors. Dr. Kim believes that all currently available anti-VEGF agents provide significant efficacy for most patients, however she finds that there are some patients who may respond better to one agent versus another, possibly due to pharmacogenetics. She also says that a ‘good response’ can also mean different things for different patients. “In some patients, we can successfully stabilize the condition and no further injections are needed. In another, continuous chronic monthly treatment may be necessary to keep the retina dry. Yet in another, the retina remains with fluid despite frequent dosing, but the visual acuity can be maintained,” she explained, adding that different diseases respond differently to anti-VEGF agents.


Selecting the ‘Right’ Fuel for High Performance Results The first variable to determine – and pardon the metaphor – is what gas to put into the car (or which anti-VEGF agent to inject). Across the board, there are three commonly used agents: bevacizumab (Avastin, Genentech); aflibercept (Eylea, Bayer); and ranibizumab (Lucentis, Novartis). “The development of anti-VEGF is revolutionary in our management of various retinovascular disorders,” said Dr. Kim. These agents are used to treat conditions like macular edema due to retinal vein occlusion (RVO), diabetic retinopathy (and associated edema), and neovascular age-related macular degeneration (nAMD). Fueling with bevacizumab. Avastin, which is used in cancer therapy, is the ‘parent’ molecule from which ranibizumab was derived for the treatment of nAMD; the cost per dose of bevacizumab is about 5-10% that of ranibizumab.2 Avastin is often used offlabel to treat nAMD based on efficacy and cost-effectiveness. In most cases of nAMD, Dr. Kim starts with Avastin. This is due to several factors including the fact that it’s readily available in her office, and its pre-authorization is not required by insurance companies. But perhaps most importantly, she notes that trial results (like those from IVAN and CATT) showed similar efficacy of bevacizumab and ranibizumab when given accordingly. “As a result, I can treat on the same day of a new patient visit or at

IVAN Study The IVAN (Inhibit VEGF in Age-related choroidal Neovascularization) trial was a head-to-head comparison between bevacizumab and ranibizumab. The investigators found that ranibizumab and bevacizumab have similar efficacy.2

the evaluation visit with Avastin. And while most patients respond favorably to Avastin, if there is no improvement, or worsening in the amount of fluid in or under the retina, my next line of treatment is Eylea . . . and many patients end up continuing on it,” explained Dr. Kim. “If the patient does

CATT Study The Comparison of Age-related Macular Degeneration Treatments Trials (or CATT) described the effects of ranibizumab and bevacizumab when administered monthly or as needed for 2 years. They found that ranibizumab and bevacizumab had similar effects on visual acuity over a 2-year period.3

not respond to Eylea, or if there is that rare patient with inflammation with Eylea, I then switch over to Lucentis.” “Likewise, for eyes with macular edema from central retinal vein occlusion or hemi-retinal vein occlusion, I also begin with Avastin and switch to Eylea if needed,” she continued, noting that this treatment is based on SCORE2 study findings. [Ed. Note: For more on SCORE2 trial results, see the full story on page 38.] “For central-involved diabetic macular edema, I try to follow DRCR. net Protocol T data, which showed no significant difference between the three anti-VEGF agents when visual acuity was 20/32 to 20/40, but Eylea

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COVER STORY

was better for visual acuity and OCT outcomes for eyes with 20/50 or worse,” said Dr. Kim. “Therefore, depending on the disease and its severity, we are fortunate to be able to choose different anti-VEGF agents, guided by clinical trial findings. While most patients can be started with Avastin and stay the course with Avastin if they are responding well, some end up switching over to a “different lane” and different drug – usually Eylea – during the course of the ‘race’,” she said. “While multi-center randomized clinical trials guide my treatment decisions, the final decision of which anti-VEGF agent to initiate the therapy, treatment frequency, and possible switching or even cessation of treatment, are based on my discussion with each patient, according to his or her clinical and social situations and other needs,” concluded Dr. Kim. Clinical trial results and cost are also two guiding factors for Dr. Anil Arora, medical director of the Central Coast Eye Specialists in Gosford, NSW, Australia. He says the three main anti-VEGF agents (Avastin, Eylea and Lucentis) are very similar – and this is supported by numerous studies and trials. “I tend to use Avastin as my first line agent as it is less of a burden to the taxpayer and health care system,” said Dr. Arora, noting that while Lucentis and Eylea are subsidized by the Australian government, they cost the healthcare system about $500 million annually, a cost that he says could be better served in other health initiatives like cancer treatment or building new hospitals. “I think that if the drugs are equally effective (as the trials suggest), then eye doctors have a responsibility to the greater health care system to do their bit to not see the cost of health care blow out and become unaffordable – hence my ‘philosophical’ bias for using Avastin,” explained Dr. Arora.

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The duration of anti-VEGF treatment regimens Like the 24 Hours of Le Mans, treatment with anti-VEGF is not a short race – often injections will be maintained for years to preserve visual acuity and anatomical benefits. Recent studies have shed light on determining how often anti-VEGF injections should be given to provide the optimal benefit to patients – and one regimen, treatand-extend or T&E, is quickly becoming a fan favorite for treating nAMD. Finding balance with T&E. Dr. Gemmy Cheung from Singapore National Eye Centre (SNEC) uses T&E as her preferred regimen. She says the advantage of T&E is that it addresses long-term needs, to the second and third year and beyond. Because nAMD is a chronic condition with no current cure, Dr. Cheung stresses that it’s important to have an open discussion with patients. “Anti-VEGF controls the condition, so therefore long-term treatment is necessary in most cases,” she said. “In fact, we have cumulating data that suggest that if treatment is not continued at adequate retreatment frequency, much of the initial visual gain will be eroded in subsequent

years,” continued Dr. Cheung. “Once we have accepted that fact, the next challenge is to make the treatment regimen and frequency practical and logistically acceptable – in other words, we need to find ways to reduce the number of return visits and injections.” Dr. Cheung says this is where individualization is the key: “We know that some patients only need retreatment every 12 weeks or so, but this is not for everyone. There is currently no accurate way to predict this at the outset – therefore T&E fits into this need very well.” “Although many clinicians have been using T&E for a while, we have not had very robust clinical trials until recently,” explained Dr. Cheung. “Now studies like ALTAIR or Trend have demonstrated that T&E can deliver good visual gain, while reducing retreatment burden. Concurrently, real world data, such as those from the Fight Retinal Blindness Registry, have also reported encouraging results using T&E.” Dr. Kim is also an advocate of using T&E in nAMD for several reasons. Firstly, clinical trial results (like those mentioned by Dr. Cheung) show that the T&E regimen can yield similar visual acuity outcomes as monthly dosing for

Although many clinicians have been using T&E for a while, we have not had very robust clinical trials until recently. Now studies like ALTAIR or Trend have demonstrated that T&E can deliver good visual gain, while reducing retreatment burden. – Dr. Gemmy Cheung

Trend The Trend study showed that T&E dosing with ranibizumab was non-inferior to monthly dosing and had clinically comparable results in visual acuity compared to monthly dosing after 52 weeks.4


ALTAIR The ALTAIR study is the first to critically compare different T&E protocols and showed that both the 2- and 4-week extension protocols for T&E regimens improved visual and anatomical outcomes through week 52.4

up to two years. “This greatly reduces treatment burden on the patient, as well as on the physicians, without compromising visual acuity outcomes,” she said. Lowering the number of injections, and thus the treatment burden, is another reason. “The HARBOR and CATT studies have shown that the number of injections required by a patient can vary greatly. Some patients required only few injections, while others required monthly injections over two years,” said Dr. Kim. “Furthermore, we currently do not have good biomarkers to know at baseline which patient is going to require more injections,” continued Dr. Kim, adding that if all patients are treated monthly, many will be overtreated. Alternately, even if patients are not treated monthly, they would still require monthly follow-up to check for changes in OCT and visual acuity – and thus, this does not alleviate the burden of number of clinic visits. “Also, a monthly visit with PRN (pro re nata or as needed) treatment is a reactive treatment rather than proactive treatment and risks recurrences with irreversible loss of visual acuity,” said Dr. Kim. “Many studies have shown that undertreatment is common in real-world data and is most likely the reason for poorer real-world visual acuity outcomes when compared to clinical trial outcomes.” Dr. Arora says that while he tends to take a PRN approach, multiple factors are taken into consideration. This includes: the state of the other

eye (if other eye is bad, he will be far more likely to treat, even if there is little or no evidence of active disease); the patient’s ability to travel and attend treatment; stability of vision and ocular findings; and what has happened in the past if treatment was delayed or withheld. “If the situation is very stable, the macula looks dry and the OCT looks good, then I’ll often go to a treat-andextend protocol,” said Dr. Arora, adding that currently there are no standardized rules regarding anti-VEGF treatment regimens. “If you ask 10 different ophthalmologists, you will get 10 different opinions.” “Studies show that patients who get regular monthly injections no matter what (e.g. even if their retina looks completely normal with no evidence of fluid or blood and vision has returned to normal) do the best in the longterm, but it is often difficult in the real world to justify the cost and the anxiety, and the low, but ever-present risk of endophthalmitis, to a patient when everything is normal,” said Dr. Arora.

Studies show that patients who get regular monthly injections no matter what (e.g. even if their retina looks completely normal with no evidence of fluid or blood and vision has returned to normal) do the best in the long-term, but it is often difficult in the real world to justify the cost and the anxiety, and the low, but ever-present risk of endophthalmitis, to a patient when everything is normal.

– Dr. Anil Arora

Overall: Preferred regimen to last for the long haul is T&E. “In my opinion, the T&E regimen is currently the best we have to offer that can minimize treatment and visit burdens to our patients, while personalizing the injection and visit frequency, avoiding under-treatment and not compromising the visual acuity,” concluded Dr. Kim.

HARBOR Trial The HARBOR trial evaluated the 24-month efficacy and safety of intravitreal ranibizumab 0.5 mg and 2.0 mg administered monthly or as needed (PRN) in patients with nAMD. Investigators reported the mean number of ranibizumab injections through month 24 was 21.4 (0.5 mg monthly), 13.3 (0.5 mg PRN), 21.6 (2.0 mg monthly), and 11.2 (2.0 mg PRN). At month 24, the mean change from baseline in BCVA was (letters) +9.1, +7.9, +8.0, and +7.6, respectively.5 These results led investigators to conclude that physicians should be comfortable optimizing treatment strategies on an individual basis.

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COVER STORY Laser: Finding its place in the pack The Indy 500 is the world’s oldest major automobile race. And laser has been investigated and used for ophthalmic purposes since the 1960s and 70s – making it one of the older, yet still effective technologies for treating certain posterior segment conditions. “Laser treatments have been with us for decades, and they can be useful in the management of localized non-center involving diabetic macular edema (DME) and proliferative retinopathies, such as sickle cell retinopathy, neovascular glaucoma, retinopathy of prematurity, proliferative diabetic retinopathy (PDR), and neovascularization following retinal vein occlusions,” said Dr. Kim. “I also use laser to treat retinal tears, limited retinal detachment, symptomatic macroaneurysm, Coat’s disease, among other conditions.” In her practice, Dr. Kim uses a Nidek (Gamagori, Japan) pattern laser system – she says that in patients who are cooperative, the pattern laser allows for faster treatment for PRP (panretinal photocoagulation). “There can be variations in uptake of laser in different parts of the eye, and the pattern laser seems to result in less intense PRP in some patients,” she said, noting that the pattern laser is also slightly more sensitive to media opacity. “Therefore, in many patients, I perform PRP with single spots or with an indirect laser,” said Dr. Kim. “Even in cooperative patients, I do not perform focal grid laser treatment with pattern, but with single spots for accuracy and safety.” In his clinic, Dr. Arora says he uses a green diode laser for extrafoveal lesions: “I think [laser] can reduce the frequency of [anti-VEGF] injections, if used in conjunction with injections for conditions like retinal vein occlusion and diabetic retinopathy.” So, why is a newer treatment like anti-VEGF speeding past an old remedy like laser? According to Dr. Kim, there

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are downsides to laser: “Focal grid laser can result in inadvertent treatment of the fovea, or expansion of the laser scar over time, that encroaches into the fovea and causes loss of visual acuity,” she said, adding that PRP is excellent as a treatment for PDR, but it has shown to reduce visual field and night vision. In addition, Dr. Arora says that laser therapy is a controversial topic, and doctors may use it in different degrees instead of, or in conjunction with, anti-VEGFs. According to Dr. Kim, recent studies suggest anti-VEGF’s superiority to laser, either as a monotherapy or

in combination, for conditions like DME and PDR. She said that for management of eyes with centralinvolved DME with vision loss, Protocol I from DRCR.net showed that anti-VEGF was superior to focal/grid laser. In eyes with DME and PDR, Protocol J found that a combination of anti-VEGF and PRP can reduce vision loss from DME worsening after PRP. Meanwhile, she said that Protocol S of DRCR.net showed a two-year benefit of anti-VEGF therapy for PDR: “There was greater area under the curve for visual acuity, less visual field loss, and less need for vitrectomy in the anti-VEGF group compared to PRP

A Summary of the Treat-and-Extend Approach from Dr. Gemmy Cheung When starting patients on a T&E regimen for nAMD, there are several steps to consider: 1. Initial counseling: Physicians should outline the need for long-term treatment – and consequences of suboptimal follow-up treatment – with patients before beginning the T&E treatment regimen. 2. Start with intensive treatment phase: Give monthly injections with the aim of establishing maximal improvement in visual acuity and anatomical response. 3. Once maximal improvement has been reached, explain the transition to the ‘maintenance phase’ to the patient. The aim is not to improve any further, but to maintain gains while reducing retreatment visits. 3a. Titration phase: During this phase, provide injections during every visit, while lengthening the return visit (if there are no signs of recurrence of disease activity). Stop further extension once recurrence occurs and return to the previous ‘dry’ interval. 3b. Stable maintenance phase: Most patients will establish their optimal retreatment interval after a period of titration. I would continue retreatment using this interval as a ‘fixed’ regimen for a minimum of 1 year. 3c. Re-challenge: For patients who have ‘failed’ a certain extension interval, I would consider re-challenging once or twice if they become stable for a couple of cycles. Dr. Cheung notes that these are general principles: “Each clinician will need to evaluate individual patients further according to their needs, their visual potential and their disease phenotype.”


group,” said Dr. Kim. “However, the 5-year data was not as strong and there was significant number of subjects who were lost to follow-up, which I believe is a significant issue.” She continued: “Furthermore, while anti-VEGF injections can even improve diabetic retinopathy severity score, after the first year of intense therapy with frequent injections, the subjects continued to require average of 3 injections, even at year 5, suggesting some eyes may require chronic intravitreal injections.”

But are there cases where laser may produce a more favorable outcome? In certain instances, and while this differs from the Protocol I and T findings, Dr. Kim says there is an advantage to laser: “Since one or two PRP sessions can stabilize PDR in most patients for the long-term – and diabetic patients tend to be sicker and are at higher risk for being lost to follow-up – I am concerned by chronic therapy with anti-VEGF for PDR, and have decided to use PRP more to give these eyes a chance for persistent stabilization.”

About the Contributing Doctors Dr. Judy Kim is a graduate of Johns Hopkins University School of Medicine, Bascom Palmer Eye Institute and the Medical College of Wisconsin. Since 2003, she has been selected one of the “Best Doctors in America” and is listed in “Top Doctors” and “M Magazine Top Docs”. She currently serves on the Executive Board of Directors of the American Society of Retina Specialists (ASRS), the Council for American Academy of Ophthalmology (AAO), the Executive Board of Women in Retina and the Editorial Board of JAMA Ophthalmology. Dr. Kim is active in the Macula Society, Retina Society, ASRS and Association for Research in Vision and Ophthalmology. She has served as the President of Milwaukee Ophthalmological Society and has been accepted into the American Ophthalmological Society. Dr. Kim has received Achievement Award and Senior Achievement Award from the AAO and Achievement Award from ASRS. Her research interests include clinical trials, telemedicine, diabetic retinopathy, age-related macular degeneration, retinal surgery and ocular imaging. She is a noted national and international expert and speaker in her field. [Email: jekim@mcw.edu] Dr. Gemmy Cheung currently serves as deputy head and senior consultant of the medial retina service for Singapore National Eye Centre (SNEC), as well as senior clinician investigator for the Singapore Eye Research Institute (SERI). Her research interests include the study of risk factors and clinical features of macular diseases that may be unique in Asian populations. Dr. Cheung has published more than 150 articles, mostly regarding age-related macular degeneration, including polypoidal choroidal vasculopathy, and conducted several clinical trials in anti-vascular endothelial growth factor therapies. Dr. Cheung has also been actively involved in training and education, and has served as an instructor on AsiaPacific Academy of Ophthalmology (APAO) and American Academy of Ophthalmology (AAO) courses and many other educational programs. In addition, she is also a volunteer faculty member for the ORBIS Flying Eye Hospital Programme. Dr. Cheung has received a number of prestigious awards, including the Macula Society Young Investigator Award (2017), APAO achievement award (2017), APAO Nakajima Award (2014), APAO Outstanding Service in Prevention of Blindness Award (2013), the Bayer Global Ophthalmology Research Award (2012), the Roper-Hall Medal (2005) and the Elizabeth Hunt Medal (Royal College of Ophthalmologists, UK). [Email: gemmy.cheung.c.m@singhealth.com.sg] Dr. Anil Arora. Dr. Arora is an ophthalmologist who has been practicing in Central Coast and in Sydney since 1998. He completed his medical degree through the University of Sydney in 1985 and after carrying out his internship and residency training at Royal North Shore, Westmead and Royal Prince Alfred Hospitals, he embarked on a career in ophthalmology. He is a Fellow of the Royal Australian and New Zealand College of Ophthalmologists (RANZCO), American Academy of Ophthalmology (AAO) and American Society of Cataract and Refractive Surgery (ASCRS). Clinical interests include cataract surgery, particularly with multifocal intraocular lenses, retinal diseases and surgery, and laser refractive surgery. He also has in interest in ophthalmology in developing countries and in charity work: Dr. Arora sponsors 60 children in all parts of the world through World Vision and has been a member of Amnesty International for over 10 years. [Email: anilarora1@hotmail.com]

Overall: While it’s played second fiddle to anti-VEGF as of late, laser still plays a vital role in treating certain conditions – and its role as a mono- or combination therapy will continue to be studied to further positive outcomes for patients.

And the Triple Crown goes to... As diagnostic and imaging technology speeds forward, therapy options and treatment regimens remain under evaluation – and time will tell as longterm trial results help dictate the course of treatment for the various sightthreatening conditions affecting the posterior segment. Until then, the race for better outcomes will be propelled forward by the continued work of researchers, ophthalmologists and those involved in the industry – and in our humble PIE opinion, it’s those people that are the ultimate ‘Ophthalmic Triple Crown’ winners.

References: Miller A, Roisman L, Zhang Q, et al. Comparison Between Spectral-Domain and Swept-Source Optical Coherence Tomography Angiographic Imaging of Choroidal Neovascularization. Invest Ophthalmol Vis Sci. 2017;58(3):1499-1505. 2 Chakravarthy U, Harding SP, Rogers CA, et al. A randomised controlled trial to assess the clinical effectiveness and cost-effectiveness of alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN). Health Technol Assess. 2015;19(78):1-298. 3 Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):13881398. 4 Wai KM, Singh RP. Treat and Extend Dosing Regimen with Anti-vascular Endothelial Growth Factor Agents for Neovascular Age-related Macular Degeneration. Am J Ophthalmic Clin Trials. 2018;1(1):1-6. 5 HARBOR Study Group, Ho AC, Busbee BG, Regillo CD, et al. Twenty-four-month efficacy and safety of 0.5 mg or 2.0 mg ranibizumab in patients with subfoveal neovascular age-related macular degeneration. Ophthalmology. 2014;121(11):2181-2192. 1

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Anti-VEGF

Pit Stop: The Cost of Fueling Treatment Around the World ...for neovascular age-related macular degeneration (nAMD)

“ Many factors contribute to medication choice, including clinical trial efficacy, clinical experience, treatment burden for patients, patient preference, access and cost. ”

01

The United States

05

South Korea

02

The United Kingdom

06

Singapore

03

India

07

Australia

04

China

During the month of January 2015 at all UK NHS ophthalmology units:

61%

of anti-VEGF drug use was ranibizumab (30,634 injections)

Cost per dose of anti-VEGFs used in the U.S:

36%

was aflibercept (18,059 injections)

Aflibercept & ranibizumab

$1950

03%

was bevacizumab (1,410 injections)

Bevacizumab

$50

01

Ziv-aflibercept

$30

02

Cost per dose of anti-VEGFs used in the UK

Ranibizumab

Aflibercept

$1041

$1145

“ Although the primary motivation for prescribing bevacizumab has likely been its low cost and similar effectiveness, the move to aflibercept is likely driven by physician desire to reduce treatment burden (i.e., number of injections).” Current global prevalence of AMD

170 million

Global prevalence of AMD by 2040

288 million


ASIA- PACIFIC According to a 2017 survey* by the American Society of Retina Specialists (ASRS), for treating nAMD in Asia-Pacific, the anti-VEGF preference is: Ranibizumab

Aflibercept

Bevacizumab

50%

50%

50%

25%

25%

75%

0%

100%

0%

42.3%

25%

75%

100%

75%

0%

100%

31.1%

23.2%

*This survey included respondents from Australia, New Zealand, India, Indonesia, Japan, Korea, Singapore, Taiwan, and Thailand

China has developed its own anti-VEGF medication for nAMD: Conbercept Cost per dose of anti-VEGFs used in China Cost per dose of anti-VEGFs used in India

Ranibizumab:

$240

Aflibercept:

$846

Ranibizumab:

$1471

Conbercept:

$1128

04

India has also launched a biosimilar to ranibizumab with promising results, and a much lower-cost biosimilar for bevacizumab is also available.

Data was not available for aflibercept, which received approval for DME and AMD in February and May of 2018.

05 Cost per dose of anti-VEGFs used in South Korea

03

Bevacizumab appears to be the primary agent for treating nAMD in Singapore.

Ranibizumab:

$749

Aflibercept:

$716

06

In a 2010-2011 study from the Singapore National Eye Centre on patients with exudative maculopathy secondary to AMD-choroidal neovascularization or PCV (n=167):

83.2% received bevacizumab

16.8% received ranibizumab

Cost per dose of anti-VEGFs used in Singapore

Ranibizumab:

$623 Aflibercept: $952

07

Cost per dose of anti-VEGFs used in Australia

Ranibizumab:

$997

Aflibercept:

$1022

*All prices are listed in USD (2016)

et al. A Multinational of Anti–Vascular Endothelial Growth FactorEndothelial Use: The United States, Source: Parikh R, Pirakitikulr N, Chhablani J, Sakurada Y, Singh RP, Comparison Modi YS. A Multinational Comparison of Anti–Vascular Growth Factor Use: the United Asia-Pacific. Retina.Crossref. 2019;3(1):16-26. The UnitedKingdom, States, theand United Kingdom,Ophthalmol and Asia-Pacific Ophthalmol Retina. 2019 Jan;3(1):16-26.


INNOVATION DME TREATMENT

DEX OF ALL TRADES Dexamethasone Implants in Treatment-naïve Diabetic Macular Edema Eyes by Joanna Lee

S

ince inflammation has been suggested as a key factor for developing diabetic macular edema (DME), intravitreal corticosteroids have entered the picture to treat this root cause. And one of these, dexamethasone (or DEX) – a type of synthetic glucocorticosteroid1,2 – is emerging as the medication of choice for treating DME. To take a closer look at its efficacy and safety as a therapy, a group of 10 centers from around the world investigated intravitreal DEX implants for DME patients – specifically comparing patients who were treatment naïve versus those who were refractory to anti-VEGF treatments in a reallife setting. The results from this retrospective investigation – called the International Retina Group Real-Life 24 Month Multicentre (IRGRel-DEX) study4 – were published in January 2019 and presented at the Asia-Pacific Academy of Ophthalmology (APAO) 2019 Congress in March. Dr. Adrian Fung, one of the study’s authors and the vitreoretinal fellowship director at Westmead Hospital in Sydney, Australia, reported results from the study, which spanned 24 months. The primary outcome measures of IRGRel-DEX were best corrected visual acuity (BCVA) changes at 24 months and changes in macular thickness (central subfield thickness or CST) in the 24 months after receiving intravitreal dexamethasone. The secondary outcome measures were changes in BCVA at six and 24 months, the number of DEX implants used, and any additional rescue antiVEGF or laser therapy. The researchers also recorded safety data including cataract surgery and rising intraocular pressure.

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To be eligible for the study, patients either had to have intravitreal dexamethasone treatment or be refractory to treatment – meaning they received at least three-monthly anti-VEGF injections, lost two or more lines of vision, or had a less than 10% percent reduction in CST. Patients’ BCVA had to be between 6/9.5 and 6/60. They also needed to have had center-involving DME, with either subretinal or intraretinal fluid and 24 months of follow-up. Overall, 130 patients with a mean age of 69 years and an average HbA1c of 8.4% were included in the study. There were 71 patients in the treatment naïve group and 59 in the refractory group. Over 24 months, all patients received a significant amount of intravitreal dexamethasone: The naïve group received almost four times (3.9) of treatment, while the refractory group received 3.1 times of the treatment. The patients could also have additional therapy, with refractory patients allowed anti-VEGF in addition to the DEX implant – on average, these patients received 10 anti-VEGF injections during the 24-month period. The chemistry of the DEX implant in both groups of DME patients produced interesting results in terms of functional and anatomical outcomes. BCVA showed a statistically significant difference between the refractory and the naïve groups: Not only did the naïve group gain 11.3 ± 10.0 letters versus the refractory group’s 7.3 ± 2.7 letters (P = 0.01), they were more likely to gain ≥10 letters. The investigators found that CST was significantly decreased compared

with baseline in both groups, and although CST was higher in refractory eyes than in naïve eyes (CST 279 ± 61 vs. 313 ± 125μm, P = 0.10), it was not statistically significant. Dr. Fung said: “In terms of baseline changes, there was a statistically significant difference between naïve and refractory eyes. The refractory eyes tended to have had prior focal laser or panretinal photocoagulation (PRP), and these factors were adjusted for in the statistical analysis.” No patients required surgery for intraocular pressure-lowering treatment; however 7.1% of naïve and 22.8% of refractory patients received intraocular pressure-lowering topical therapy. At the end of the study, results showed positive effects on patients’ functional and anatomical conditions


(with a low rate of intraocular pressurelowering therapy) among DME patients receiving DEX implants. “There was also a suggestion that earlier treatment, in other words, patients who received treatment when they were naïve, tended to do better than patients who have had any previous VEGF therapy or refractory treatment,” explained Dr. Fung. Overall, he said that this study’s findings are consistent with previous real-life studies on DEX implants in DME patients.5-7. Editor’s Note: The APAO 2019 Congress was held in Bangkok, Thailand, on March 6-9, 2019. Reporting for this story also took place at APAO 2019. Media MICE Pte Ltd, PIE Magazine’s parent company, was the official media partner at APAO 2019.

Are DEX implants in your DME toolbox?

References: Dexamethasone. Drug Information. Available at: https://www.drugs.com/mtm/dexamethasoneophthalmic.html 2 Dexamethasone. WebMD. Available at: https://www.webmd.com/drugs/2/drug-75004/ dexamethasone-ophthalmic-eye/details 3 Pareja-Ríos A, Ruiz-de la Fuente-Rodríguez P, Bonaque-González S, et al. Intravitreal dexamethasone implants for diabetic macular edema. Int J Ophthalmol. 2018;11(1):77-82. 4 Iglicki M, Busch C, Zur D, et al. Dexamethasone implant for diabetic macular edema in naive compared with refractory eyes: The international retina group real-life 24-month multicenter study. The IRGREL-DEX Study. Retina. 2019;39(1):44-451. 5 Escobar-Barranco JJ, Pina-Marín B, Fernández-Bonet M. Dexamethasone implants in patients with naïve or refractory diffuse diabetic macular edema. Ophthalmologica. 2015;233(3-4):176185. 6 Guigou S, Pommier S, Meyer F, et al. Efficacy and safety of intravitreal dexamethasone implant in patients with diabetic macular edema. Ophthalmologica. 2015;233(3-4):169-175. 7 Malclès A, Dot C, Voirin N, et al. Real-life study in diabetic macular edema treated with dexamethasone implant (The Reldex Study). Retina. 2017;37(4):753-760. 1

INDUSTRY UPDATE

ZEISS Receives FDA Clearance for CLARUS 700

T

he CLARUS 700® (Carl Zeiss Meditec, Jena, Germany) has received 501(k) clearance from the U.S. Food and Drug Administration (FDA). The system is the first highresolution, ultra-widefield imaging with true color and a complete range of fundus imaging modalities, including fluorescein angiography (FA), for advanced care specialists. This is a boon for diagnostics and disease management: With Ultrawidefield FA, eye care specialists can identify more severe forms of diabetic retinopathy earlier – this includes neovascularization and retinal diseases like uveitis, choroidal masses, retinal tears, detachments and peripheral ischemia. In addition, high-resolution and high contrast images of the FA from the CLARUS 700 allows clinicians to capture the smallest details, from the macula in the early phase to the periphery in the late phase.

Powered by Broadline Fundus Imaging, the ZEISS CLARUS 700 captures images that closely resemble the natural coloration of the fundus as it appears under direct clinical observation. According to Dr. Jesse Jung from East Bay Retina Consultants, that is where he thinks CLARUS is making some significant progress: “I think the main goal of any fundus imaging system is to really get the panretinal view of the retina in true color,” he explained. In addition, it allows eye care specialists to manage all the needed modalities including true color (with RGB separation), autofluorescencegreen, autofluorescence-blue, stereo image pairs, external eye and FA. This can all be done in one session, from one device – and without having to reposition the patient – which provides a more comfortable exam experience. Using a simple and intuitive

interface with time-saving data acquisition features, the CLARUS 700 provides a comprehensive fundus exam that aids in diagnoses, treatment planning and disease management. Plus, using its deep learning algorithms, retina specialists can maximize the workflow efficiency in their practice and image all patient types, including elderly and sick who may have trouble maintaining their fixation. “ZEISS has been at the forefront of industry-defining advancements that have made CLARUS the industry’s standard of care for identifying retinal and glaucoma disease,” said Jim Mazzo, global president of Ophthalmic Devices at Carl Zeiss Meditec. “From early detection to postoperative evaluation, we’re here to support our customers, every step of the way,” he added. For more information, visit www. zeiss.com/meditec.

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INNOVATION ARTIFICIAL INTELLIGENCE

Robots Are Upon Us Diagnosing Diabetic Retinopathy with AI Technology by Gerardo Sison

A

s artificial intelligence (AI) spearheads its way through multiple industries, it’s no surprise that healthcare is becoming one of the largest to utilize newer technology. And, with the rise of machine learning capabilities, it’s only a matter of time until the field of ophthalmology catches on – or, maybe it has already. Dr. Michael Abramoff, MD, PhD, is a distinguished, award-winning ophthalmologist, computer scientist and founder of IDx. He has spent years pioneering AI technology for diagnostic use in diabetic retinopathy (DR). And now, after decades of development, IDx-DR, a fully autonomous diagnostic system, has been cleared by the US Food and Drug Administration (FDA) as of 2018.

IDx-DR and how it works “The diagnostic AI system uses advanced imaging to detect hemorrhages, microaneurysms, new vessels and exudates indicative of diabetic retinopathy,” explained Dr. Abramoff. “But it’s more than just an algorithm; it’s a precise imaging system that provides an immediate diagnosis within 30 seconds.” With its feature-recognition-based system, the IDx-DR analyzes images from the Topcon NW400 camera (Tokyo, Japan) to report a positive or negative result. Based on biomarker imaging, the system will yield a result represented as “more than mild diabetic retinopathy” or “negative for mild diabetic retinopathy”. From this information, the participant can then be referred to a specialist or retested in 12 months.

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Leaving DR diagnosis to AI allows more time for treatment and patient consultation.

Current diagnostic practices

The origin of ‘The Retinator’

China, India, and the United States are the top three countries with the highest prevalence of diabetes according to the International Diabetes Federation (IDF). While DR may be slow to develop, it is still largely undiagnosed. “Diabetic retinopathy affects millions of people worldwide as the leading cause of vision impairment and blindness,” said Dr. Abramoff. “Therefore, it is critical to accurately screen for DR for further evaluation by an eye care provider.” Even with the growing need for DR diagnosis, current practices may not be efficient or accurate enough. Many physicians’ processes differ in how they might diagnose an imaging panel. Some studies on screening with wide-angle retinal cameras and imaging interpretation techniques have shown a mere 33% sensitivity. By utilizing treatment-based reference standards, AI technology can produce more accurate results with greater sensitivity.

Dr. Abramoff’s journey in developing IDx-DR started almost 21 years ago. After discovering a need for more efficient diagnostic processes for diabetic retinopathy, Dr. Abramoff decided to focus on perfecting assessment tools for early DR diagnosis. Dr. Abramoff joined the University of Iowa (UI-COMM) Faculty in 2004 and dedicated years to pinpointing algorithms to identify and diagnose diabetic retinopathy. He later founded his AI company, IDx in 2010. Developing IDx-DR was not without obstacles. In fact, when Dr. Abramoff presented his AI proposal to the FDA it was initially returned. As with most experts who go against the grain, Dr. Abramoff had trouble garnering a supportive response. While few people were on board with AI technology in 2010, others were starting to see the true potential of autonomous systems. He was given the name “The Retinator” by the Ophthalmology Times for his AI work in ophthalmology.


Despite setbacks, Dr. Abramoff continued optimizing his algorithms. For instance, one major obstacle of other diagnostic systems included bias from other variables such as age or ethnicity, (i.e. varying retinal tone and color could disrupt an accurate diagnosis). “Bias was always a concern,” explained Dr. Abramoff. “You don’t want an AI system that’s very accurate for one group or race but not for another – you need to deal with it in the design phase. For this reason, we built the IDx-DR to be age or racially invariant. Because subgroups may look different, the system identifies diagnostic lesions and hemorrhages to protect against bias.”

Pivotal trial of an autonomous AI-based diagnostic system In recent years, the FDA has criticized AI technology for its lack of uniform certification in quality and safety. Intensive peer-reviewed studies have since been published, determining the capabilities of AI to amass trust and support for its use. One such study was the clinical trial that tipped the FDA’s decision in favor of approval. In the trial, 900 subjects with diabetes underwent diagnostic testing in primary clinics across the US. The trial used a patient outcome-based reference standard to diagnose patients. Results showed that the autonomous AI-based system exceeded all pre-specified superiority endpoints of sensitivity, specificity and diagnosability to achieve acceptable safety, efficacy and equity. “Clinical trials need to be focused on these three endpoints across different populations,” said Dr. Abramoff. “The AI system needs to be generalizable to ensure proper evaluation of the clinical outcome.” It can be easy to disregard new technologies without sufficient clinical support. But the evidence for the IDx-DR is clear. With refined protocol and training processes, IDx-DR has a proven 96% diagnosability in de novo primary care offices. After testing more than 25 camera types and delivering thousands of exams from minimally trained

operators, Dr. Abramoff’s system has been maximized with assistive AI and advanced imaging analysis. Its ease of use has also proved to be a plus for those specialists looking to enhance current workflows. Specialists can often take weeks or months to finalize a diagnosis. But, with the IDx-DR capabilities, true diagnoses are revealed within minutes. Interestingly enough, the operators of the AI system can be trained in only four hours. In other words, it can even be operated by someone with a high school education. “There was a question of whether we can get a number of high quality images in the primary care setting by someone who is not experienced in diagnostic imaging,” said Dr. Abramoff. “So now with the IDx-DR, it improves workflow with little operator involvement.” This feature also allows for greater accessibility and utilization in lesser developed communities who are in the greatest need of medical care. Especially where a specialist visit can be costly, the system can be quite economical while ultimately decreasing the incidence of blindness.

Will machines take over? One concern that many physicians share is how AI and technology will affect the career landscape. Many physicians who go through years of schooling might not be pleased to find out that a robot can do their job faster while providing accurate results. While systems like IDx-DR are meant to be fully autonomous, they

can also complement the practice of ophthalmology. By utilizing AI technology, physicians can focus more on treatment rather than diagnosis while spending more time on developing crucial relationships with the patient to address any concerns. Because IDx-DR has gone through extensive validation, testing and clinical analysis, it has become a reliable tool in the physician arsenal and the community as a whole.

Future developments for AI systems Dedicated to promoting the benefits of AI based diagnostics, IDx may develop diagnostic algorithms for other parts of the eye. By helping to increase the rate of diagnosis, AI systems can help drive more patients to treatment. When carried out properly, it’s a win-win for both the patient and the physician. Since 2018, the AI system has now been able to produce quick point-of-care results for thousands of patients. Even without a present retinal specialist, the system can provide specialist quality diagnostics in primary care settings. No human review or oversight is needed. Dr. Abramoff and his company are continuing to forge partnerships to increase awareness and accessibility to IDx-DR. Not only is it gaining momentum, but it is also paving the way for favorable public perceptions of AI technology. While the company has plans to distribute it globally, IDx-DR is now being implemented in numerous clinics throughout the US.

About the Contributing Doctor Dr. Michael Abramoff is the Robert C. Watzke, MD Professor in Retina Research at the University of Iowa. He is a retinal specialist, computer scientist and entrepreneur who spent over 20 years researching artificial intelligence and its application in the diagnosis and assessment of retinal disease. Much of his research has focused on identifying signs of diabetic retinopathy. As the founder and president of IDx, Dr. Abramoff developed the first FDA cleared autonomous diagnostic AI system in any field of medicine. He has been awarded multiple honors including the Charles D. Phelps Memorial Award for Glaucoma Research in 2016 and the Young Investigator Award in 2013. Dr. Abramoff has authored over 260 peer-reviewed works, some of which has been cited over 23,000 times. Nicknamed “The Retinator”, Dr. Abramoff is the inventor of more than 15 US and international patents focused in retinal imaging and informatics. [Email: abramoff@eyediagnosis.net]

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ENLIGHTENMENT ANTI-BLINDNESS

Fighting Blindness in Asia by Hazlin Hassan

During a session at the APAO 2019 Congress in Bangkok, Thailand, delegates heard that better access to eye care and earlier intervention can help to reduce blindness. The speakers emphasized that blindness and visual impairment are statistically more prevalent in poorer people living in marginalized and rural areas. To reduce blindness and visual impairment in these groups, ease of access to eye care services can be improved by strengthening public healthcare services.

Punching out preventable blindness “In China, higher medical insurance coverage and better medical care have raised the cataract surgical rates to over 2,000 per million people at the end of 2016 – and enabled better surgical outcomes,” said Professor Ningli Wang from Beijing Tongren Eye Center, Capital Medical University, Beijing Institute of Ophthalmology, during his presentation (which was delivered by a representative). Cataracts are reported to be the primary cause of blindness in China, and increasing numbers of young people suffer from them. While cataract surgical rates in China have been increasing since 2000, Prof. Wang notes that studies have shown that the uptake was only 20-30% in rural China. Some of the barriers included a lack of knowledge about cataracts and cataract surgery, financial constraints (including transportation costs and medical expenses), and concerns about the surgical skills of local ophthalmologists. Many who refused screening were the elderly, less educated and those with no income. However, worsening visual acuity did lead patients to accept free surgery. Prof. Wang explained that basic medical insurance covers 95% of the Chinese population, and a new rural cooperative medical scheme established in 2003 (which targets farmers), covers 99% of rural residents. The 2009 reform of the medical health system also provides higher

30

quality affordable medical care to most Chinese people, including cataract surgery. That same year, the government financially supported the “Free Cataract Surgeries for a Million Poor Patients Project”, which carried out 1.09 million cataract surgeries. As of 2015, there were 36,000 ophthalmologists in China, 36% of whom could perform cataract surgery independently, while 12.2 % could perform phacoemulsification independently. In 2014, over 85% of county hospitals had established an ophthalmology department and 75% of county hospitals could perform cataract surgery independently. Postoperative infection rates for cataract surgeries were 1:3 for urban and rural areas, respectively. In 2014, cataract surgical coverage in China was 62.7% in rural China. This indicates that 4 in 10 SVI cataract patients went without surgical treatment. So, what needs to be done next? “China needs to improve the cataract surgical rate to 8,000 in order to achieve a 95% cataract surgical coverage,” noted Prof. Wang. “More medical funds and cataract surgeons are needed to ensure the sustainability of cataract service.”

Hitting back at diabetic eye disease On the other hand, in the developed city state of Singapore, health providers succeeded in shortening screening times, while cutting costs and optimizing

uptake of care for diabetic eye diseases. “Diabetic eye diseases such as diabetic retinopathy (DR) and macular edema (DME) are among the most common visual complications of diabetes and are leading causes of visual impairment in working-aged adults,” said Professor Ecosse Lamoureux, the director at Population Health, Singapore Eye Research Institute (SERI). The global prevalence of DR among individuals with diabetes is 34.6% and is projected to increase from 126.6 million in 2011, to 191 million by 2030. He noted that the age-standardized DR prevalence among Singaporeans by ethnicity were 30.7%, 26.2% and 25.5% in Malays, Indians and Chinese with diabetes, respectively. Corresponding DME estimates were 9.5%, 6.15% and 5.7%. In those aged 65 and above, the prevalence rates for DR and DME were around 33 and 14% respectively. “DR and DME have a substantial impact on patients, on visual functioning and quality of life, particularly at the vision-threatening stages,” said Prof. Lamoureux. “There tends to be disruption of family functioning, relationships and roles, increased social isolation and dependence, deterioration of work prospects, and increased financial strain. Patients also experience fear, anxiety, vulnerability, guilt, loss of confidence, anger, stress and poor selfperception,” he added. Common risk factors for diabetic eye diseases include diabetes, hypertension, stroke and cardiovascular disease. “There


is a high level of unawareness, with almost 80% of those with DR unaware they have the condition. Strategies should be focused on tackling classic risk factors for diabetes and improving literacy,” noted Prof. Lamoureux. Further, he shared details from the successful Singapore Integrated Diabetic Retinopathy Programme (SiDRP), which was set up to improve traditional diabetic retinopathy (DR) screening. The national screening program for DR covered around 100,000 to 120,000 persons with diabetes in 19 polyclinics across Singapore. Digital retinal photos were taken via a tele-ophthalmology platform with photos read centrally by non-physician technicians. Reports were then sent back to clinics on the same day with 95% being sent in less than an hour, resulting in a reduced grading time of 165,806 reports within one hour to one day, with high accuracy. Previously, DR screening models in Singapore were comprised of ad hoc screenings at government polyclinics and GPs where the turnaround time to grade retinal photos took up to four weeks. The SiDRP also has financial benefits as it can save up to S$173 per person. For the approximately 170,000 patients with diabetes screened yearly, an estimated S$30 million could be saved. However, several challenges remain due to limited sustainability or manpower resources for the screening of DR. The solution would be the development of a deep learning system for DR and related eye diseases using retinal images from multiethnic populations with diabetes. He added that some 40% of those with diabetes in Singapore suffer from microvascular complications such as DR nephropathy and foot complications. Annual screening and early intervention are crucial to prevent morbidity from these complications. High rates of non-adherence show 50% of persons with diabetes do not attend annual eye re-screenings. Diabetic eye conditions and associated vision loss are highly prevalent in Singapore, especially among those aged over 65.

“The effects are expected to worsen rapidly as Singapore transitions to an aged society over the next decade. Several models of care are needed to address this public health problem, including national and community-level screening and intervention models,” he said. “Progress has been made but many inherent challenges remain, which may be addressed by DR-specific literacypublic health education programs at schools, workplaces, community centers, as well as holistic and coordinated screening, and care models.”

Slap down myopia with screenings In addition, high rates of myopia in the region and uncorrected refractive errors could be overcome by the availability and accessibility of eye care services and public awareness. “The prevalence of myopia in Singapore is 83%, while in Japan, Taiwan and Hong Kong the rate is 70%. It’s 55% for Europe; 20% for Australia and the United States; and just 10% for Nepal,” said Professor Seang-Mei Saw, head of the Myopia Unit at the Singapore Eye Research Institute (SERI). Some 68% of low vision is caused by uncorrected refractive errors. According to the Beijing Study of Visual Impairment in Children, of 17,699 patients aged 3 to 6 years, some of the causes for low vision were refractive error, congenital motor nystagmus, amblyopia and congenital cataracts.1 For patients with uncorrected refractive errors and low vision, the plan should be to increase the uptake of spectacles or contact lenses and optimize correction. Strategies to combat uncorrected refractive errors include the availability and accessibility of eye care services, as well as educating the public on the need for regular visits to the optometrists

to update spectacles – especially in children where myopia continues to progress. Vision screening in schools is useful, as well as the affordability of glasses and low vision optical devices.

A knock-out combo for PCV “A study2 has shown that combination therapy outcomes are better than monotherapy for polypoidal choroidal vasculopathy (PCV),” said Dr. Kelvin Teo, consultant for the Medical Retina Department at Singapore National Eye Center (SNEC). PCV, which primarily affects the vascular layer of blood vessels in the choroid, damages the overlying retina where the photoreceptor cells responsible for vision are located. Patients with PCV often experience blurred vision or a blind spot in or near the center of their vision in one or both eyes. “Initial studies suggest that PCV did not seem to respond well to antiVEGF monotherapy,” Dr. Teo said. To see if combination therapy would be a more effective solution, a randomized clinical trial to determine the efficacy and safety of ranibizumab with or without verteporfin photodynamic therapy (PDT) for PCV was conducted. Practitioners located in Australia, New Zealand, Switzerland and Singapore contributed the data for the study. “The results of the study2 showed that combination therapy outcomes are better than monotherapy for PCV in a real-world cohort for vision, lesion activity and treatment burden,” concluded Dr. Teo. Editor’s Note: The APAO 2019 Congress was held in Bangkok, Thailand, on March 6-9, 2019. Reporting for this story also took place at APAO 2019. Media MICE Pte Ltd, PIE Magazine’s parent company, was the official media partner at APAO 2019.

References: Lu Q, Zheng Y, Sun B, et al. A population-based study of visual impairment among pre-school children in Beijing: the Beijing study of visual impairment in children. Am J Ophthalmol. 2009;147(6):1075-1081. 2 Chong Teo KY, Squirrell DM, Nguyen V, et al. A Multicountry Comparison of Real-World Management and Outcomes of Polypoidal Choroidal Vasculopathy: Fight Retinal Blindness! Cohort. Ophthalmol Retina. 2019;3(3):220-229. 1

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ENLIGHTENMENT WOMEN IN OPHTHALMOLOGY

For the Love of

the

Retina Medical College, and subsequently moved to Chandigarh for her residency at the Post-Graduate Institute of Medical Education and Research (PGIMER), a prominent medical and research institution in India. “I was fortunate to have Prof. Amod Gupta as my guide and mentor who introduced me to the beautiful world of retina and uveitis that I continue to cherish today. After residency, I continued my journey at PGIMER, Chandigarh, as a senior resident and then presently as member of the faculty,” she said. Dr. Gupta shared that she chose to work in the medical field because it gave her the opportunity to have not only an academic career, but also to serve people in need: “I practice in a tertiary care, government-funded hospital because I genuinely enjoy working in an environment that promotes ethical clinical practice. It also gives me the chance to serve society, carry out R&D, help the government in several initiatives, and above all, teach and train the next generations to be not only future leaders in the field, but also show empathy and sympathy towards each and every patient that comes to them.”

by Tan Sher Lynn

F

or Prof. Dr. Vishali Gupta, the retina is what prompted her to become an ophthalmologist. After graduating from medical school, she attended a research project on diabetic retinopathy – and there, she saw fundus pictures and fluorescein angiograms for the first time and was fascinated by the images.

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Early years Dr. Gupta hails from Jammu, a small city in the northern part of India. Her childhood was simple and she grew up in an atmosphere filled with love and support from her parents, siblings, cousins and friends. After graduating from high school, she completed her medical school training at Jammu

Breakthrough in ocular TB Intraocular infections and inflammations in ocular tuberculosis (TB) have always been Dr. Gupta’s special interest. Back in 1998, and under the guidance of her mentor Prof. Amod Gupta, Dr. Gupta was analyzing patients with serpiginous choroiditis when they realized that nearly all of them were having recurrences


on systemic corticosteroids and immunosuppressive therapy. “This response to corticosteroids and immunosuppressants made us look for a specific cause – and in 2003, we for the first time, reported an association between serpiginous choroiditis and tuberculosis. To further strengthen our hypothesis, we observed that use of anti-TB treatment helped in reducing these recurrences to less than 10 percent. This work was accepted globally and in the current scenario, all patients with serpiginous-like choroiditis are investigated for underlying TB as a cause,” she shared. One major achievement in the field has been to bring together a group of nearly 81 experts from 25 centers in the field of uveitis from all across the globe to form the Collaborative Ocular TB Study (COTS) group, where they publish real world data on the diagnosis and management of ocular TB along with standardizing the nomenclature for ocular TB. In addition, the group developed expert consensus guidelines on initiating anti-TB treatment in ocular TB to convince internists across the globe to start anti-TB therapy in cases of ocular manifestations of the disease, which can be pulmonary inactive. Research aside, Dr. Gupta also held the post as secretary of the VitreoRetinal Society India (VRSI) from 2014 to 2016. VRSI is an exclusive group with over 90 percent of India’s actively practicing vitreo-retina specialists participating as life members. “VRSI is a wonderful society that has been like a family to most of us. I am really thankful to Prof. Mangat Dogra and Dr. Ajit Babu Majji for showing their faith in me and offering me the position of secretary. After 2016, I continued as chair of the scientific committee for the next two years during which we tried to raise the bar for VRSI. I am proud to say that currently VRSI is one of the best and largest retina meetings in the world,” she said.

Family life

Fearless femininity

Dr. Vishali Gupta is happily married to her classmate from medical school, Dr. Rajesh Gupta, a renowned professor in surgical gastroenterology. They have a daughter named Sarakshi. “My husband and I both worked together for our entrance exam to get residency. We got our residency, senior residency and faculty position together in the same institution,” she reminisced. “Our daughter kind of grew up in an academic atmosphere. Since childhood, she has traveled with me to conferences. She is currently pursuing her internal medicine residency in the U.S. and wishes to build a career in academics in the field of hematologyoncology and precision medicine. Both my parents and in-laws have always been extremely supportive of my career. I feel blessed to have family, friends and colleagues who have helped me at every stage of my personal and professional life,” she said. During her free time, Dr. Gupta loves to go hiking, traveling, watching movies, cooking, shopping and catching up with friends. She also enjoys going to the spa and relaxes by simply doing nothing.

Dr. Gupta believes that female ophthalmologists are able to excel in their chosen field as long as they set their heart on it. “I was fortunate to have very secure and well-established mentors like Prof. Amod Gupta and Prof. Dogra, who supported and promoted me without any hesitancy. However, I do hear my junior retina faculty members mentioning that they want more men colleagues in the field of retina, which only shows their insecurity as surgeons and researchers. In my department at PGIMER, I have noticed that all women faculty members are much more prominent and established than most men, so I do not let these issues deter me. Personally, I feel that the common goal of all physicians should be to promote better healthcare and research practices irrespective of gender,” she asserted. To women practicing in ophthalmology, she has one bit of advice: “Let no one come in your way. You are the best. Just keep moving forward and grab what is rightfully yours.”

Personally, I feel that the common goal of all physicians should be to promote better healthcare and research practices irrespective of gender.

About the Contributing Doctor Prof. Dr. Vishali Gupta is an accomplished vitreo-retina and uvea expert of international repute working at the Post-Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. She has keen interest in the inflammation and infections of the eye and has a lot of original work on intraocular tuberculosis, fungal infections and diabetic retinopathy. She is a sought-after speaker and has delivered more than 870 invited lectures and conducted several instruction courses at various international and national meetings. She has more than 200 publications in peer-reviewed journals; has edited five books and contributed 72 book chapters in textbooks. She is the secretary of the International Uveitis Study Group, and member of the American Academy of Ophthalmology, Club Jules Gonin and The Macula Society. She is currently the president of the Uveitis Society of India. She has received several named awards and also holds a US patent for multiplex PCR. Dr. Gupta is a member of PIE Magazine’s Advisory Board. [Email: vishalisara@yahoo.co.in]

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CONFERENCE HIGHLIGHTS APAO 2019 COVERAGE

Oculoplastic Conditions and Current Strategies in Practice by Gerardo Sison

Advances in the oculoplastic techniques have emerged to treat an array of conditions affecting the orbit, eyelids, tear ducts and face. Experts shared their own experiences with current oculoplastic practices at a symposium held at the 34th Congress of Asia-Pacific Academy of Ophthalmology (APAO 2019) in Bangkok, Thailand. Their methods were developed to address several conditions that arise in practice, such as the management of trigeminal nerve hypesthesia and recurrent conjunctival hyperemia.

Based on a presentation titled, “Trigeminal Nerve Hypesthesia: A Sign of Bad Things” by Dr. Daniel Rootman, assistant professor from Jules and Doheny Eye Institutes.

that it’s important to keep awareness up in evaluating cranial V palsies. Otherwise, it could be a sign of bad things to come.

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Based on a presentation titled, “Sebaceous Cell Carcinoma: The Big Picture” by Dr. Weerawan Chokthaweesak, Faculty of Medicine at Ramathibodi Hospital.

rigeminal nerve hypesthesia is characterized by a postoperative loss of sensitivity, partially affecting the corresponding nerve. According to Dr. Daniel Rootman, this may be a sign of severe, often occult and potentially fatal disease. Therefore, testing for numbness is critical in orbital evaluation. “Obstacles in assessing trigeminal nerve hypesthesia can be found in larger nerves and more unmyelinated fibers,” reported Dr. Rootman. “Redundancy in the nerve also means clinical impact is not as noticeable. This can lead to less common occurrences and assessments for this particular condition.” While less commonly presented in oculoplastics, trigeminal nerve hypesthesia tends to be severe when it does occur. This is because clinical symptoms do not usually appear until greater damage has already been done. It also tends to be more subject to perineural spread due to a greater number of nerve endings versus motor nerves. Severity was exemplified by a greater than 50% mortality rate in Dr. Rootman’s case series. He concluded

S

ebaceous cell carcinoma is an uncommon, malignant tumor that occurs in the eyelid and can often be deadly. Without correct diagnosis and proper treatment, sebaceous cell carcinoma can lead to poorer outcomes. Therefore, as recommended by Dr. Chokthaweesak, it is important to first differentiate malignant from benign tumors with a proper biopsy. “Malignant lesions often tend to outgrow their blood supply with distortions in normal eyelid architecture,” stated Dr. Chokthaweesak. “What may look like a chalazion can often appear benign on the outside. However, it is always important to look inside the eyelid and obtain a biopsy if any doubt or suspicion arises.” Dr. Chokthaweesak further discussed performing a full-thickness eyelid biopsy where a permanent section is required for the correct diagnosis.

Sebaceous cell carcinoma commonly presents in the elderly. In the young, however, sebaceous cell carcinoma is clinically associated with Muir-Torre Syndrome (MTS), a rare disorder with sebaceous neoplasia and visceral malignancy. Overall, Dr. Chokthaweesak reinforced correct diagnosis, proper investigation and prompt treatment especially in cases that may need more clarification.

Based on a presentation titled, “Recurrent Conjunctival Hyperemia with Ptosis as Symptoms of Systemic Amyloidosis” by Dongmei Li, professor at Beijing TongRen Eye Center.

A

myloidosis is a disorder of protein folding in which normally soluble protein fibrils are deposited as insoluble amyloid protein fibrils within the extracellular tissues. It can be defined as localized (specific organs and tissues) or systemic (widespread effects). “This can lead to conjunctival amyloidosis which can present with hyperemia, bumpy ptosis, proptosis, and infiltration and diffusion,” as experienced by Dr. Li. Orbital amyloidosis is almost always localized. According to her case study, Dr. Li stated that only 6% of

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CONFERENCE HIGHLIGHTS APAO 2019 COVERAGE cases exhibited systemic disease which can often lead to serious complications and poor prognosis. “For this reason, a histological diagnosis of amyloidosis should prompt further investigation to exclude systemic involvement,” explained Dr. Li. In one of her cases, a patient showed recurrent conjunctival congestion and prolapse for six years with ptosis that worsened for four years. She reported that excision of papillomatous conjunctival lesion and left levator resection and advancement was critical for her patient case. Dr. Li advised debulking of the amyloid and debriding deposits while making sure to respect the tissue planes and preserve eyelid tissue.

Based on a presentation titled, “Challenging Conventions: Do Dermal Fillers Even Have A Role in Orbital Disease?” by Dr. Tomoyuki Kashima, Head Director of Oculo Facial Clinic in Tokyo.

F

iller injections for the periorbital region are often used for eyelid scars, expansion, and volume increases. While various methods have been developed for different conditions, Dr. Tomoyuki presented his case series for the use of dermal fillers. In his own practice, he mentioned the use of hyaluronic acid gel injections due to its reversibility and fewer complications. Dermal fillers were successfully implemented in the correction of eyelid ectropion after a facial burn for one patient. Another case showed that visual acuity was even improved in the treatment of an upper eyelid retraction after reconstruction following sebaceous carcinoma. One patient with a facial burn just after birth with lower eyelid ectropion experienced improved function and appearance after injection. Another 70-year-old patient with facial nerve palsy was given filler injection for synkinesis. “She was given a filler injection which yielded improvements in asymmetrical facial

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expression and reduced overacting muscles,” reported Dr. Kashima. “The shape of her mouth was more symmetrical after injection.” Dr. Tomoyuki concluded that dermal filler injection to the periorbital area is effective for changing the contour of the upper eyelid, lower eyelid, and overall facial expression. Because the filler injection is easy, fast and cheap compared with surgery, it is useful for both patients and doctors.

Based on a presentation titled, “Is This Orbital Inflammation… Or Something Else?” by Dr. Morgan Yan, from the Singapore National Eye Centre.

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rbital inflammation is a descriptive term but makes no reference to the underlying disease process. This can often raise questions of whether there is true inflammation or something else occurring. Additionally, there is also the question of what may be causing the inflammation. When the inflammatory picture is more aggressive in appearance, Dr. Yan advised to always think of an infective process. “Orbital cellulitis is commonly mistaken for conjunctivitis with an accompanying viral flu accounting for fever in children,” explained Dr. Yan. “This is because symptoms in children can often be less florid and more atypical.” He also mentioned that specialists should also keep in mind the possibility of community acquired MRSA, which can prove to be quite resistant. Pitfalls in orbital cellulitis include awareness of atypical organisms and a less “angry-looking” clinical pictures in children. In cases of “pseudotumors”, it is important to always biopsy when in doubt, exclude malignancy, and be wary of concurrent pathologies, according to Dr. Yan. She concluded her discussion with recommendations to construct a list of differentials after careful clinical evaluation.

Based on a presentation titled, “Unusual Caruncular Mass Lesions” by Dr. Rajendra Maurya, assistant professor of ocular oncology and oculoplasty at Banaras Hindu University, Varanasi, India.

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aruncular neoplasms are rare despite their diverse histological composition. As stated in Dr. Maurya’s experience: “Ninety-five percent of caruncular mass lesions are benign while the other 5% of biopsied caruncular mass lesions end up malignant.” Caruncular epithelial inclusion cyst is a common condition where small lesions are usually asymptomatic. However, observation, monitoring and surgical excision are recommended by Dr. Maurya. “Lobular capillary hemangioma is usually seen in early childhood with spontaneous regression being reported in some cases.” He also recommended watching out for hemangioma which can present as a diffuse, soft, cherry red mass, adherent to the globe in left caruncular area. Caruncular mass lesions are rare although diagnosis is difficult in pre-malignant and malignant cases. However, most cases are benign in nature. Papilloma, hemangioma and nevus account for the majority of benign tumors, while sebaceous cell carcinoma is the most common caruncular malignancy. Some caruncular malignant lesions have a benign aspect, hence the need for careful monitoring, close photographic follow-up and early complete excision when necessary. Editor’s Note: The APAO 2019 Congress was held in Bangkok, Thailand, on March 6-9, 2019. Reporting for this story also took place at APAO 2019. Media MICE Pte Ltd, PIE Magazine’s parent company, was the official media partner at APAO 2019.


The 35th Congress of Asia-PaciďŹ c Academy of Ophthalmology in conjunction with

The 25th Congress of Chinese Ophthalmological Society

Celebrating our Diamond Jubilee (1960~2020)

(852)3943-5827 secretariat@apaophth.org http://2020.apaophth.org/ HOSTS:


CONFERENCE HIGHLIGHTS ARVO 2019 COVERAGE

-VEGF Battle Royale Anti SCORE2 and LEAVO Results Reveal the Winners

by Brooke Herron

B

y targeting neovascularization and edema, intravitreal antiVEGF injections are rapidly becoming a first-line therapy for certain posterior segment conditions like central retinal vein occlusion (CRVO). And as such, there are now a variety of anti-VEGF formulations to choose from like aflibercept, ranibizumab and bevacizumab. At the recent Association for Research in Vision and Ophthalmology (ARVO) Congress in Vancouver, Canada, delegates gathered to hear results from the recent Phase III SCORE2 and LEAVO noninferiority trials, both of which compared different anti-

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VEGF agents as treatment for macular edema secondary to CRVO. Both of the government-sponsored SCORE2 and LEAVO trials have similar characteristics, including a 5-letter inferiority margin and a primary outcome of mean change in visual acuity (VA) letter scores (VALS) from baseline. However, there are also differences between the two, including treatments used, that provide complementary and additive details. According to SCORE2 Study Chair Dr. Ingrid Scott, a professor of ophthalmology and public health sciences at Penn State College of Medicine (Pennsylvania, USA),

the results of these trials will assist clinicians in selecting the type, frequency and duration of treatment for their patients.

SCORE2: The first six months Although aflibercept is FDA approved for the treatment of macular edema due to CRVO, bevacizumab is often used off-label due to cost – despite a lack of supporting evidence. Therefore, SCORE2 investigated whether bevacizumab was noninferior to aflibercept in treating this condition. SCORE2 included 362 patients with macular edema due to central retinal or hemiretinal vein occlusion,


who were randomized 1:1 to receive either intravitreal injections of bevacizumab (1.25 mg; n = 182) or aflibercept (2.0 mg; n = 180) every 4 weeks through month 6. At month 6, the primary outcome of mean change from baseline in VALS between groups was assessed: The bevacizumab arm VALS was 69.3 (a mean increase from baseline of 18.6); the aflibercept arm VALS was also 69.3 (a mean increase from baseline of 18.9). This led the investigators to conclude that at month 6, bevacizumab was noninferior to aflibercept based on a VALS margin of 5. In addition, both groups showed statistically significant SD-OCT central subfield thickness (CST) decreases from baseline through month 6. These results led investigators to conclude that, “among patients with macular edema secondary to central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept with respect to VA after 6 months of treatment”.

Among patients with macular edema secondary to central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept with respect to VA after 6 months of treatment.

Keeping Score: From months 6 to 12 According to SCORE2 Co-Chair Dr. Michael Ip, at six months eyes were divided into having had either a good or poor response to initial therapy. This was based on a defined protocol that relied on VA and OCT and that was followed until month 12. “Eighty-four percent (84%) fell into the good responding group, versus 16% for the poor response group,”

said Dr. Ip, who is a professor in the department of ophthalmology at the David Geffen School of Medicine at the University of California Los Angeles. Eyes in both groups with a good response were re-randomized to continue treatment with the originally assigned drug, either on a monthly or treat-and-extend (T&E) basis. Those with a poor response were changed to an alternate treatment. “From baseline to month 5, there was excellent adherence to the treatment protocol in both the aflibercept and bevacizumab monthly arms, with both receiving a mean monthly 5.8 injections,” said Dr. Ip. In the good responder groups, from months 6 to 12, the monthly aflibercept group received 5.8 injections and the T&E group received 3.8. In the bevacizumab treated eyes, the monthly group had 5.8 injections, versus 4.5 for T&E – which was statistically significant. From months 6 to 12, there were no statistically significant differences in VALS between the monthly and T&E regimens in both arms, and no meaningful difference in OCT central subfield thickness between groups. So, what about those who responded poorly? Few eyes met the protocol for a “poor response” definition. Fifteen eyes that responded poorly to aflibercept were reassigned to receive intravitreal dexamethasone implant treatment. The 39 eyes in the poor responding bevacizumab group were reassigned to aflibercept. “In the bevacizumab group, there was an immediate rise in visual acuity from months 6 to 9 when switched to aflibercept . . . and this stayed stable up to month 12,” said Dr. Ip, noting that there was no difference in the aflibercept group’s VALS after treatment with dexamethasone. He continued: “In the aflibercept poor response group, there was no change to central subfield thickness. In distinction, those in the bevacizumab group, when switched to aflibercept, had an immediate reduction in residual edema which stayed stable up to month 12.”

SCORE2: Months 12 to 24 During the first 12 months of the SCORE2 trial, participants followed a protocol designed treatment schedule. However, after month 12, there was no treatment protocol and physicians could treat participants at their own discretion, using any commercially available drug (or no drug). At month 12, 330 (of 362 enrolled) participants completed the SCORE2 study and were targeted for month 24 follow-up. Of those, 236 of the original cohort completed a visit at month 24 (called ‘completers’), with similar retention among both the aflibercept and bevacizumab groups. “What we see from months 12 to 24 translates to between 3-4 injections per participant during that time period,” explained Dr. Scott, noting that about a quarter of completers received no treatment from months 12 to 24. “Among the remainder, the mean number of treatments between months 12 to 24 was 3.6 in the aflibercept group and 4.5 to those originally assigned to bevacizumab.” How did VALS fare? In both groups VALS improved significantly during the first six months, when patients received monthly treatment. There was a much smaller improvement from months 6 to 12, when the groups were randomized to continue monthly or T&E. However, between months 12 to 24, when there was no treatment protocol, VALS worsened in both groups – although they were still significantly better than baseline. Dr. Scott said that similar results were observed in CST: “Central subfield thickness improved significantly in the first six months in both groups. Between months 6 and 12 when they were randomized, there was a much smaller improvement in CST in the bevacizumab group, and a small worsening in CST in the aflibercept group. Between months 12 and 24, CST worsened in both groups – although the CST at month 24 was still significantly better than at baseline.” Overall, these results led investigators to conclude that with

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CONFERENCE HIGHLIGHTS ARVO 2019 COVERAGE Results of SCORE2 indicate the chronic nature and variability in disease course in CRVO and HRVO. This in turn points out the importance of continued monitoring and individualized treatment to optimize visual acuity outcomes.

respect to VALS and CST, participants improved significantly compared from baseline to month 6 (the period of monthly injections). There were lesser improvements from months 6 to 12 when half of the good responders were treated according to a T&E regimen; and worsened outcomes when patients were treated by investigator discretion and fewer treatments were received. “The outcomes worsened more notably in those patients who received no treatment from months 12 to 24. Nonetheless, month 24 outcomes were significantly better than at baseline,” explained Dr. Scott. “Results of SCORE2 indicate the chronic nature and variability in disease course in CRVO and HRVO. This in turn points out the importance of continued monitoring and individualized treatment to optimize visual acuity outcomes,” she said. “We will continue to follow participants out to five years to continue to collect outcome information.”

The LEAVO Clinical Trial LEAVO is a multi-center, Phase III, double-masked, randomized, controlled, noninferiority trial comparing the clinical and cost-effectiveness of intravitreal therapy with ranibizumab versus aflibercept and bevacizumab for macula edema due to central retinal vein occlusion. When the LEAVO study occurred in 2014, ranibizumab was the only UK-licensed treatment for CRVO at that time – and therefore it became the comparator versus aflibercept and bevacizumab, which were unlicensed and considered to be the investigative interventions within the trial protocol.

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According to Dr. Philip Hykin a consultant ophthalmologist at Moorfields Eye Hospital, the primary objective was to compare the clinical effectiveness, side effect profile and relative cost effectiveness of the three selected anti-VEGF agents. The study randomized 463 patients with macular edema due to CRVO, with the primary endpoint in best corrected visual acuity from baseline to 100 weeks in the study eye of all participants. “There were mandated visits at weeks 4, 8 and 12,” said Dr. Hykin. “Then PRN (pro re nata or as needed) injections at weeks 16 and 20. Following that, we went to 4 to 8 weekly visits with PRN injections, going to 8 weekly if stability was met.” “The best corrected ETDRS visual acuity at baseline was approximately 54 letters across arms,” said Dr. Hykin, noting that 87.9% of patients completed the 100-week analysis. The mean gain in BCVA at 100 weeks was 12.5 letters for the ranibizumab group, 15.1 for aflibercept and 9.8 for bevacizumab. “Looking at the primary outcome, during the initial phase of the study there was a rapid improvement in vision with mandated injections,” he said. “With the early PRN injection phase at 16 and 20 weeks, there was a small decrease in visual acuity . . . and out to 100 weeks visual acuity remained relatively stable.” At 100 weeks, the difference between ranibizumab and bevacizumab was -1.73 letters, falling above the noninferiority scale of -5 letters, therefore bevacizumab was noninferior to ranibizumab. Between aflibercept and ranibizumab, the difference was +2.23 letters in favor of aflibercept; making it noninferior to ranibizumab, but not superior. “The post hoc analysis of aflibercept versus bevacizumab at 100 weeks was -3.96 letters, below the preset noninferiority margin of -5 letters,” said Dr. Hykin. These results led the investigators to conclude that compared to baseline, aflibercept, bevacizumab and ranibizumab substantially improved and maintained

VA up to 100 weeks, however they do not support bevacizumab as interchangeable for treating macular edema due to CRVO in the longer term. For OCT CST across study arms at 100 weeks, there was a decrease in thickness initially during the injection mandated phase, a slight increase during the PRN phase (that was consistent and mirrored well the VA data) and then slowly decreased again out to one hundred weeks. Differences at 100 weeks were not statistically significant. The number of injections per treatment arm was significantly less for aflibercept at week 100 (-1.8), at week 52 (-1.1) and at week 24 (-1.4). Dr. Hykin summarized: “For the management of macular edema due to CRVO, ranibizumab, aflibercept and bevacizumab provided substantial and sustaining proof of visual acuity throughout the study. At least eight weekly follow-ups and prompt treatment in the second year maintained first year visual acuity gains and no huge safety concerns were identified.” “In conclusion, in the UK, for routine treatment of ME due to CRVO, these data support that the EMA (European Medicines Agency) license medications aflibercept and ranibizumab for syndication, and do not support bevacizumab for being interchangeable for this indication,” concluded Dr Hykin. Editor’s Note: The ARVO 2019 Congress was held in Vancouver, Canada, from April 28 to May 2. Reporting for this story also took place at ARVO 2019.

In conclusion, in the UK, for routine treatment of ME due to CRVO, these data support that the EMA (European Medicines Agency) license medications aflibercept and ranibizumab for syndication, and do not support bevacizumab for being interchangeable for this indication.


CONFERENCE HIGHLIGHTS ASCRS 2019 COVERAGE

Posterior segment posters stand out at ASCRS.

Highlights of Retina Posters at

ASCRS 2019 San Diego

by Olawale Salami

W

hile the annual meeting of the American Society of Cataract and Refractive Surgeons (ASCRS) mainly deals in anterior segment topics, there’s a small section on the posterior segment too. Here are some of the highlights of the retina posters at the recent ASCRS 2019 in San Diego that caught our attention . . .

Vitreolysis lasers need to be cool too! “Using a laser system equipped with an active air-cooling module would be advantageous when performing procedures that require a large number of shots, such as laserbased floater treatment of YAG laser vitreolysis.” - Dr. Paul Singh Pulsed Nd:YAG lasers feature a solid-state cavity design that is precisely tuned. A key element of pulsed Nd:YAG laser’s cavity design is the establishment of precisely

aligned internal mirrors – and this is where maintaining consistent cavity temperature becomes critical. At the recent ASCRS 2019 San Diego, Dr. Paul Singh shared key insights into important considerations related to thermoregulation and stability of energy delivery during vitreolysis. According to Dr. Singh, vitreolysis treatment requires multiple laser shots, causing the heat of the flash lamp to be absorbed into the metal and glass components of the solid-state cavity. This leads to a slight change in the alignment and characteristics of the laser pulse emitted by the cavity. In order to moderate the negative effects associated with heat buildup, traditional pulsed cavity design relies on ambient cooling and a limited assumption of shots required in a given time frame. This ambient cooling method of heat dissipation in turn puts a limit on treatment effectiveness, cavity longevity and treatment stability – all of which come with inherent risks to treatment outcomes.

An active air-cooled cavity adds a closed loop cooling system to the flash lamp, and this dissipates the heat before it has an opportunity to soak into the solid-state cavity. In addition, this method allows more rapid shot placement, reduced treatment times, increased system stability and arguably, increases cavity longevity. Each of these benefits adds to the safety and efficacy of selective laser trabeculoplasty (SLT) and vitreolysis treatments. Vitreolysis requires a higher number of shots than a YAG capsulotomy. Previous studies by Dr. Singh and colleagues demonstrated that average number of laser shots to sufficiently vaporize floaters amorphous clouds was 568. With so many shots fired Dr. Singh asked: “Does the delivery of energy stay the same throughout the entire procedure? Will the laser need to cool down during the procedure to stabilize the delivery of energy?” Dr. Singh then evaluated if the air-cooling cavity reduces and/or

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CONFERENCE HIGHLIGHTS ASCRS 2019 COVERAGE stabilizes the delivery of energy emitted over a few hundred shots from a newly designed Q -Switched Nd:YAG laser. A test system was set-up using a 1064nm, Q-Switched Nd:YAG laser with an air-cooling module (Ultra Q Reflex, Ellex, Adelaide, South Australia). The system was set to deliver 2.0mJ per shot and 300 shots fired with the air-cooling enabled. Next, the system was turned off for 30 minutes, the air-cooling module was disabled, and a second round of 300 shots was fired. Actual energy delivered with each shot was recorded. With the active air-cooling enabled and 300 shots fired at 1 shot per second, the range of energy recorded was 1.99-2.44mJ, with a standard mean deviation of 3.53%. However, with the active air-cooling disabled, 300 shots fired at 2.0mJ, the energy range increased to 1.85-2.93 mJ with a standard mean deviation of 10.05%. Dr. Singh observed: “With active air-cooling disabled in the Ultra Q Reflex laser, the actual energy delivered increased up to 46.5% from the selected 2.0mJ to 2.93mJ. This increase was well outside standard safety tolerances.” Dr Singh concluded that active air-cooling of the laser cavity can help to maintain a stable range of energy delivery over hundreds of shots. In addition, he emphasized that using a laser system equipped with an active air-cooling module would be advantageous when performing procedures that require a large number of shots, such as laser-based floater treatment of YAG laser vitreolysis.

Beat the heat with an active air-cooling cavity for pulsed Nd:YAG lasers.

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Ocular syphilis and HIV: Here’s what you need to know “With proper identification and adequate treatment with IV penicillin, ocular syphilis can have equivalent visual outcomes regardless of the severity of the concomitant HIV.” - Dr. Mariam Mathai Syphilis is out there. It’s sexually transmitted and caused by the spirochete bacterium Treponema pallidum. Lately, there’s been an upsurge in the incidence of syphilis in the United States, particularly among HIV positive patients. Ocular syphilis is rare, and it typically occurs with secondary or tertiary syphilis. Studies have shown that the progression of syphilis to more advanced stages is faster among patients with HIV infection. In a paper presented at the recent ASCRS 2019 meeting, Dr. Mariam Mathai and colleagues at the MedStar Georgetown Washington Hospital Center, shared results of their study in which they evaluated whether uncontrolled HIV has an effect on visual outcomes in immunocompromised patients diagnosed with ocular syphilis. The investigators conducted a retrospective chart review on patients diagnosed with ocular syphilis between August 2017 and June 2018. Diagnosis of ocular syphilis was made via the clinical identification of uveitis, retinitis or optic neuritis on ocular exam, and was supported by laboratory serum RPR, FTA-Abs and/ or CSF VDRL. Six patients (twelve eyes) were identified during this period, all of whom were found to be HIV positive. Visual acuities at presentation and after two weeks of treatment with intravenous (IV) penicillin were recorded. The patients were then stratified based on absolute CD4 count (<200 cells/uL vs. >200 cells/uL) and HIV viral load (<500 copies/mL vs. >500 copies/mL). The data was analyzed using a Wilcoxon signedrank test, comparing visual acuities at presentation and at the end of treatment between patients with

controlled and uncontrolled CD4 count and viral loads. Of the six patients in the cohort, three knew of their HIV positive status prior to presentation, and two of those patients were on antiretroviral therapy. All patients were male with an average age of 28.8 years. Four identified as African American, one Hispanic and one Caucasian. Eightythree percent (83%) reported their sexual orientation as men who have sex with men (MSM). Dr. Mathai noted that all study patients presented to the clinic because of the development of ocular symptoms, and they did not have any other symptoms compatible with primary, secondary or tertiary syphilis. Additionally, 100% of eyes in this study had posterior segment involvement, emphasized Dr. Mathai. This tendency has been previously reported in literature. Visual recovery of at least one Snellen acuity line was seen in all affected eyes. According to Dr. Mathai, there was no statistical difference in visual acuity at presentation or after treatment in patients with lower CD4 counts or higher viral loads, suggesting that “with proper identification and adequate treatment with IV penicillin, ocular syphilis can have equivalent visual outcomes regardless of the severity of the concomitant HIV”.

Catching DR early with fractal dimension and OCTA “Fractal dimension is a useful method for differentiating diabetic retinopathy.” - Dr. Harrison Chiu Diabetic retinopathy (DR) is a primary cause of visual impairment worldwide, and may be associated with ophthalmoscopically nonvisible neurovascular damage that progresses before the first clinical signs of DR appear. Therefore, there is an urgent need to develop highly sensitive screening tools. Vascular abnormalities such as changes in the retinal vessel caliber and architectural indices have been investigated to evaluate the early stages


of DR. Dr. Harrison Chiu and colleagues evaluated the effect of varying parameters in determining fractal dimensions (FD) of macular optical coherence tomography angiography (OCTA) images and its role in differentiating microvascular differences between normal and diabetic eyes. Their findings were presented at the recent ASCRS 2019 meeting. The investigators conducted a retrospective study using OCTA images of 3x3mm and 6x6mm scans for superficial and deep capillary plexuses from 49 control eyes and 58 eyes with diabetic retinopathy. ImageJ (a Java-based image processing program developed at the U.S. National Institutes of Health and the Laboratory for Optical and Computational Instrumentation or LOCI, University of Wisconsin), was used to

standardize and binarize grayscale OCTA images with default, 20% and 40% thresholding of background pixel values. Fractalyse (a software developed by the research team “Mobilities, city and transport” from the research center ThéMA) was used to determine FD and the correlation coefficient via the box-counting method, with an exponential factor of 2 and a circular mass-radius method centered at the barycenter. Using the box-counting method, Dr. Chiu and colleagues found a significant difference between FD of control and diabetic eyes in the superficial 3x3mm scan and in the deep scans with default threshold; in the superficial and deep 3x3mm scans with 20% threshold; and deep 3x3mm scan with 40% threshold (p < 0.05). Similarly, with the mass-radius method,

they discovered a significant difference between FD of control and diabetic eyes in superficial 3x3mm scan and deep 3x3mm scan for both default and 20% threshold (p < 0.05). Therefore, the investigators concluded that fractal dimension is a useful method for differentiating diabetic retinopathy. However, they cautioned that “there are variations in FD based on thresholding, image resolution and method of estimation. The study provides evidence for the necessity of standardizing parameters such as OCT scan size and thresholding prior to fractal analysis.” Editor’s Note: The ASCRS 2019 Annual Meeting was held in San Diego, California, USA, from May 3-7, 2019. Reporting for this story also took place at ASCRS 2019.

INDUSTRY UPDATE

Xtreme Research Award Presented at ARVO

D

rs. Chantal Dysli and Lydia Sauer were jointly awarded Heidelberg Engineering Xtreme Research Award for their research on Fluorescence Lifetime Imaging Ophthalmoscopy (FLIO) at the recently held Association for Research in Vision and Ophthalmology (ARVO) 2019 Congress in Vancouver, Canada. FLIO is a novel, non-invasive imaging modality that is able to detect early metabolic changes preceding morphological changes in the retina. It provides in-vivo autofluorescence lifetime measurements of natural retinal fluorophores upon laser excitation. While it’s not commercially available yet, Dr. Dysli from Inselspital University Hospital in Bern, Switzerland, says that “FLIO is a fascinating novel technique opening a new dimension in retinal imaging by providing information about basic pathophysiological mechanisms within the retina”. Both Drs. Dysli and Sauer have been involved in numerous studies demonstrating that many retinal pathologies display distinct metabolic

patterns in FLIO images before any other diagnostic imaging method can identify structural signs of disease. FLIO detects changes related to AMD, albinism, Alzheimer’s disease, diabetic retinopathy, macular telangiectasia type 2, retinitis pigmentosa and Stargardt disease. Some of these changes can be detected in healthy eyes, serving as potential early indicators of retinal disease. Other changes in already affected eyes seem to reveal disease progression. “The FLIO technology is useful in the diagnosis of many retinal diseases and as our research attests, it detects changes in the eye even before damage is visible with conventional imaging techniques. FLIO’s ability to show metabolic change before actual damage manifests could also lead to earlier interventions,” noted Dr. Sauer, who works at the Moran Eye Center of the University of Utah (USA). Once the technology becomes widely available, the diagnostic information provided by FLIO images could be used for early

diagnosis and therapy monitoring. “For me, it has been very inspiring to follow the development of FLIO from bench to bedside and to see the progress and future clinical applications of such an innovation,” said Dr. Dysli. Dr. Sauer agreed that FLIO is an exciting technology to work with: “Invivo metabolic imaging could become a new clinical milestone in our field, so we are delighted to be part of its development . . . I feel honored to be a part of this exciting research.” Ali Tafreshi, head of product management and clinical affairs at Heidelberg Engineering, commended the winners for their innovative research: “Dr. Dysli and Dr. Sauer have been a driving force in the clinical development and validation of fluorescence lifetime imaging as a diagnostic aid in the detection and management of various ocular and systemic conditions. Their clinical research paves the way for functional ocular imaging as the means to advance the field towards earlier detection of diseases.”

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