PIE Magazine Issue 09: The ebook version (The Recipes Issue, APAO 2019 Edition) by Media MICE

ASIA-PACIFIC’S FIRST MAGAZINE ON THE POSTERIOR SEGMENT

THE RECIPES ISSUE March/April 2019

magazine

www.piemagazine.org

posterior segment • innovation • enlightenment

Marriage, Moving and Maternity:

The 3M’s in a Woman Ophthalmologist’s Life Page

Seeking: Inspired Ideas for

The Next Generation of Innovation Page

Cover Story

PIE Magazine Advisory Board Member Prof. Mark Gillies reimagined as a baker of pies

Fresh from the Oven Retina Cases Made Less Complicated by Treatment Recipes

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THE WORLD’S FIRST FUNKY OPHTHALMOLOGY MAGAZINE

Inside this issue...

Posterior Segment Matt Young

CEO & Publisher

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Mining for Ophthalmic Gold in India: Predictions and Insights from VRSI

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When the Sides Collide: On Managing Crossover Complications

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Aflibercept Offers Promising Versatility in the Treatment of Retinal Diseases

Robert Anderson Media Director

Hannah Nguyen

Production & Circulation Manager

Gloria D. Gamat Chief Editor

Brooke Herron Associate Editor

Ruchi Mahajan Ranga Project Manager

Alex Young

Publications & Digital Manager Graphic Designers

Winson Chua Patalina Chua Writers

Gerardo D. Sison III Hazlin Hassan Joanna Lee John Butcher Khor Hui Min Olawale Salami Tan Sher Lynn Cover Art

Prafulla Badgujar

COVER STORY Fresh from the Oven: Retina Cases Made Less Complicated by Treatment Recipes

Even to the most skilled surgeons, complex vitreoretinal surgeries are complicated. Let’s find out what intricate ‘recipe’ they follow.

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Innovation page page

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Optimizing Innovations in Retina

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Smartphones and Innovation: Creating Novel Solutions in Ophthalmology

Photobiomodulation: An Innovative, Mitochondriatargeted Therapy for Dry AMD and Other Ocular Diseases

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Enlightenment page

Marriage, Moving and Maternity: The 3M’s in a Woman Ophthalmologist’s Life

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The Future of Ophthalmology: Break On Through to the Other Side

Seeking Inspired Ideas for the Next Generation of Innovation

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Society Friends

Conference Highlights Asia-Pacific Academy of Ophthalmology

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Treating Diseases of the Retina in Infants and Children Shedding Light on Monotherapy and Updates in the Management of PCV

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RISHI at VRSI 2018 Highlights the Crucial Role of Imaging in Retinal Diseases Acknowledging the Role of Steroids in RVO Treatment

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Vitreo Retina Society of India

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PIE MAGAZINE LETTER TO READERS Media MICE, Parent Company to PIE and CAKE Magazines, Celebrates its 10th Birthday

Dear Reader, T

en years ago, Media MICE CEO Matt Young was in a hotel room overlooking the beach in Nha Trang, Vietnam, pondering his next business venture with a map of potential locations: Sao Paulo, Barcelona or Singapore. And today, that business venture – Media MICE – is celebrating a milestone: its 10th Birthday (i.e. anniversary). Based as it turns out in Singapore (due to world-class client access and great Malaysian resources 1 km away), the company began with one employee: Matt (pictured with family and friends in the photo series below over the last 10 years). At that time, his work with the help of capable freelancers focused on Show Dailies for conferences across a range of industries, like engineering, water, furniture, and… ophthalmology. Matt continued on this path for the next year until Hannah Nguyen (Media MICE CFO and Matt’s wife) came onboard. Now a two-person team, their focus switched more exclusively to the field of ophthalmology where Matt had previously worked as a writer and international columnist (after an initial reporting stint covering homicides). They began expanding into more client-based work like custom opthalmic magazines, cutting-edge interactive storytelling, and manuscript writing and editing services. It was during this time – during Media MICE’s successful Bayer-sponsored Google Glass events in Zurich and London – that Matt realized he himself could be a Key Opinion Leader (KOL) if he could think and act differently than the rest of the industry. “And that’s why we see banana suits in ophthalmology conferences today,” joked Matt, referencing the attentiongrabbing costumes that he and some of his employees wear to congresses worldwide. With the same unconventional attitude, Matt launched PIE Magazine in March/April 2017. Standing for Posterior Segment, Innovation and Enlightenment, the magazine provides scientific ophthalmic content with a funky vibe – and is the first magazine serving the posterior segment in Asia-Pacific. “PIE created opportunities for clients to partner with us and spread their message,” said Matt, noting that traditional advertisements and advertorials, among other things, can be purchased to ‘get a slice of the action’. Fast forward to March/April 2019, and Media MICE is launching its second magazine: CAKE (Cataract, Anterior Segment, Kudos and Enlightenment). By entering the anterior

segment, the company’s publications ‘complete the eye’ and offer a full range of services for its ophthalmic clients. Both PIE and CAKE are grateful to be the official media partners of the Asia-Pacific Academy of Ophthalmology (APAO). And of course, this success wouldn’t be possible without the support of the company’s clients. “Some people like to thank the little people; I like to thank the big people that have helped us achieve this growth,” said Matt. These include leading names in the industry like Alcon, Allergan, Bausch & Lomb, Bayer, Santen and Zeiss…alphabetical but by no means exhaustive. “For a small business, we started out with the biggest clients in ophthalmology,” said Matt. “With their support, we can now move smaller, like the Media MICE we are.” Today, Media MICE has 20 employees operating in different countries around the world including Singapore, Malaysia, the United States, the Philippines, India, and Vietnam, where Matt now lives on the beach in Danang with some of the team. And this year, PIE and CAKE will join its team members in this worldwide presence by going global. The expansion began last year when PIE Magazine forayed out of Asia-Pacific to publish on location at the 2018 ARVO (Honolulu, Hawaii), EURETINA (Vienna, Austria) and AAO (Chicago, USA) Congresses. From now on, look for PIE and CAKE hardcopies at every major ophthalmology conference worldwide. So, why ‘officially’ go global? “Truth is, my dream is to build a collegiate atmosphere of people sharing and enjoying things around the world ... and as a byproduct of that, we get to change the world of vision,” explained Matt. “Some people might start with the end goal in mind, but we start with each other.” With that belief as a foundation, the future looks bright for Media MICE. So, what’s next? Matt says more layers are coming to build on the base of PIE and CAKE and that it will be a great surprise. “Before, each step slowly gave way to the next step, but today . . . we are starting to run.” Sincerely, Brooke Herron Associate Editor PIE & CAKE Magazines

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 â&#x20AC;&#x201C; 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]

POSTERIOR SEGMENT VITREORETINA

Mining for Ophthalmic

Gold in India

Predictions and Insights from VRSI

Like high-jumpers, ophthalmologists also seek to raise the bar.

by Brooke Herron

At PIE Magazine, our team often travels both far and wide to uncover the latest in all that is retina. One recent journey took us to Jaipur for the 2018 annual meeting of the Vitreo Retina Society –India (VRSI). Here, we spoke with two doctors to explore both future “goldmines” and current “gold standards” of ophthalmic care in this large and diverse subcontinent.

s he attended various sessions during VRSI, Dr. Jaffe, from Duke Ophthalmology, Duke University School of Medicine, in North Carolina, U.S.A., noticed that the topics discussed were very similar to those in Europe and the United States. “The thing that I was impressed with, in general, is the high level of care provided by Indian vitreo-retina specialists . . . and I think the practices that are commonly adhered to in countries where it’s the gold standard, that’s also practiced here,” he said. Echoing those sentiments was Dr. Raja Narayanan from the L V Prasad Eye Institute, in Hyderabad, India, and the Honorary Secretary of VRSI. “[At VRSI], you’ve heard numerous scientific presentations . . . some of them were

top-notch – and some gave insights into what’s coming in the near future,” he explained.

Unlocking the potential of new technology Dr. Narayanan expects to see a lot of changes in the few years – and these advances are certain to raise the bar and elevate the standard of care in India even further. Specifically, he’s looking forward to new developments in stem cell treatment and artificial intelligence (AI) to enhance care and provide improved patient solutions. “Stem cell treatment – especially for retinal diseases – has been a very difficult challenge for retina specialists,” he said. “We have stem cell treatments for other eye diseases, like corneal

diseases. But for retinal diseases, although we have come a long way, there are still many challenges.” He is cautiously optimistic on this front, predicting that within the next five years, there will be some sort of stem cell treatment for (at the very least) retinal dystrophies. “But it’s still going to be a challenge to determine how much impact [this treatment] will have on patients who are completely visually disabled,” Dr. Narayanan explained, noting that patients with partial disability may experience more improvement. These types of cutting-edge treatments could be especially crucial for patients with dry age-related macular degeneration (AMD). “For dry AMD, there are stem cell trials going on – and at the same time there are pharmacological interventions happening,” said Dr. Narayanan. “Hopefully, there may be some impact of slowing down the process of macular degeneration.” In this instance, he believes there is a role for both stem cells and medical (or pharmacological) treatments. “With

stem cells alone – it’s not going to be easy,” he explained. “There are a lot of issues, it will involve surgery, and it might have a higher risk than other ocular procedures.” Even so, he remains hopeful. “People are doing a lot of work in this field,” continued Dr. Narayanan. “[I hope] in the next five years we’ll have some treatment for these diseases . . . at this point there’s no treatment available.”

Finding a goldmine in standardization After attending different sessions at VRSI, Dr. Jaffe discovered one area where the ‘gold bar’ could be raised (universally) – and that’s better defining terms used for various findings on imaging modalities: “I think it would be helpful to have a gold standard for terminology and more dissemination of what’s understood about the terminology.” Dr. Jaffe says that some of this relates to working toward a consensus – and this can lead to better treatment and patient care. He discussed one

example that was brought up during a retina imaging symposium regarding the term “subretinal hyperreflective material” or SHRM. “One of the points that was brought up [during the symposium], is when that term was first coined, it was used to refer to an OCT finding that included choroidal neovascularization blood fibrosis,” he explained. “But with the multimodal imaging we have now – and when you combine it with the OCT findings – you can be more specific about what you’re describing with SHRM. We can say that it’s associated with fibrosis, as opposed to neovascularization . . . and that’s important, because depending on the appearance it has prognostic applications, it has treatment information.” “For example, if you see fibrosis associated with photoreceptor loss as a reflection of the SHRM, the patient may not do as well with treatment,” said Dr. Jaffe, who added that this also highlights an unmet need to develop treatments for fibrosis. “On the other hand, if the subretinal hyperreflective material has a more

exudative appearance, it may reflect favorably for treatment with (for example) anti-VEGF therapy,” he said. “So, the point is, that by more carefully designing the terms that we use, we can better relate the therapy with those findings.” And across Asia, Dr. Jaffe is optimistic about the gold standard of ophthalmic care in the future. He notes that while not all countries in the region possess the same resources, or have enough retina specialists, the situation might be improving: “I think one of the things that is happening, is that as these more developed countries are able to take on and practice at a higher level, they are disseminating information to their neighbors – and this will raise the overall level for the countries that aren’t as fortunate to have those resources.” Editor’s Note: PIE Magazine’s parent company, Media MICE Pte Ltd, was the official media partner at the VRSI 2018 annual meeting in Jaipur, India. Reporting for this story also took place at VRSI 2018.

INDUSTRY UPDATE

OCULUS Director Rainer Kirchhübel Celebrates 40th Anniversary

or more than 120 years, Oculus has been a partner for eye care professionals around the world – and for about one-third of that time, Mr. Rainer Kirchhübel has served as the company’s director. Mr. Kirchhübel began his career at Oculus in 1979, and for most of that time, he has served as its director. From his start at the firm, Mr. Kirchhübel led it to be a successful, worldwide hightech company. The Director celebrated his 40th anniversary at the company on February 1, 2019 in Wetzlar Dutenhofen, Germany. During his speech, Mr. Kirchhübel said: “For 38 of my 40 years at Oculus, I’ve been the

director. These years saw many great challenges, but I always enjoyed it.” And while it is a global business, it is still a family company. Mr. Kirchhübel’s sons Christian and Matthias are executives, and his wife Rita has been director of marketing for more than 25 years. During the anniversary event, his son and Oculus Co-Director Christian Kirchhübel told the crowd how his father has dedicated his entire working life to the company. In speaking to his father, he said: “You have taken on all the challenges, and you lead the company with level-headedness and foresight. Your visions have led us to many successes. You always maintain

the right sense of proportion in your work within Oculus, as well as outside of it at ISO, the Chamber of Industry and Commerce and many other institutions, and you are well respected by your contacts everywhere.” Mr. Kirchhübel was also presented with a certificate in honor of his 40th work anniversary by Mr. Andreas Tielmann, the managing director of the Chamber of Industry and Commerce (IHK) in Lahn-Dill, Germany. Later in the year, all 380 employees will have another opportunity to toast their boss at the annual summer party. For more information about OCULUS, visit www.oculus.de.

POSTERIOR SEGMENT ANTERIOR SEGMENT COMPLICATIONS

When the Sides Collide On Managing Crossover Complications Choosing cases for combined cataract and vitrectomy surgery

Crossover complications can be scary . . . but they don't have to be.

lthough the anterior and posterior are two distinctly different segments, surgical complications can sometimes blur those lines of separation. Therefore, it’s critical that vitreoretinal surgeons not only recognize potential risk factors but can also manage complications that may arise in the front of the eye. This important topic was explored in a symposium called “Management of Anterior Segment Surgery Complications,” at the recently held 2018 Asia-Pacific Vitreo-retina Society (APVRS) congress in Seoul, Korea. Below, we look at some of the most important take-home messages from that symposium. by Joanna Lee

Regarding silicone oil removal and IOP Based on a presentation called “Incidence and Management of Elevated Intraocular Pressure After Silicone Oil Removal” by Dr. Miho Nozaki, from Nagoya City University’s Department of Ophthalmology and Visual Science, Japan.

f silicone oil (SO) is not removed completely following retinal surgery, it can leave a nasty little reminder behind – in the form of elevated intraocular pressure (IOP). In a previous study, Dr. Nozaki reported that 21.7% of patients experience elevated IOP following SO removal using a 20- to 25-gauge system. This led her team to another study – this time, they would record the incidence of IOP using only a 25-gauge system. Would a smaller gauge make a difference?

It turns out, it did. In their latest study 16 of 61 eyes experienced elevated IOP during SO tamponade; and following SO removal, 11 of those 16 eyes returned to normal IOP. This led the researchers to state that overall, 9.8% of eyes had elevated IOP following the procedure. Regarding SO removal, Dr. Nozaki suggests using the viscous fluid controller (VFC) system with fluidair exchange. She also highlighted feedback from other experienced AsiaPacific surgeons, many of whom prefer using the VFC system. She and her team concluded that the duration of SO tamponade was significantly longer in the elevated IOP group – therefore the duration should be limited to three to four months. In addition, the likelihood of SO migration to the anterior chamber is more likely in IOP elevated eyes.

Based on a presentation called “Combined Cataract and Vitrectomy Surgery: Pros and Cons” by Dr. Doric Wong, adjunct associate professor and senior consultant from Singapore National Eye Centre (SNEC).

ccording to Dr. Wong, the coexistence of cataract and retinal pathologies can occur – especially in older patients, whose cataract has been accelerated by intraocular procedures, like vitrectomy. Therefore, in certain cases, he suggests combining cataract and vitrectomy surgeries into one: phacovitrectomy. In his presentation, he discussed a few scenarios where this combined procedure would be ideal – for example, in patients with macular holes, myopic macular retinoschosis or with “simple” vitreous hemorrhage. In these instances, he says that phacovitrectomy has several advantages: it shows a better outcome; it helps decrease costs by avoiding two separate surgeries; and it reduces the number of visits, which saves patients’ time off work. “The procedure would also be useful for treating posterior polar cataracts,” noted Dr. Wong. Of course, the combined procedure may not be ideal for all patient cases. Dr. Wong notes that there could be potential complications in patients with iris neovascularization in diabetic vitrectomy, or those with intraocular lenses (IOLs). Therefore, Dr. Wong suggests that surgeons first perfect the phacovitrecomy technique and then choose patient cases wisely.

On managing dislocated IOLs Based on a presentation called “Management of Dislocated IOL”, by Dr. Andrew Chang, from the Retinal Unit Sydney Eye Hospital, Australia.

dislocated IOL is an unfortunate complication of cataract surgery. When this occurs, surgeons must consider several factors to manage and correct the problem. Dr. Chang explained that there are several replacement options for dislocated IOLs, including one-piece IOLS, three-piece IOLs and anterior chamber IOLs (ACIOL). He advised that when selecting the replacement IOL, surgeons take into consideration the degree of capsule support required, as well as the skill and comfort level of the surgeon in each approach. In addition, Dr. Chang explained that scleral fixation options can be used – including suture and suture-less options, noting that Prolene sutures were prone to breakage. However, he offered a tip learned from another surgeon to remedy these breaks: “If you tie the suture with two sutures in a one knot technique (within the scleral flap), it could last up to 25 years, with only a 0.5% breakage rate.”

When endophthalmitis strikes Based on a presentation called “Updates on the Prevention and Management of Post-Operative Endophthalmitis” by Dr. Manoharan Shunmugam, a Paediatric Vitreoretinal Surgeon at Pantai Hospital Kuala Lumpur in Malaysia.

ndophthalmitis is a severe complication of ocular surgery. Fortunately, it occurs rarely following surgery, affecting 0.03 to 0.70% of cataract patients; 0.2 to 1.5% of glaucoma patients; and 0.052% of vitrectomy patients. However, he notes there is also a risk of developing endophthalmitis through other procedures, like intravitreal injections: “Being prone to endophthalmitis after intravitreal

injections is something we’re hearing more of, sometimes with devastating effects, so we need to be aware of this,” he explained. It has various risk factors, including: local factors like blepharitis; systemic factors like diabetes renal disease; and intraoperative complications such as posterior capsule ruptures or vitreous loss. Dr. Shunmugam also says that longer surgeries pose an increased risk – he says that after 45 minutes, endophthalmitis could develop. Cleanliness and hygiene are key measures to prevent endophthalmitis. “Be careful about factors within the clinical environment – this includes air-conditioning, solutions and medications, surgical instruments, gloves and face masks, as well as tissues like skin, lashes and mucus,” cautioned Dr. Shunmugam. If a patient develops endophthalmitis, they must be monitored and treated immediately. So, how do we treat it? Dr. Shunmugam shared insights from the recent Complete and Early Vitrectomy for Endophthalmitis (CEVE) study, which concluded that patients should not be operated on too early: If there’s good red reflex, or some visible retinal details, treat it with intravitreal antibiotics and corticosteroids and monitor it closely. If there’s no improvement, no red reflex and no red retinal visibility, then a complete vitrectomy should performed, regardless of visual acuity. (This is in contrast with older protocol suggested by the Endophthalmitis Vitrectomy Study (EVS), which prescribes early vitrectomy surgery to treat postoperative endophthalmitis.

Insights in choroidal complications Based on a presentation called “Management of Choroidal Problems” by Dr. Sung Soo Kim, a professor at the Department of Ophthalmology at the Institute of Vision Research at Yonsei University College of Medicine, Korea.

r. Kim defines choroidal effusion (either serous or hemorrhagic) in

two ways: as the clinical observation of abnormal serous fluid in the ciliary body and choroid; or the condition with abnormal accumulation of serous or blood in the suprachoroidal space. Any condition that results in low IOP can be considered a risk for choroidal effusion development – this includes: glaucoma surgery, and systemic and topical medications, among other factors. He iterated that acute or chronic hypotony after ocular surgery may induce critical choroidal effusion and suprachoroidal hemorrhage in patients with risk factors such as old age, those on anticoagulants or high myopia, among other conditions. That’s why, according to Dr. Kim, a big part of management lies in prevention including reducing preoperative IOP; using medication to optimize perioperative heart rate and blood pressure; ceasing anticoagulant medication and observing intraoperative and postoperative hypotony control. Medical management, with the use of topical or systemic steroids, cycloplegics and analgesics has been recommended. To manage vision threatening postoperative choroidal complications, he suggests that physicians identify the reason for hypotony, control inflammation, and choose the proper technique for effusion and treat concurrent vitreoretinal complications. In addition, other presenters described other instances of posterioranterior crossover – including cataract surgery in cystoid macular edema (CME) to a dropped nucleus – and provided tips to resolve each complication. Overall, it’s safe to say that the main take-home message was this: When vitreoretinal surgery causes an anterior issue, it’s critical that surgeons anticipate and recognize signs and that they are proactive in treatment, despite lack of guidelines or standardized therapy (in some cases). Editor’s Note: The APVRS 2018 Congress was held in Seoul Korea, on December 14-16, 2018. Reporting for this story also took place at APVRS 2018.

POSTERIOR SEGMENT ANTI-VEGF AGENT

Aflibercept Offers Promising Versatility in the Treatment of Retinal

Diseases

by Gerardo D. Sison III

etinal disease in the form of diabetic macular edema (DME), polypoidal choroidal vasculopathy (PCV), and neovascular age-related macular degeneration (nAMD) can ultimately lead to a substantial loss of vision and decreased quality of life. Not only is proper treatment crucial to improvements in prognosis, but optimal timing is a valuable concern as well. Clinicians should be informed about anti-VEGF treatment, namely aflibercept, which has since become center stage in current treatment advances for retinal disease. Acclaimed doctors and specialists contributed to this topic at a symposium held at the recent 5th Annual Congress on Controversies in Ophthalmology: AsiaAustralia (COPHy AA 2019) which took place in Shanghai, China.

On the importance of early, intensive treatment Based on a presentation called â&#x20AC;&#x153;Controversies in DME: Importance of Early, Intensive Treatmentâ&#x20AC;? by Dr. Gemmy Cheung, associate professor from Singapore National Eye Centre (SNEC). VEGF and PGF both contribute to the development of retinal vascular leakage and edema in diabetic eye disease. Add to this the vicious cycle of impaired retinal blood flow and vessel occlusion, and it is no wonder that the most effective treatment targets elevated VEGF and PGF in patients with diabetic retinopathy and macular edema. So what is aflibercept and how is it used? Aflibercept is a recombinant fusion protein that was specifically designed for high-affinity binding to

Finding the right treatment can be a balancing act. Thankfully, aflibercept is showing promise as an effective and versatile anti-VEGF agent.

both VEGF and PGF. Compared to other anti-VEGF agents such as ranibizumab and bevacizumab, aflibercept exhibited the highest binding affinity in vitro with VEGF-A. In assessing the efficacy of aflibercept in patients with visual impairment due to DME, Dr. Cheung discussed two important studies: VIVID and VISTA. In two multicenter, double-masked trials, patients were

randomized 1:1:1 to receive aflibercept 2 mg given intravitreally every 4 weeks, aflibercept 2 mg given intravitreally every 8 weeks (after 5 initial monthly doses), or laser photocoagulation. Looking at the results, patients showed improvements in visual and anatomic outcomes after 5 doses, gaining on average, 8 letters. About 15 to 18% of patients gained an additional 5-letter gain by the end of the first year.

Dr. Cheung emphasized notable clinical significance of these results, saying: “Five-letter gains can impact quality of life for patients in their day to day activities and improve their ability to read the newspaper and drive in difficult conditions.” Not only did intensiveness of treatment affect results, but delaying aflibercept treatment also led to suboptimal vision gains. For instance, patients in the laser group were eligible to receive aflibercept on an as-needed basis from Week 10 if they met vision loss and OCT criteria. As a result, almost 50% of this same group in both studies received aflibercept PRN from Week 100 to Week 148. However, they did not receive the maximal benefits they would have received if they had just started treatment with aflibercept. Dr. Cheung stated: “The important lesson to remember, therefore, is not to delay treatment and save aflibercept as second-line therapy because there might be a later price to pay.” In addition to the VIVID and VISTA studies, another study known as the Protocol T compared the efficacy of three anti-VEGF agents: aflibercept, bevacizumab and ranibizumab. Results found that those treated with aflibercept gained significantly more letters than those treated with either comparator at the 1-year primary endpoint (change in visual acuity from baseline). At year 1, significantly greater vision gains were achieved with aflibercept than with either comparator in patients with baseline visual acuity less than 69 letters (less than 20/40), Dr. Cheung said. A post hoc analysis further solidified significantly greater visual acuity gains over 2 years with aflibercept than with comparators, she said. Overall, however, after 6 monthly doses of any anti-VEGF treatment, the proportion of eyes with persistent DME decreased, according to the post hoc analysis. Staying the course with aflibercept provides robust VA gains in patients with a limited early visual response.

“

The important lesson to remember, therefore, is not to delay treatment and save aflibercept as second-line therapy because there might be a later price to pay. – Dr. Gemmy Cheung

”

The eyes with limited early VA response (18%) after three initial monthly doses showed improvements with continued aflibercept. In Protocol T, 23% of aflibercept-treated eyes had limited early VA gains (<5 letters) at Week 12; 38% of these achieved gains of more than 10 letters at Week 104. Aflibercept is also associated with disease modification and progression in patients with DME. According to the VIVID EAST study, which assessed the efficacy of aflibercept in Asian and Russian populations, a high proportion of aflibercept-treated patients achieved greater than a 2-step improvement in the Diabetic Retinopathy Severity Score (DRSS) at Week 52. More specifically, around 60% of patients treated with aflibercept achieved noticeable improvements compared to laser treatment.

The role of aflibercept monotherapy in PCV Based on a presentation called “Aflibercept Monotherapy in PCV” by Dr. Suqin Yu, professor from Jiao Tong University, Shanghai. Before the advent of anti-VEGF agents, photodynamic therapy (PDT) was the standard of care for the treatment of PCV. Since 2002, research has demonstrated the efficacy of verteporfin PDT with favorable short to mid-term results in improved vision and polyp regression.

However, as explained by Dr. Yu, long-term outcomes of PDT monotherapy may be associated with a high rate of PCV recurrence, deterioration of VA and risk of complications. For example, a pooled analysis of 29 different studies reported a PCV recurrence rate of up to 80% after years 2 and 3 in eyes treated with PDT. Other concerns regarding overtreatment with initial and repeated use of PDT include efficacy and safety, practicality, and cost, Dr. Yu said. The procedure often results in several side effects over the long term and proves to be quite costly, he said. In addition, the procedure may be more timeconsuming compared to intravitreal anti-VEGF injections due to necessary specialist equipment and training, Dr. Yu explained. Dr. Yu added to the discussion by reviewing two trials to support her case: EVEREST II and PLANET. The EVEREST II trial is a 24-month multicenter study that compared ranibizumab monotherapy versus combination ranibizumab and PDT combination therapy in Asian participants. In this trial, vision gains were notably greater with ranibizumab and prompt PDT than with ranibizumab alone. The PLANET study evaluated the use of aflibercept monotherapy versus aflibercept plus PDT combination therapy. The study protocol implemented 3 monthly injections of aflibercept with a follow-up protocol of treat and extend (T&E). Results showed that patients in both study arms gained over 10 letters from baseline at Week 52. What’s remarkable, according to Dr. Yu, is that vision gains were maintained at Week 96 with T&E dosing. In both study arms, over 94% of patients did not experience loss of over 15 letters over 96 weeks. In comparison, one-third of patients receiving aflibercept monotherapy had complete polyp regression while over 80% of patients had complete polyp inactivation

POSTERIOR SEGMENT ANTI-VEGF AGENT at Week 96. Furthermore, in the second year, T&E with aflibercept was associated with a reduced injection number compared with the first year. In the same fashion, around 40% of patients had injection intervals of 12 weeks or more with the same regimen. Dr. Yu concluded that aflibercept monotherapy leads to favorable vision gains and high rates of polyp inactivation. She also noted that more than 80% of patients never required rescue PDT over 2 years. Therefore, aflibercept monotherapy may be a promising option for certain patients.

Optimized aflibercept therapy in nAMD Based on a presentation called “Proactive Treatment in nAMD” by Dr. Paul Mitchell, professor from University of Sydney, Australia. Treat-and-Extend (T&E) has become a preferred regimen for clinicians who treat patients with nAMD. With this specific plan of dosing, clinical

decision-making has become clearer with support from findings in the ALTAIR and ARIES studies. So what exactly is T&E? Dr. Mitchell contributed to this particular aspect of aflibercept therapy by defining it as the initiation of treatment with loading doses until the disease is stable. Gradually extending the time between treatments until fluid recurs or VA declines can determine a maximal fluid-free interval. Of course, Dr. Mitchell mentioned that “it’s important to treat more frequently if VA and/or anatomic outcomes deteriorate”. In contrast with a reactive PRN regimen, it is important to use a proactive T&E regimen, according to Dr. Mitchell. This way, clinicians can minimize the risk of over-treatment and certainly avoid under-treatment. Consequently, proactive T&E regimens can relieve injection burden and improve visual outcomes while maintaining personalization of treatment. In the ALTAIR study, a multicenter randomized trial, two groups were assigned to receive either aflibercept T&E with 2-week interval adjustments

or 4-week interval adjustments. As confirmed by Dr. Mitchell, the study sought to assess the efficacy of two different T&E regiments with aflibercept in nAMD over 2 years. While adjustment of T&E treatment intervals were guided by specific criteria, rapid vision gains were achieved in both groups and maintained to Week 52 of the study. Moreover, vision gains that were maintained to Week 96 with half the number of injections given in the first year. The study ultimately found that almost 60% of patients both reached treatment intervals of 12 weeks or more after the first year and also maintained these intervals into the second year. The ARIES study compared the efficacy of early versus late initiation with aflibercept in nAMD over 2 years. The study served to supplement the growing evidence of aflibercept for proactive T&E dosing starting in the first year. Results found that visual and anatomic outcomes were similar in both early and late initiation groups. Plus, T&E patients were also receiving fewer injections as demonstrated in the ALTAIR study.

Implications in real-world practice So, how does this discussion translate to real-world practice with aflibercept? With relatively low safety concerns, intensive and early treatment with aflibercept has become an emerging option for clinicians to treat patients with retinal disease. Overall, studies about aflibercept demonstrated its superiority and versatility in certain treatment regimens for DME, PCV and nAMD. Editor’s Note: Reporting for this story took place at the 5th Annual Congress on Controversies in Ophthalmology: Asia-Australia (COPHy AA 2019) in Shanghai, China. Aflibercept is a versatile 'swiss army knife' in treatment for retinal disease.

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COVER STORY

Sometimes complicated cases hit you like a pie in the face.

Fresh

fro

Retina Cases Made Less Com

ith a magazine called PIE, it’s clear we have a love for sweet treats. Now, of course, PIE and pie are quite different: one is an acronym for Posterior Segment, Innovation and Enlightenment . . . and the other is a delicious baked dessert. Most people (bakers and ophthalmologists alike) would agree that the two couldn’t possibly have much in common. However, we (at PIE) are not most people – and we immediately saw a parallel between the posterior segment and pie: In surgery, as in baking, a list of materials is required and a set of guidelines is followed; precision is critical, and some cases (or recipes) can be more complex than others. Complicated vitreoretinal cases are challenging, even to the most skilled surgeons, and follow their own intricate recipe. Below, four vitreoretinal surgeons from Asia-Pacific share their recipes to resolve complicated cases in the posterior segment.

That doesn’t belong in the pie

Removing IOFBs

This complex case involves an unfortunate 42-year-old male, who had a metal foreign body (FB) enter his right eye and lodge in his inferior retina. PIE-appointed baker and consultant vitreoretinal surgeon Dr. Kenneth Fong treated the patient, who presented with a self-sealing corneal laceration, traumatic cataract and localized retinal detachment around the foreign body impact site. To remove the intraocular foreign body (IOFB), Dr. Fong performed a 20-gauge pars plana vitrectomy. During the

procedure, a posterior vitreous detachment was induced by suction over the optic disc (vacuum 250 mm Hg, infusion pressure 25 mm Hg), which resulted in a complete vitrectomy. “To remove the metal IOFB, I used 19-gauge foreign body forceps and removed it via the enlarged pars plana incision,” he explained. The IOFB measured 6mm in length. “I had a 19-gauge intraocular magnet on standby in case it was difficult to remove the IOFB, but I didn’t need to use it as the IOFB forceps were adequate,” said Dr. Fong. The next step in the recipe called for endolaser, which was performed around the FB impact site. He then inserted 1000cs of silicone oil and sutured the sclera and conjunctiva with 7/0 Vicryl. “Silicone oil insertion for any case of IOFB embedded in the retina helps prevent retinal detachment and allows for a good view of the retina postoperatively compared with gas,” shared Dr. Fong. Following the surgery, the patient was given topical Prednisolone AcetateGatifloxacin eye drops, to be used every three for three weeks, as well as oral moxifloxacin (400mg/day for five days) to prevent endophthalmitis. Just like pies need to set before they’re served, some vitreoretinal cases need time between steps. In this case Dr. Fong says: “It’s not necessary to remove the cataract in the first surgery, as it may induce further inflammation.” Therefore, three months following the initial procedure, the patient underwent phacoemulsification for the traumatic cataract and the silicone oil was removed.

rom the Oven

omplicated by Treatment Recipes by Brooke Herron

COVER STORY

~ Baker’s Tips ~

Silicone oil insertion for “ any case of IOFB embedded in the retina helps prevent retinal detachment and allows for a good view of the retina postoperatively compared with gas.

”

Dr. Kenneth Fong

“Early removal of silicone oil combined with cataract surgery allows for early recovery of vision, as well as preventing any complications from the oil,” added Dr. Fong. “The retina was attached postoperatively and his best corrected visual acuity was 20/50.”

exam showed a soft eye with choroidal effusion, and almost complete apposition of the retina in posterior pole (kissing choroidals),” said Dr. Valero. The patient was scheduled for surgery for the following day. Preoperatively, Dr. Valero decided to place the infusion cannula in the small free space at 12 o’clock and to perform the sclerostomies inferonasally and inferotemporally to drain external fluid prior to vitrectomy. “However, because the eye was soft, the G25 infusion trocar would not penetrate into the vitreous cavity,” said Dr. Valero, adding that repeated attempts at inflating the eye with balanced salt solution (BSS) through a limbal site were performed, but eye would not stay firm enough. At this point, he notes two main ingredients were needed: an anterior chamber (AC) maintainer – and patience. “The AC maintainer was inserted through a limbal stab incision,” said Dr. Valero. This allowed for infusion through the AC, while maintaining the eye rigidity required for the surgeon to perform the sclerotomies.

When pies fall apart

Repairing retinal detachments

In another complex recipe, Dr. Sherman Valero, vitreoretinal consultant at The Medical City, Philippines, details a case involving a 64-year-old male who presented with an acute off-macula retinal detachment, with the right eye showing multiple breaks positioned at 3 and 11 o’clock. In ophthalmology, as in baking, things can go awry. In this case, Dr. Valero scheduled the patient for an immediate pars plana vitrectomy (PPV), but the patient’s anxiety got the best of him, and he didn’t show up for the surgery. A month later the patient returned, complaining of sudden pain in the right eye that had begun the previous week. “The

~ Baker’s Tips ~

Make sure that patients “ are well informed of details of surgery, including possible complications if it not done within a particular time frame.

”

Dr. Sherman Valero

“There was moderate drainage of choroidal effusion, which created enough space for the trocars and instruments to be placed in the vitreous cavity safely,” he added. The vitrectomy was then performed and the subretinal fluid was drained through breaks. “The retina was successfully reattached, but there was a note of residual choroidal effusion infratemporally . . . this residual effusion was left behind,” said Dr. Valero, adding that the breaks were lasered and silicone oil was placed in the cavity. On day one post-op, the retina was attached, but there was still some inferior choroidal effusion. By day seven, the choroidals were resolved and the inferior retina remained attached, however, the oil level dropped to 80 percent. Dr. Valero says the patient’s final best corrected visual acuity (BCVA) was 20/100, and silicone oil removal is planned for the future. While the patient’s initial retinal breaks were alarming enough, waiting a month to have surgery caused unnecessary complications and risks. Therefore, Dr. Valero counsels: “Make sure that patients are well informed of details of surgery, including possible complications if it not done within a particular time frame.”

Any way you slice it

“A stab in the eye”

Sometimes, complications during surgery can result in a complex recipe for patient recovery – which is what happened to Dr. Andrew Chang, head of the Retinal Unit at the Sydney Eye Hospital in Australia. In this case, the patient had an accidental globe perforation by a peribulbar anesthetic needle – or “a stab in the eye.” The patient, a 71-year-old high myope, underwent an uneventful cataract surgery in the morning. However, when the eye pad was removed that afternoon, the patient’s vision was very blurred. Dr. Chang examined the eye and found that visual acuity (VA) was reduced to hand movements only.

“Through the vitreous hemorrhage, a superior retinal tear and detachment was noted,” said Dr. Chang. “It was suspected that the patient had a globe perforation by the anesthetic needle.” According to Dr. Chang, these cases are often diagnosed the next day after the eye pad is removed. “The vision is unexpectedly poor, and a vitreous hemorrhage is often present,” he said, adding that accidental globe perforation is more common in large and unusually shaped myopic eyes with staphylomata. Unfortunately, with this complication, the prognosis is often guarded as various problems can arise: “With the initial injury, the needle may damage the macula, cause multiple tears and detachment, and can result in subretinal or choroidal hemorrhage,” said Dr. Chang. “Additionally, anesthetic agent may be injected inadvertently into the eye itself. These cases often develop proliferative retinal scarring resulting in retinal re-detachment and vision loss.” Therefore, it’s imperative to make the correct preoperative diagnosis. “An ultrasound of the globe will show the extent of damage – like a retinal detachment or subretinal or choroidal hemorrhage,” he explained. “It will show the shape and size of the globe.” It’s also vital to consider the type of anesthesia to use for the vitrectomy: “If the globe is large due to myopia, then general anesthesia or sub-Tenon’s local anesthesia is considered,” said Dr. Chang. In addition, he advises to check the intraocular pressure (IOP) – if it’s low, it could indicate a large scleral wound, which could require external suture repair. Once the preoperative preparation was complete, he immediately took the patient to the operating room. During surgery, Dr. Chang confirmed that the needle had passed through the interior of the globe upward, which caused a tear of the superior retina and ultimately a detachment. This complex ‘pie’ called for various ingredients and cooking methods (or surgical techniques). He

~ Baker’s Tips ~

Heavy liquid “ perfluorocarbon (PCFL) is useful for stability and as tamponade in the retina.

”

proliferative vitreoretinopathy (PVR) and re-detachment of the retina,” explained Dr. Chang. Postoperatively, it’s critical to closely monitor the patient for complications like retinal scarring, which could result in a re-detachment of the retina or an epiretinal membrane formation. In this case, the retina detached again and required further surgery. “Ultimately the retina was stabilized with the use of silicone oil tamponade,” he added.

A perfectly baked crust Dr. Andrew Chang

performed a three-port PPV, separated the vitreous hyaloid and relieved traction from around the perforating wounds. Dr. Chang notes that good illumination is key – and surgeons should take care when placing the infusion line, as there could be a choroidal thickening. He continued with some expert baking tips: “Heavy liquid perfluorocarbon (PCFL) is useful for stability and as tamponade in the retina.” To treat the entry and exit wounds, as well as other tears, laser photocoagulation was applied. “Silicone oil tamponade is often required as these eyes may be at high risk of

Closing macular holes

If baking a pie takes some know-how, then closing macular holes takes a lot. This complex recipe comes from Dr. Vaibhav Sethi, a vitreoretinal consultant at Arunodaya Deseret Eye Hospital, Gurgaon, Haryana, India. His pie recipe begins with a 55-year-old patient who complained of decreased vision and metamorphopsia. After consultation, the patient was diagnosed with myopic maculopathy with macular schisis and a full thickness macular hole (more than 400 microns wide), associated with posterior staphyloma. The patient’s BCVA was 20/200, with a myopia of -22D. Preoperatively, the patient underwent counseling and Dr. Sethi explained the guarded visual prognosis. He was prescribed antibiotic eyedrops.

Not an accurate demonstration of the 'pinch and peel' maneuver.

COVER STORY

~ Baker’s Tips ~

Doing such cases is a “ challenge... They require all available armamentarium – and lots of patience.

”

Dr. Vaibhav Sethi

Of course, a complex diagnosis begets a complicated surgery. Dr. Sethi began by making three ports and placing a chandelier light system at 11 and 1 o’clock. Then he performed an anterior and core vitrectomy. Triamcinolone was injected to stain the posterior hyaloid. Dr. Sethi said that posterior vitreous detachment (PVD) was thought to be induced (with great difficulty). “Restaining with tricot revealed vitreoschisis and finally, PVD induced from the edge of the staphyloma,” he explained. He stained the internal limiting membrane (ILM) with blue under air but says both the stain quality and contrast were very poor. As there was extensive chorioretinal degeneration present, he re-stained for a longer duration (two minutes) and minimal staining was achieved. “It was difficult to reach and grasp the internal limiting membrane with ILM forceps due to the extremely long axial length and posterior staphyloma,” said Dr. Sethi. So, he removed one cannula and slightly lowered the IOP to reach further into the posterior staphyloma. “The ILM forceps just about reached the surface and the pinch and peel maneuver was then done,” explained Dr. Sethi. “The problem is this piecemeal ILM removal, and not being sure about the depth of pinch

due to posterior staphyloma and myopic degeneration.” He then used a finesse loop to scrape the ILM tissue up to the hole’s edge as much as possible. Following that, Dr. Sethi employed the inverted ILM flap technique to place the ILM tissue attached to the hole’s edge over the hole’s surface. “[I then performed a] fluid-air exchange . . . but the ILM flap became amputated and dislodged,” he said. Dr. Sethi placed PCFL on the hole in the posterior staphyloma and replaced the dislodged ILM film over the hole under the PFCL bubble using ILM forceps. “A cutter tip was used to stabilize the ILM flap over the hole and 12 percent C3F8 gas was injected,” he added. In the final steps, the periphery was checked and Dr. Sethi removed the chandelier & other cannulae.

Postoperatively, the patient did well, with BCVA improving to 20/80. At week one following surgery, the hole closed. Like expert bakers creating the perfect pie, cases like these involve multiple ingredients and a high level of expertise. “Doing such cases is a challenge,” said Dr. Sethi. “They require all available armamentarium – and lots of patience.” Vitreoretinal surgery is complex and even more so in these complicated cases, leaving the surgeon to rely on expertise, intuition and the counsel of others. Recipes like those shared above, and first-hand knowledge and experience from other surgeons, are key ingredients to treating challenging posterior segment conditions. And we think that for ophthalmologists (and bakers alike), the most challenging cases (or pie recipes) are the most rewarding.

About the Contributing Doctors Consultant Vitreoretinal Surgeon Dr. Kenneth Fong, MA MB BChir (Cambridge), FRCOphth (UK), FRANZCO (Aust), CCT (UK), AM (Mal), is recognized as an ophthalmologist in the UK, Australia and Malaysia. He graduated with a medical degree from the University of Cambridge in 1998 and trained to be an eye surgeon in London. Dr. Fong then spent two more years training in the UK and at the Royal Perth Hospital in Australia to subspecialize in retina. After 18 years of working in the UK and Australia, he returned to Malaysia in 2009 to serve at associate professor and consultant ophthalmologist and retinal surgeon at the University of Malaya in Kuala Lumpur. He currently works full-time at his private practice at Sunway Medical Centre. Dr. Fong is the president of the Malaysian Society of Ophthalmology and serves as a council member for the Asia Pacific Vitreo-retinal Society. [Email: kcsfong@gmail.com] Dr. Sherman Valero, MD, FPAO, is an ophthalmologist specializing in diseases and surgery of the retina, vitreous and macula and is currently connected with The Medical City, Makati Medical Center and The American Eye Center. He obtained his medical degree from the UERM College of Medicine in 1993 and finished his residency training in ophthalmology at the Makati Medical Center in 1998. He underwent subspecialty training both at the University of Hawaii, USA and the University of Toronto, Canada from 1999-2001. Dr. Chang is the residency training officer of the Department of Ophthalmology at The Medical City, as well as the Head of its Service Clinic Department. He also serves as the Head of Research at the Department of Ophthalmology of Makati Medical Center. He is currently the Secretary of the Vitreoretina Society of the Philippines as well as a Councilor of the Philippine Academy of Ophthalmology. [Email: valeromd@yahoo.com] Associate Professor Andrew Chang, MBBS (Hons), PhD, FRANZCO, FRACS, is a vitreoretinal ophthalmologist and surgeon. He is the medical director of the Sydney Retina Clinic, head of the retinal unit and consultant vitreoretinal surgeon at Sydney Eye Hospital (Australia), and clinical associate professor at University of Sydney. Dr. Chang attended medical school at the University of Sydney, followed by ophthalmology training at Sydney Eye Hospital and fellowship training at Royal Victorian Eye and Ear Hospital and in the United States. In addition, he was awarded a PhD for research into retinal and choroidal angiography performed in the Universities of California and Sydney. He is involved with numerous organizations in Asia-Pacific, including serving as secretary-general for the Asia-Pacific Vitreo-retinal Society (APVRS). Professional awards include the Achievement Award and Distinguished Service Award of the Asia Pacific Academy of Ophthalmology (APAO) and the RANZCO Excellence in Teaching Award. [Email: achang@sydneyretina.com.au] Dr. Vaibhav Sethi currently works a vitreoretinal consultant at Arunodaya Deseret Eye Hospital, Gurgaon, Haryana, India. He completed his ophthalmology residency at the famous Aravind Eye Care Institute, Tamil Nadu, India and his vitreoretinal fellowship from the prestigious L.V. Prasad Eye Institute, Hyderabad, Telangana. Additionally, he holds a diploma from Fyodorov Microsurgical Eye Institute, Moscow, Russia. Dr. Sethi has been on the panel of various national and international vitreoretinal meetings. His key areas of interest are retinal detachment and macular holes. [Email: drvaibhavsethi@gmail.com]

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INNOVATION OIS @EURETINA 2018

Optimizing Innovations in Retina by Khor Hui Min

Held at the joint EURETINAESCRS 2018 Congress in Vienna, Austria, the Ophthalmology Innovation Summit (OIS) discussed the latest developments in a variety of retina-related topics. The Summit was chaired by Dr. Emmett Cunningham Jr. (USA) and Prof. Dr. Sebastian Wolf (Switzerland).

Protecting ideas with patents

or aspiring inventors, Dr. Cunningham gave an interesting presentation on “Helpful Tips for Aspiring Entrepreneurs – A Venture Capital Perspective”. Here, he explained how ideas can be protected and emphasized the importance of filing before the idea is published or presented, noting that prior art is no

longer patentable. He also stressed the importance of choosing the right advisers, and explained what it takes to bring tools, devices and drugs to market, among other things. “You have to protect the intellectual property. That means you have to file with a patent office. In some countries, writing it all down in a notebook is enough to set a precedent, but not all,” said Dr. Cunningham. “Also, if you talk about something in public before you file, you can no longer file. If you talk about something you hope to patent in a scientific meeting like this, and the patent office can be shown you did that, then you cannot file that patent,” he warned. “You need to file before you present.”

Straight from the horse’s mouth: New developments in idea protection, screening, diagnosis and treatment

Screening newborns with AI There was also a fascinating presentation on artificial intelligence (AI), prepared by Dr. Jochen Kumm (CEO and founder of Healio) and Prof. Dr. Darius M. Moshfeghi (from Stanford University Medical Center). Here, they discussed using deep learning to screen all healthy newborn babies for eye diseases to prevent blindness. In this case, using AI is attractive because AI has business liability and not malpractice liability (in the case of physicians), it is scalable and reproducible, and it minimizes marginal costs. “Preventing blindness in babies has a large societal impact,” said Prof. Dr. Moshfeghi. “We have a database of over half a million images right now – the only database in the western world, because nobody else is actively

screening. The AI we developed has sensitivity between 93 and 98 percent.” “Initially, we will be screening the images to determine whether they are normal or abnormal,” he added. “After FDA approval, we will be screening for specific diseases.”

New molecule to treat uveitis In his presentation, Dr. Franz Obermayr, CEO of Panoptes Pharma (Austria), talked about the immune modulator PP-001. He explained that it was a unique anti-inflammatory novel molecule, with differentiating mode-ofaction, and it can be used to treat noninfectious uveitis (intravitreal PaniJect) and dry eye disease (nano carrier eye drop PaniDrop). He stated that PaniJect can be a replacement for steroids and other therapies. “Uveitis is a borderline orphan disease. Close to half a million patients in the USA are affected by noninfectious uveitis, and it’s one of the leading causes of blindness. And these people go blind (or are in danger of going blind) within three years. We are talking about 20 to 30 percent, despite all the treatments administered,” said Dr. Obermayr, adding that the current treatment is dominated by steroids.

The next generation of diagnosis An interesting presentation by Dr. Carlos Ciller, co-founder and CEO of RetinAI (Switzerland), discussed how technology will reshape the world of eye care. Here, he talked about improving workflows in diagnosis, access and integration, and enabling disruptive hardware. In diagnosis, he spoke about automatic biomarker detection for a multitude of eye diseases affecting the retina. Furthermore, Dr. Ciller talked about low-cost and smartphone-based integrated solutions, enabling remote access. He discussed next-generation devices that will provide low-cost but high-end medical hardware.

“

AI is changing the way we use images and information to accelerate the way we diagnose. We also need to educate the patients on how AI is going to help support the process, and educate clinicians that AI is going to empower them, not replace them.

”

– Dr. Carlos Ciller, co-founder and CEO of RetinAI (Switzerland) “Sometimes, eye diseases don’t manifest, they are already there. There are chronic conditions that cause irreversible damage if left untreated. And in cases we see all over the world, the diseases are not treated on time. That’s why eye disease screening is important,” said Dr. Ciller. “AI is changing the way we use images and information to accelerate the way we diagnose. We also need to educate the patients on how AI is going to help support the process, and educate clinicians that AI is going to empower them, not replace them,” explained Dr. Ciller.

Non-viral gene therapy to treat ocular disease Dr. Ronald Buggage from Eyevensys (Paris, France), presented on innovative non-viral gene therapies for the treatment of ocular diseases. He emphasized the need for new treatment approaches in retinal diseases, especially intravitreal injections, ocular implants, viral gene therapy, and systemic administrations. He then talked about the Eyevensys technology that provides an innovative

drug delivery platform that turns the eye into a biofactory. “Most of the approaches we have for delivering drugs to the back of the eye, although they may have resulted in commercially interesting treatments, have limitations,” said Dr. Buggage. “For example, with injections, you can inject anything in the eye, but the need to repeat those injections at intervals at high frequency has caused this commercially successful treatment approach to become a burden to both patients and the hospital system,” explained Dr. Buggage. “On the other hand, ocular implants do away with the need for frequent injections, but most of these implants only contain corticosteroids. So, what we end up doing with these types of treatments is trading off the management of the initial disease with the problem of managing the systemic complications of corticosteroids. We have to use a very high level of systemic treatment,” shared Dr. Buggage. “For now, gene therapy is limited to a small group of patients with inherited retinal diseases. We are just beginning to realize the potential of gene therapy, but it has to be administered with an invasive procedure, that is often not extended to the whole retina,” he said. “So, the ideal treatment strategy would be to take the good points from the commercially successful treatments (like injecting drugs and sustained ocular delivery) and using implants with no side effects, and then having these proteins that you would be producing in the eye, be replicated in the disease pathogenesis. That ideal treatment is what we are looking to develop,” Dr. Buggage explained. Editor’s Note: The Joint EURETINAESCRS 2018 Congress was held in Vienna, Austria, on September 20-26, 2018. Reporting for this story also took place at EURETINA-ESCRS 2018.

INNOVATION OPHTHALMIC TOOLS

Smartphones and Innovation

Creating Novel Solutions in Ophthalmology by John Butcher

nnovative ways to create costeffective ophthalmic equipment were presented by ophthalmic experts at the 12th Asia-Pacific Vitreo-retina Society Congress (APVRS 2018) in Seoul, Korea. Smartphones and cameras can provide an alternative to expensive commercial equipment that may be out of the reach of developing countries, they said. Dr. Anubhav Goyal, a consultant in vitreoretina and retinopathy of prematurity (ROP) services at Giridhar Eye Institute in India, spoke about a smartphone guided widefield imaging system for retinopathy of prematurity (ROP) that he has been working on, which he described as “a novel cost-effective initiative for a developing country.” “ROP is a vasoproliferative disorder of the retina seen in pre-term infants that is prevalent in India, where the incidence rate is 20 to 50 percent,” said Dr. Goyal. “On the other hand, the incidence rate of high-risk ROP is 10 to 25 percent.” “The incidence of blindness due to ROP is relatively low however; at around one case in 820 infants, due to good neonatal care and appropriate screening and treatment,” he added.

The smartphone solution According to Dr. Goyal, common tools for ROP screening include indirect ophthalmoscope, RetCam (Natus Medical, CA, USA), 3Netra Neo (Forus

Out with the old...

Health, Karnataka, India) and Optos ultra widefield retinal imaging (Optos PLC, Dunfermline, UK). “Digital fundus photography is used for ROP imaging and documentation and helps with consultation in difficult cases as well as contributing to medicolegal affairs,” Dr. Goyal told the audience. He explained that the portability and price of smartphone fundoscopy could share the advantages of widefield fundus imaging, either to document fundus status or to consult experienced ophthalmologists elsewhere, with a wider audience.

Dr. Goyal described his own observational study conducted between January and May this year using a smartphone (iPhone 5S) and either a 20D, 28D or 40D lens, to record video, using the original camera settings and a constant coaxial inbuilt light source. He said the image was good for 89 percent of test eyes, providing a clear view of optic nerve and vessels, where the grader could easily discern the dilation and the tortuosity of vessels or the presence of various ROP stages. “That was comparable to 90 percent to 99 percent good quality

“

We are moving from an era of bulky equipment that provided a lower resolution of fundus images to portable devices which are giving very good resolution of fundus images at a lower cost.

”

– Dr. Ashish Ahuja, Aravind Eye Hospital, India

images using the RetCam, 3Netra Neo and Optos,” he said. In addition to being cost-effective, he said the smartphone system was light-weight, portable and allowed for single-hand capture of images, leaving the other hand free for rotation and scleral depression for good periphery view. “For non-institutional practices and single practitioners, cost and portability are a major issue,” emphasized Dr. Goyal. “The smartphone system was also a useful tool for medico-legal documentation and telemedicine,

especially in developing countries such as India, where cost remains an important factor,” he added.

Portable, low-cost images for the win Furthermore, Dr. Ashish Ahuja, of Aravind Eye Hospital in India, also introduced his own “novel technique” for a low-cost video indirect ophthalmoscope. “We are moving from an era of bulky equipment that provided a lower resolution of fundus images to portable devices which are giving very good

resolution of fundus images at a lower cost,” he told the audience. The prototype he had been working on used a telephoto lens, a spy camera and a diffuser for illumination. The specifications of the spy camera were a resolution of 1080p, a 12 megapixels image at 30 frames per second, he added. “We used butter paper over the light source to create a diffuse illumination,” Dr. Ahuja told the audience. “Costing just 4,000 Indian rupees, the system allowed images to be viewed and transferred to others via Wi-Fi.” Aside from being an operating instrument, the system could be used as a training tool, allowing students to view an operation in progress, providing audio narration as well as images. “The future of fundus imaging should be portable, easy to use, nonmydriatic and provide good resolution at a low cost,” he said, before making a call for collaboration between scientists, engineers and others, as well as for funding, to develop such systems. Editor’s Note: The 12th Asia-Pacific Vitreo-retina Society Congress (APVRS 2018) was held in Seoul, Korea, on December 14-16, 2018. Reporting for this story also took place at APVRS 2018.

INNOVATION AMD THERAPY

Photobiomodulation

An Innovative, Mitochondria-targeted Therapy for Dry AMD and Other Ocular Diseases by Olawale Salami and Joanna Lee At the EURETINA 2018 congress, Janis Eells, Ph.D. and professor from the University of WisconsinMilwaukee, USA, provided a summary of the tremendous amount of work that has been done over the last 15 years toward better understanding the mechanisms of photobiomodulation.

hotobiomodulation is the process by which we obtain a biochemical reaction specifically by exposure to light. Following light absorption, photons stimulate mitochondrial cytochrome oxidase and turn on, via transcription factors, specific gene expression and protein synthesis.1 According to Dr. Eells, mitochondrial dysfunction plays a key role in cellular aging and degenerative disease. And in the retina, mitochondrial dysfunction is a contributing factor in the pathogenesis of retinitis pigmentosa (when mutations in the MT-ATP6 gene affect protein structure2), glaucoma, age-related macular degeneration (AMD) and diabetic retinopathy (DR). Ultimately, this progressive mitochondrial dysfunction results in oxidative damage, retina cell death and blindness. Dr. Eells explained that photoreceptors are highly active metabolically and are very vulnerable to oxidative stress. “Therefore, protection against mitochondrial dysfunction and oxidative stress in the retina is extremely important,” she said. In relation to oxidative stress, an animal study on the mechanism of photobiomodulation indicated that

Could light therapy help improve visual acuity in dry AMD patients?

low-level light therapy increases the proliferation of reactive oxygen species (ROS) in normal cells. However, when aimed at cells which are oxidatively stressed, the ROS levels are decreased, thereby reducing oxidative stress. Similarly, in inflammatory cells, it has been shown to produce an antiinflammatory effect and reduce reactive nitrogen species and prostaglandins in animal models as well. What’s more, photobiomodulation is said to affect the cell’s metabolism when general hemoproteins and cytochrome c oxidase (COX) absorbs the lowlevel light.3 In another study, the reprogramming of the photoreceptor’s metabolism offered a “survival advantage” for photoreceptors.4

As a reversible inhibitor of cytochrome oxidase, formic acid also plays a role in mitochondrial dysfunction. Dr. Eells and colleagues have shown that in animals, this can be reversed by photobiomodulation. Furthermore, in a rat model of retinitis pigmentosa, light treatment resulted in significant improvements in retinal function, and photoreceptor cell numbers. In an animal model of AMD, Dr. Eells and colleagues have also shown that specific wavelengths of light are protective against AMD, as shown by retinal cell numbers and functionality. “Randomized controlled trials will be needed to confirm these effects in human patients,” Dr. Eells noted.

To discuss the safety and efficacy of photobiomodulation in dry AMD subjects, Samuel N. Markowitz, M.D., director of the Low Vision Rehabilitation Program, Department of Ophthalmology, University of Toronto, Canada, on behalf of the study team, presented findings from the recently completed LIGHTSITE 1 trial.

IGHTSITE 1 was a clinical trial that assessed the safety, tolerability and efficacy of photobiomodulation in subjects with dry AMD. In the trial, 30 patients were randomized into two groups to receive either standard of care treatment for dry AMD plus photobiomodulation treatment with the LT-300 system (LumiThera, Washington, USA), or standard of care treatment for dry AMD plus sham treatment with the LT-300 system. The study’s primary outcome measure was visual acuity changes from baseline to month 12, while the secondary outcome measure was contrast sensitivity. Patients with dry macular degeneration in the study eye and best corrected visual acuity between 20/40 and 20/200 were included. Study participants were also required to provide consent. The study excluded patients with visually significant cataracts, presence of a visually significant posterior capsule (if prior cataract surgery has been performed), and patients with any visually significant disease process in any ocular structure that would affect vision, unrelated to macular degeneration. Also excluded were patients with severe clinically significant disease or unstable medical disorders including cardiovascular, hepatic, renal, neurological, endocrine, and gastrointestinal, CNS or life-threatening disease or current malignancy at the discretion of the investigators. The patients were treated with photobiomodulation to the retina at specific wavelengths to the eye three times a week for three weeks, repeated at six months and underwent follow-up for up to 12 months.

Visual acuity (VA) was measured using ETDRS VA letter scoring to test the difference between the sham and treatment subjects in mean change from baseline to month 12. Contrast sensitivity was measured using the FACT Contrast Sensitivity Chart to test the difference between the sham and treatment subjects from baseline to month 12. The study team also utilized questionnaires to assess the quality of life of patients following photobiomodulation treatment. Dr. Markowitz concluded that “photobiomodulation treatment in patients with dry AMD resulted in statistically significant improvements in visual acuity over the course of 12 months as compared to the sham treatment, improved contrast sensitivity and quality of life with no associated safety concerns”. Consultant ophthalmologist Dr. Igor Kozak from Moorfields Eye Hospital Centre in the United Arab Emirates further explained how this treatment, which has no thermal effects, works. “Photobiomodulation is also known as near infrared (NIR) light therapy which has been shown to increase

cellular metabolism, energy supply and metabolic repair processes5,” he said. “Its application to dysfunctional RPE in diseases such as age-related macular degeneration (AMD) is being hypothesized to restore function and attenuate the pathogenesis of AMD. It is believed that the effect is mediated via neutralizing reactive oxygen species from oxidative stress to mitochondria6,” Dr. Kozak continued. “AMD has been a clinical target for photobiomodulation therapy. The pivot clinical studies of photobiomodulation in AMD patients have reported some encouraging improvements7,” he said, adding it was hoped the results from the completed LIGHTSITE trial in Canada would help establish effective treatment parameters. Editor’s Note: The Joint EURETINAESCRS 2018 Congress was held in Vienna, Austria, on September 20-26, 2018. Reporting for this story also took place at EURETINA-ESCRS 2018. Dr. Kozak was generous enough to contribute on this story, but he was not a part of the mentioned studies.

References:

Geneva II. Photobiomodulation for the treatment of retinal diseases: a review. Int J Ophthalmol. 2016;9(1):145-152. 2 Rai PK, Russell OM, Lightowlers RN, Turnbull DM. Potential compounds for the treatment of mitochondrial disease. Br Med Bull. 2015;116:5-18. 3 Kim, H. P. Lightening up Light Therapy: Activation of Retrograde Signaling Pathway by Photobiomodulation. Biomol Ther (Seoul). 2014; 22(6): 491–496. 4 Wubben TJ, Pawar M, Smith A, et al. Photoreceptor metabolic reprogramming provides survival advantage in acute stress while causing chronic degeneration. Sci Rep. 2017; 7(1):17863 5 Karu T. Mitochondrial mechanisms of photobiomodulation in context of new data about multiple roles of ATP. Photomed Laser Surg. 2010;28:159–160. 6 Fuma S, Murase H, Kuse Y, et al. Photobiomodulation with 670 nm light increased phagocytosis in human retinal pigment epithelial cells. Mol Vis. 2015;21:883-892. 7 Merry GF, Munk MR, Dotson RS, et al. Photobiomodulation reduces drusen volume and improves visual acuity and contrast sensitivity in dry age-related macular degeneration. Acta Ophthalmol. 2017;95:e270–7. 1

About the Contributing Doctor Igor Kozak, MD, PhD, is a vitreoretinal surgeon and a retina and ocular imaging specialist who specializes in introducing the newest technologies into clinical practice. He is a graduate of P.J. Safarik University in Kosice, Slovak Republic and has completed both vitreoretinal and uveitis fellowships at the University of California, San Diego (UCSD). He also holds a master’s degree in clinical research from UCSD. He is currently a clinical lead at the Moorfields Eye Hospital Centre in Abu Dhabi, United Arab Emirates. His clinical interests include age-related macular degeneration, diabetic and hypertensive retinopathy, uveitis and vitreoretinal surgery. In his research, Dr. Kozak focuses on retinal diagnostic imaging and image analysis, retinal pharmacology and drug delivery systems. [Email: igor.kozak@moorfields.ae]

ENLIGHTENMENT WOMEN IN OPHTHALMOLOGY

Marriage, Moving and

Maternity

Managing the 3 M’s in a Woman Ophthalmologist’s Life by Tan Sher Lynn

ven today, women who choose to have both a career and family often find themselves in a precarious balancing act. This sensitive topic was explored by Dr. Nilutparna Deori during the All India Ophthalmological Society-Young Ophthalmologists Society of India (AIOSYOSI) Forum, held on November 25 in New Delhi, India. Her presentation, titled “Marriage, Moving and Maternity: Managing the 3 M’s in a Young Woman Ophthalmologist’s Life,” explored how a woman can thrive in her career, as well as in her family life. According to Dr. Deori, a pediatric ophthalmologist at Sri Sankaradeva Nethralaya (India), although marriage is a blissful relationship between a man and a woman, it comes with its own set of responsibilities, including household chores and childcare. In many societies, the lion share of domestic responsibilities and childcare still falls upon the female’s shoulders. “When male counterparts take on more household and childcare responsibilities, it will become easier for women to juggle career and home life. So, as a woman, if you have a partner who agrees and commit to pursue the same life path, values and goals, then it becomes easier for you. The most important and critical part is to

have a compatible partner in terms of personality, temperament and goals,” she said. After marriage, another phase often arrives – maternity. “Most working females avoid or delay maternity due to the fear of having to juggle a career and childcare. Those who attempt to do both may suffer from the criticism that they are not doing justice to both. There’s also the fear that they cannot be perfect mothers. The guilt comes in especially when they look at the face of their child, and it keeps increasing exponentially,” shared Dr. Deori. “So, women need to remember that they cannot be perfect. You cannot give 100 percent to both roles at the same time,” she remarked. Furthermore, Dr. Deori said that like the title of the book by Anuranjita Kumar, Can I have it all?, many career women wonder how they can flourish both in the home and at work. “Dr. Indra Nooyi [who is the chairman of American multinational corporation PepsiCo and was named the second most powerful woman in business by Fortune magazine in 2015] has publicly acknowledged that at some point, balancing family and work is a zero-sum game and she has chosen work, despite having a twinge of guilt that was sometimes hard to get past. Being a working woman means that you need to make adjustments, compromises and sacrifices every day,

which is inevitable,” she noted. After giving birth, some women may choose to take a career break in order to care for the child. “Taking a career break can be as fulfilling as it is daunting with its own set of challenges, including imbalances in spousal relationship, erosion of confidence and challenges of re-entry into the workplace,” she said. “After a maternity break, some women try to move forward with support from their family. Nevertheless, moving on comes with its own challenges and obstacles as well, because after taking a career break, you may be lost, confused, and unsure of where to start,” explained Dr. Deori. “You may not know your peers, your friends may have gone ahead of you . . . and you’re not sure how to build confidence. It can be a daunting period.” Because of this, Dr. Deori stressed the importance of planning ahead. “Sometimes, your career break can extend beyond the expected period and you need to have a backup plan. You need to keep in touch with people who are likeminded, who know your capabilities and believe that you can return to your dynamic self after a career break. Networking is

“

Freelance if you can. Teach classes for optometrists or students, or make yourself available to solo practitioners during times when someone can look after the baby.

”

not only important in academics and conferences, but also when you want to make a comeback.” She proceeded to share some tips on what women can do during their career break to make reentry to the workplace easier and smoother. “Freelance if you can. Teach classes for optometrists or students, or make yourself available to solo practitioners during times when someone can look after the baby,” advised Dr. Deori. She noted that doing so allows women to show in their resume that the time they took off is accounted for. It is also important to keep reading books and stay updated in subspecialties. “It’s easy to fall into a rut. So shake off the ennui and stay motivated and focused on getting back to work when the time comes. Reevaluate and streamline. You need to look at the schedule of your child and your working hours. How you streamline your life is depending on you – whether you make a

mess out of it or the most out of it. After having a child, there will be a significant shift in perspective in regards to how you treat your career,” she noted. She also stressed the importance for women to help each other in bridging the gap of a career break. “The statistics on working women in India shows that only two percent of women work in the healthcare sector. It is our role to bring that number up. We need to help one another to reach the podium of success,” she said. Dr. Deori concluded her session with a quote by Hema Ravichandar, former Global Head of HR for Infosys Ltd: “Remember, dear re-entrant, that you are the same capable person you were before your break – just a little out of practice. But wiser beyond years.” Editor’s Note: The AIOS-YOSI’s “Young Ophthalmologist – The Way Ahead” Forum was held on 25 November 2018 in New Delhi, India. Reporting for this story also took place at the AIOS-YOSI Forum.

INDUSTRY UPDATE

HOYA Surgical Optics Acquires Mid Labs and Fritz Ruck

OYA Surgical Optics (HSO), the intraocular lens (IOL) and related products division of HOYA Group (Tokyo, Japan), has acquired two medical device companies: Mid Labs (California, USA) and Fritz Ruck (Eschweiler, Germany). These acquisitions will broaden the company’s product portfolio, enabling it to better serve its customers’ broader needs for high quality ophthalmic products, equipment and services. Mid Labs is company focused on research, innovation, development,

engineering and manufacturing of ophthalmic medical surgical devices used to prevent blindness caused by certain retinal diseases and traumatic injuries. By leveraging Mid Lab’s bestin-class vitrectomy cutters, machines and other vitreoretinal surgical products, this acquisition provides HSO with the opportunity to enter the global retina market and continue its expansion beyond the current cataract market. Meanwhile, Fritz Ruck manufactures dual function phacoemulsification machines and

accessories, as well as distributes other ophthalmic devices and instruments. This will aid HSO in its aim to accelerate the growth of IOL sales, further solidifying its position as the fastest growing IOL company in the world and the global market leader in developing preloaded IOLs, the company said. HSO announced a definitive agreement to acquire Mid Labs and Fritz Ruck on 18 October 2018. For more information about Hoya Surgical Optics and its products, visit www. hoyasurgicaloptics.com.

ENLIGHTENMENT OPHTHALMIC FUTURE

The Future of Ophthalmology

Break On Through to the O by Khor Hui Min

phthalmologists and industry experts alike continuously put their heart and soul into developing the best diagnoses and treatments for eye disease – and these efforts are helping to raise the bar and yield better results. For example, artificial intelligence (AI) is a popular buzzword today, not only in ophthalmology, but in many other industries as well. Its potential usefulness is only limited by the imagination. “I had glaucoma and I had already lost 40 percent of my eyesight. The problem with my disease was that it couldn’t be detected. Finally, I could detect the disease with the help of my co-founder, who is a medical doctor,” said Kevin Choi, CEO of Medi Whale, South Korea. “I realize that low symptoms or no symptoms can be a very big problem. That’s why I set up Medi Whale. We

try to detect eye diseases in their early stages,” explained Mr. Choi. Medi Whale develops autoscreening products using AI to help people detect eye diseases. It is quite impressive that their AI can make a diagnosis in 30 seconds. Besides South Korea, this could possibly benefit other Southeast Asian countries that have problems involving combinations of eye disease and diabetes, for example. Currently, the screening system covers diabetic retinopathy, cataract and age-related macular degeneration (AMD). For each disease, 95 percent accuracy has been achieved. In early stage diagnoses and detection of eye diseases, there might be some false positives, but it is nonetheless a great benefit to society. And with these results, ophthalmologists can look forward to making more diagnoses with higher accuracy using AI in the future.

Looking toward lasers Although lasers have been used in eye disease treatment for quite some time, could they be the next gold standard? “In our training, we used antiVEGF for AMD treatments. I still prefer anti-VEGF treatment and only use laser treatment for patients who do not respond well to anti-VEGF, as a second line therapy,” said Dr. Kuo Chi-Hung, from the Department of Ophthalmology at National Taiwan University. “There are a few different types of anti-VEGF. If a patient doesn’t respond well to one, the ophthalmologist can switch to another anti-VEGF. The patient might have a better response to that. So, we have a few options for treatment,” added Dr. Kuo. “Laser always has some trauma on the macula. That’s the last thing we want to see, because it might cause scar formation. The patient’s vision might be affected.” Nonetheless, in the anterior segment, laser incision – instead of

“

What was not possible 10 years ago is easier to achieve now. For example, with 3D printing, we now can print using nylon, and even metal printing is possible. I think it’s possible that 10 years from now, everyone can have a 3D printer in their house, and the only intellectual property in it is the SD and files.

”

Other Side using microkeratome – has become a gold standard. Microkeratome is a precision surgical instrument with an oscillating blade that’s used to create the corneal flap in LASIK or ALK surgery. It is used to cut the cornea flap all over the world. “Maybe there is a future for lasers in the posterior segment. It might be useful for the treatment of diabetic macular edema (DME). Of course, younger ophthalmologists would like to try new things. And in Taiwan, we’re able to discuss new methods or ways for treatment with our teachers,” said Dr. Kuo.

Collaboration begets affordable care In India, many people do not have access to good healthcare and technology. Cost is a very big issue in India, and Dr. Ashish Ahuja is one of the doctors who is trying to solve this problem by bringing better healthcare to people, in even the most remote parts of the country.

Dr. Ahuja plans to set up an innovation lab in Mumbai to create a platform where doctors and engineers can collaborate. Many people have creative solutions and some of these innovations have the added advantage of being low cost as well. But sometimes, doctors do not know who to approach and how to go about it. “We will have software developers, virtual reality app developers, people who are working on augmented reality, data scientists, people working on artificial intelligence, 3D printing experts, biomedical engineers, mechanical engineers, etc., on one platform. They will be able to tell us the limitations – what is possible and what is not. And we can share our ideas on what devices we want,” shared Dr. Ahuja. “What was not possible 10 years ago is easier to achieve now. For example, with 3D printing, we now can print using nylon, and even metal printing is possible. I think it’s possible that 10 years from now, everyone can have a 3D printer in their house, and the only intellectual property in it is the SD and files. The files will be ready for 3D print, and we will be able to print whatever devices or components we need,” he added. So, how can we have good retinal eye care across India, even in the smallest villages in the rural areas? In the rural areas, the best quality equipment is not a necessity, but a working model will do. “For example, for a microscope, we can just get the lenses we need, and then we can use a 3D printer to print the components to hold the lenses. It is possible to decrease the cost by a factor of 10,” said Dr. Ahuja. “The technology that we have now was probably science fiction 20 years

ago. In the future, we might have fundus cameras located in convenient public places, where people can have images taken, and a report printed out. They can then go to see a doctor with this report.” “Also, the smartphone cameras of the future should probably be able to take good quality fundus images, which you can take in the comfort of your own home and send to your doctor.” During his fellowship, Dr. Ashish Ahuja worked on a video recording system for ophthalmology. Everybody was working on fundus imaging using smartphone cameras, but he decided to do research on something else. He devised a headset with condensing lenses to be used to image the retina. “I fixed a small spy camera in front of one of the eye pieces, and I used a telephoto lens. I could get a reasonably good video out of this setup. The device also has a Wi-Fi antenna and it relays the images to a smartphone for easy sharing. The cost is really low – about 4,000 Indian rupees. And it was a good working prototype,” said Dr. Ahuja enthusiastically, who received an award for his invention at the Asia-Pacific Vitreo-retina Society Congress (APVRS 2018), recently held in Seoul, Korea. It’s an exciting moment in the field, with ophthalmologists collaborating with various experts, to bring patients the machines, diagnoses and treatments of the future. And as technology advances, they will be able to bring costs down, so that patients can enjoy the best cutting-edge eye care at more affordable prices. Editor’s Note: This article is an excerpt of the PIE Talks Series, APVRS Seoul Edition. Full videos can be found in PIE Magazine’s YouTube Channel.

ENLIGHTENMENT YOUNG OPHTHALMOLOGIST

Seeking Inspired ideas for the next generation of innovation

by Tan Sher Lynn

ccording to vitreoretinal surgeon Dr. Ashish Ahuja, the brain can be trained to be innovative. Dr. Ahuja recently shared his insights and ideas about this interesting topic at the All India Ophthalmology SocietyYoung Ophthalmologists Society of India (AIOS-YOSI) forum in New Delhi, India. “I was working in a government hospital where a resident doctor often forgot to switch off the slit lamp light,” he explained. “This incidence made me think, how can we build a sensor which can automatically turn off the light after three to five minutes?” This kind of “innovation” – that is, finding simple solutions to improve aspects of both clinical practice and patient care – can sometimes be right in front of us. For example, in another

instance, he saw the need for a sensor to track the body posture of a patient who needed to maintain a face down position after vitrectomy surgery for 24 hours. As a result, the post-vitrectomy recovery device-sensor was born. Dr. Ahuja notes that ophthalmologists can also look at other subspecialties for inspiration.

“Charles Kelman revolutionized cataract surgery by using a dental instrument. We should go through the atlases of other subspecialties, like orthopedic, gynecology, cardiac surgery instruments . . . and ask ourselves: How can we use it [the instrument] in another way for eye care?” he said.

“Another way to be innovative is to question everything you see,” said Dr. Ahuja. “Can we use the instrument in a different way? Can a particular thing be made with a lower cost? Can we use some other material?” “It is important to prepare for failures and persist,” he added. “Focus on one project at a time and surround yourself with inspiration. It’s also important to discuss your ideas with others. Some people fear that their ideas might get stolen, but to the contrary, the idea gets more refined . . . and you will get a better outcome with teamwork,” he added.

From idea to innovation . . . Dr. Ahuja is also an advisor for a digital healthcare startup that is working on an artificial intelligence (AI) platform for screening retinal diseases. Here, he shares some his personal experience and work, some of which has been published. His first development is a smartphone-based clip lens which provides 30 times magnification of

the ocular surface1 – an idea that came to him when he read an article where researchers analyzed the blood constituents (red and white blood cells) using a smartphone. And smartphone-based technologies are increasingly being used and developed. Dr. Ahuja noted a few examples that have caught his eye, including: Smartphone Slit Illumination Imaging (by Chinese company MediWorks); Smartphone Autorefractor and the Smartphone Lensmeter (by Eyenetra), both of which are commercially available; smartphonebased thermal imaging; and a wideangle smartphone lens with that is in development in Hong Kong. His second innovation is the DIY Reduced Eye Model for Fundus Examination2 which consists of a stack of three lenses – one 18D and two 20D lenses (making 58D) attached together. These are taped to the Reti Eye plastic model at one end, and a piece of cardboard is placed in front of the lenses and the plastic film with a 6mm opening in the center, representing the pupil. This reduced eye model can be attached to the slit-lamp headrest with tape and viewed with a 90D or 78D lens or with the indirect ophthalmoscope. It is a low-cost model which would be helpful for training purposes as it will decrease the learning curve of the fundus examination. Dr. Ahuja’s third innovation is the low-cost video indirect ophthalmoscope (IO)3 made using an IO, telephoto lens and small spy camera (which is 1-2mm in size and has an antenna with battery), mounted to the side of the IO. Dr Ahuja is currently working with engineers to refine the model. Another technology rapidly gaining steam is AI. “Aiseon Healthcare is developing the diabetic retinopathy screening using artificial intelligence.

Computer generated algorithms marks out the images and aneurysms and gives a printed report whether the disease is referable or not. This technology will really pick up in the next five years,” he said. Also, Dr. Ahuja highlighted that 3D printing technology is gaining momentum – this is because printing 3D components can reduce the cost of vitreoretinal surgery. He shared his experience with 3D printing from the Moscon Hackathon 2018, which is the annual conference of the Maharashtra Ophthalmological Society. At this event, a team of doctors, mentors and engineers successfully developed a smartphone based gonioscope imaging device with the use of 3D printed mold and lenses in just two days – a feat which would have required months to accomplish without teamwork. “Teamwork is crucial for exponential innovation. With teamwork from experts consisting of electronic, mechanical, optic and biomedical engineers; 3D printing experts; artificial intelligence experts and virtual reality app developers; and with funding, more and more low-cost devices can be invented, ultimately benefitting the ophthalmology industry which is heavily dependent on gadgets,” explained Dr. Ahuja. With hope for a future where healthcare is accessible and affordable, he concluded: “A group of UK researches has developed an ultrasound probe prototype which costs about three to four-thousand rupees ($43 to 57 USD), so it is really possible to make innovative low-cost devices.” Editor’s Note: The AIOS-YOSI’s “Young Ophthalmologist – The Way Ahead” Forum was held on 25 November 2018 in New Delhi, India. Reporting for this story also took place at the AIOS-YOSI Forum.

References:

Ahuja AA, Kohli P, Lomte S. Novel technique of smartphone-based high magnification imaging ocular surface. Indian J Ophthalmol. 2017; 65(10): 1015–1016. 2 Ahuja AA, Adenuga OO, Ahuja AS. Do it yourself: Reduced eye for fundus examination. J Clin Ophthalmol Res. 2018;6:35. 3 Ahuja AA, Kamble A. Commentary: Change in trends of imaging the retina. Indian J Ophthalmol. 2018; 66(11): 1620–1621. 1

23 - 25 JUNE 2019 PARIS, FRANCE REGISTER NOW AT

www. macular t-meeting. c om FACULTY LIST Francesco Bandello • Caroline Baumal • Mohamed Bennani • Bahram Bodaghi • Alexander Brucker Neil Bressler • Susan Bressler • Usha Chakravarthy • Gemmy Cheung Chui Ming • Itay Chowers Salomon Yves Cohen • Catherine Creuzot Garcher • Karl Csaky • Emmett Cunningham • Diana Do Pravin Dugel • Michael Elman • Amani Fawzi • Bailey Freund • Alain Gaudric • Mark Gilles Agnes Glacet Bernard • Frank Holz • Lee Merrill Jampol • Laurent Kodjikian • Adrian Koh Alfredo Garcia Layana • Nicolas Leveziel • Anat Loewenstein • Bruno Lumbroso • William F. Mieler Joseph Moisseiev • Jordi Mones • Quan Dong Nguyen • Kyoko Ohno-Matsui • Giuseppe Querques Sam Razavi • Elias Reichel • Kourous Rezaei • Daniel Roth • Srinivas Sadda • Jose Sahel David Sarraf • Ursula Schmidt-Erfurth • Johanna Seddon • Oudy Semoun • Michael Singer Lawrence Singerman • Jason Slakter • Theodore Smith • Eric Souied • Richard Spaide Mayer Srour • Giovanni Staurenghi • Nadia Waheed • Lawrence Yannuzzi • Marco Zarbin Sandrine Zweifel

Dear Colleagues and Friends,

Dear Colleagues and Friends, MaculArt is an is international meeting dedicated to the wonderful state ofstate the art MaculArt an international meeting dedicated to the wonderful of in the field the of macula. It is our great pleasure to announce the third International MaculArt art field of macula. It is our great pleasure to announce the second Meeting, which willMaculArt be held inMeeting, the beautiful on June 23-25, International whichcity willofbeParis, held France in the beautiful city of 2019. Due to the great success of the first and second editions, the committee decided to renew this wonderful experience and organize MaculArt 2019.

Due to the great success of the first edition, the committee decided to Top Ophthalmologists from experience around the globe will be present sharetwo theiryears. knowledge renew this wonderful and organize MaculArttoevery and discuss major advances infrom our field. The scientific of MaculArt Top Ophthalmologists around the globeprogram will be present 2019 to will include clinical case sessions, poster sessions, free paper sessions, and 14 faculty share their knowledge and discuss major advances in our field.

sessions dedicated to exudative AMD, vein occlusion, diabetic maculopathy, myopic maculopathy, uveitis, and much more.

case sessions, poster sessions, free paper sessions, and 14 faculty

sessions dedicated to opportunity exudative toAMD, veininnovations, occlusion, diabetic MaculArt 2019 will also give the highlight hot topics and new imaging such as OCT angiography in addition to 3and lectures and 4 symposia given by maculopathy, myopic maculopathy, uveitis, much more. experts. We are also pleased to host a panel of international experts, which will provide a forum for retina thought leaders to present data and engage in a lively discussion. A topics and the newbest imaging such asPrize OCTAward. angiography in addition jury will nominate MaculArt image Finally MaculArt 2019 to will also 3 lectures and 4 symposia bybyexperts. Weand arefellows also pleased to host hold the Retina Games, a challengegiven driven residents

a panel of international experts which will provide a forum for retina thought to present data andprogram engage by in asubmitting lively discussion. We encourage you toleaders contribute to the scientific your abstracts A jury will nominate the best image Prize Award. and look forward to your support andMaculArt active involvement in this exciting event.

We encourage youus to incontribute to city the and scientific program by submitting We welcome you to join our magical enjoy all that Paris has to offer, from abstracts and look forward to your support and active hauteyour cuisine, world-class entertainment, summer shopping sales,involvement to breath-taking in this exciting event. museums. We welcome you to join us in our magical city and enjoy all that Paris has to offer, from haute cuisine, world-class entertainment to breath-taking museums. We will be honoured with your presence.

We will be honored by your presence.

Eric SOUIED SOUIED and and the the FFM FFM Organizing Organizing Committee Committee Eric Eric Souied, Mayer Srour David Sarraf, Johanna Seddon, Oudy Semoun

2 â&#x20AC;&#x201C; 4 JULY 2017 PARIS, FRANCE www.maculart-meeting.com

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APRIL 1, 2019

PIE MAGAZINE

SEOUL

APVRS 2018

CONFERENCE HIGHLIGHTS APVRS 2018 COVERAGE

Treating Diseases of the Retina

in Infants and Children by Hazlin Hassan

At the recently held Asia-Pacific Vitreo-retina Society congress (APVRS 2018) in Seoul, Korea, several ophthalmologists shared their experience and pearls of wisdom in managing potentially devastating conditions affecting children in a session called: Pediatric Retina and Retinopathy of Prematurity.

ith still developing or as immature organs, children’s eye care and visual needs differ from those of adults. For example, diseases like retinopathy of prematurity (ROP) – which predominantly affects premature infants – pose specific challenges in both examination and treatment. Overcoming these challenges is vital as this common cause of visual loss among children can lead to lifelong vision impairment if left untreated.

ROP risk: What are the factors? Dr. Sang Jin Kim, M.D., Ph.D., from the University School of Medicine in Seoul, explained that ROP is a very complex disease with a host of risk factors, including prematurity and oxygen treatment. There are maternal risk factors like hypertension, age, medication and smoking; prenatal and perinatal causes like chorioamnionitis, assisted conception and mode of delivery; as well as infant factors like race, ethnicity and gender. In addition, multiple births may also play a role, and there are other contributing influences like anemia, transfusions, thrombocytopenia, sepsis, and nutrition. “There is also evidence for a genetic basis for susceptibility to ROP,” continued Dr. Kim. “Whole exome sequencing of 100 phenotypically extreme preterm

infants revealed several variants with differences in allele frequency between severe and mild, or no ROP.” This is important as it suggests genetic factors may predispose patients to ROP. Dr. Kim noted several studies that investigated the frequency of specific genetic variants in premature infants with or without ROP. And although no genes reached genome-wide significance, the results revealed genes and pathways that may be important in the development or progression of ROP – which could ultimately aid preventing vision loss and blindness in these cases.

The effect of ROP progression on diagnosis and management Prompt diagnosis is imperative in all sight-threatening conditions – especially when dealing with children. In addition, keeping a watchful eye on disease progression and managing those changes is vital to patient care. “Proper screening and timely treatment of severe ROP are essential for successful outcomes,” began Dr. Park Shin Hae from the Catholic University of Korea, Seoul St. Mary’s Hospital. This is true for ROP – and for important markers of the disease’s severity, like plus disease, which is

Here’s to stopping pediatric retinal disease in its tracks.

characterized by severely abnormal dilation and tortuosity of central, posterior retinal blood vessels.* Dr. Park agreed: “It’s also essential to diagnose plus disease in an accurate and timely manner.” In her presentation, she explained that ROP could be understood as a disease of a continuous spectrum of retinal vascular abnormalities – and identification of vascular progression toward plus disease is critical for proper management. “A single retinal image may be insufficient to understand how the infant’s eye has been doing,” she cautioned. Currently, for ROP, wide-angle digital retinal photography is generally utilized – this allows serial comparison of vascular changes over time. “The role of serial montage images is important in the modern management of ROP as they allow direct comparison of retinal vascular progression over time,” explained Dr. Park. In addition, she says an automated algorithm could be a useful tool to monitor the progression of plus disease in infants undergoing ROP screening: “An incorporation of computer-based image analysis could provide a more consistent and precise identification of retinal vascular progression from serial photographs.”

Looking at outcomes: Anti-VEGF for ROP According to Dr. Wei-Chi Wu, M.D., Ph.D., from the Chang Gung Memorial Hospital in Linkou, Taiwan, treating ROP with anti-VEGF may have advantageous outcomes. “One benefit of anti-VEGF for ROP includes a higher success rate for zone1, or aggressive posterior retinopathy of prematurity (APROP). It [anti-VEGF] is also good for cases with tunica vasculosa lentis (TVL) and unstable systemic conditions,” explained Dr. Wu, noting that while less refractive errors are seen with anti-VEGF, there is also slow retinal vascularization. However, he notes that the long-term outcome of macular structures following anti-VEGF in ROP eyes remains unclear. Here, Dr. Wu describes a prospective study from January 2014 to June 2016. The study included children aged 4 to 6 with a history of type 1 ROP. The researchers found that patients treated with intravitreal bevacizumab (IVB) showed greater anterior chamber depth, thinner macular thicknesses and a greater incidence of normal foveal depression than children who underwent laser treatment. In addition, IVB-treated eyes were associated with less myopia and better bare vision than laser-treated eyes. This led Dr. Wu, along with the researchers, to conclude that “antiVEGF use for ROP may result in better anatomic and functional outcome if applied judiciously in selected cases.”

Managing surgical complications in ROP With any surgery, there is always a risk of complications – and patient outcomes depend on the physician’s ability to manage and correct any problems that arise. For delicate procedures, like vitrectomy for Stage 4 ROP, extra precautions might be taken to avoid or mitigate serious issues. During the session, Dr. Shunji Kusaka, M.D., from the Kindai University Faculty of Medicine in Osaka, Japan, shared his surgical

strategy for a successful procedure. Dr. Kusaka relayed several tips regarding this particular surgery. This included sparing the lens – or performing lens-sparing vitrectomy (LSV) if possible; releasing traction to the neovascular membrane (NVM); and not being aggressive, or not completely removing the NVM to avoid creating iatrogenic retinal breaks. He also recommended using anti-VEGF if neovascular activity is high for the 2 to 5 days before surgery – this will ensure less bleeding intra- and postoperatively. “Less is more,” he advised, noting while surgical results for vitrectomy for Stage 4 ROP are relatively good, various complications can occur, including: iatrogenic retinal breaks, breaks in the posterior retina, bleeding and lens damage. “The vitrectomy should be performed carefully and less aggressively.” “There patients should also be monitored long-term,” he continued. “Even after a successful vitrectomy for ROP, various complications can develop postoperatively, like vitreoretinal complications, myopia, glaucoma and cataract.”

Managing other pediatric conditions: Coats disease Coats disease was first described by George Coats in 1908. We now know that it presents in five stages, each with increasing severity. Dr. Peiquan Zhao, from Xinhua Hospital at the Shanghai Jiaotong University in China, shared his experience with managing stage 3 Coats disease in China. In his approach, Dr. Zhao uses a combination of instrumentation and medication, including: external subretinal fluid (SRF) drainage with a 24-G IV catheter; a two-port nonvitrectomy endolaser; anti-VEGF; and pars plana vitrectomy (although this is used less in cases of vitreous hemorrhage, retinal breaks and severe fibrosis, and tractional retinal detachment). “Using a two-port non-vitrectomy endolaser proved to be thorough and efficient,” he said, noting that

the endolaser ablation of normal and aneurysmal vessels was especially efficient in shallow retinal detachment. He also explained that in Coats disease, the aqueous VEGF level is increased – this can be reduced by laser and anti-VEGF. Dr. Zhao combines anti-VEGF with laser treatment, and has found that together they reduce vascular leakage, exudation and macular edema. “However, do be cautious of the risk of fibrosis after antiVEGF,” he added. In an explanation of this procedure, Dr. Zhao detailed results from his study, which comprised 28 eyes of 28 patients with stage 3 Coats disease. The study ran from June 2013 to June 2017, and included 24 males and 4 females, aged 1 to 11. The follow-up period was from eight to 68 months. Initial treatment included external SRF drainage with a 24-G IV catheter, two-port non-vitrectomy endolaser and anti-VEGF (intravitreal ranibizumab). In this study, no cases received pars plana vitrectomy (PPV) as initial treatment. Regarding anatomic outcomes, there were no cases that progressed to stage 4 or stage 5 and retina attachment was achieved in 26 cases (or 93 percent). As far as functional outcomes, he said that visual acuity (VA) could be measured in 22 cases. “Anatomic success can be attained, but it is difficult to improve vision in stage 3 Coats’ disease,” he said. “This modified treatment − external SRF drainage using 24-G IV catheter, endolaser photocoagulation via non-vitrectomy approach, antiVEGF treatment − is efficient for stage 3 (exudative total retinal detachment) Coats’ Disease as an initial treatment,” said Dr. Zhao, concluding that further studies are needed in the future. * Wallace DK, Freedman SF, Hartnett ME, Quinn GE. The Predictive Value of Pre-plus Disease in Retinopathy of Prematurity. Arch Ophthalmol. 2011; 129(5): 591–596.

Editor’s Note: The APVRS 2018 Congress was held in Seoul, Korea, from December 14-16, 2018. Reporting for this story also took place at APVRS 2018.

CONFERENCE HIGHLIGHTS APVRS 2018 COVERAGE

Shedding Light on Monotherapy and Updates in the Management by Joanna Lee and Brooke Herron

he future is looking a bit brighter for patients with polypoidal choroidal vasculopathy (PCV). Not only is imaging technology making it easier for clinicians to diagnose PCV, but recent studies are laying the groundwork to establish treatment guidelines. To discuss these revelations in PCV diagnosis, imaging, treatment and management, world-renown ophthalmologists recently convened at a Bayer-sponsored symposium at the Asia-Pacific Vitreo-retina Society’s annual congress in Seoul, Korea (APVRS 2018).

On clinical features and diagnosis While there is no universally accepted definition of PCV – its epidemiological aspects, clinical features and imaging characteristics can help with diagnosis. And according to Dr. Glenn Jaffe, from Duke University, North Carolina, USA, PCV has a variety of features. “It’s thought to be a subtype of age-related macular degeneration (AMD), characterized by a branching or polypoidal vascular network that lies between Bruch’s membrane and the retinal pigment epithelium (RPE),” he explained. In addition, Dr. Jaffe says that there is typically a choroidal thickening in PCV, and serous retinal detachments are more likely to happen in eyes with PCV than with neovascular AMD (nAMD). Its differential diagnoses include a variety of conditions: typical nAMD, central serous retinopathy (CSR), pathological myopia with choroidal neovascularization (CNV), choroidal hemangioma (with potential serious detachments), metastasis with serious detachments and lesions in the choroid, and posterior scleritis. To diagnose PCV, physicians must be aware of its characteristics on the various imaging platforms – and Dr. Jaffe says using a multi-modal

approach with different systems can help physicians make the most accurate diagnosis. Many ophthalmologists consider indocyanine green angiography (ICGA) to be the gold standard in PCV diagnosis. “With ICG angiogram you can have branching vascular networks, along with polyps . . . you can have polyps alone, and you can see these. I like to use dynamic ICGA because you can see different features in different phases of the angiogram that can give diagnostic, and even therapeutic, information,” shared Dr. Jaffe, adding that the late phases provide diagnostic information, too. “You can see a washout phase where the leaking goes away in a lesion that is not active. But in an active lesion, the hypercyanescence persists, so you know that the lesion is still active.” Of course, not every clinic has access to ICGA. And according to Dr. Jaffe, PCV can be diagnosed on other platforms quite effectively – if physicians know what they’re looking for. Using optical coherence tomography (OCT), PCV is seen as multiple, peaked pigment epithelial detachments (PED), (which may or may not be related to hemorrhages, exudation, pachychoroid or pachydrusen). It can also appear as a “string of pearls,” with multiple PCV structures under the surface of a detached RPE. He explained that on fundus photography (FP), orange-yellowish polyp lesions are an indicator of PCV, and OCT angiogram (OCTA) provides additional three-dimensional information about the lesion’s structure. Dr. Jaffe says that fundus autofluorescence (FAF) is an interesting way to look at the lesions, and the polyps can have a variety of appearances: “Most commonly, in about half of the cases, you see a hypo auto-florescent lesion with a surrounding ring of hyper autoflorescence . . . you can also see a

of PCV

reverse pattern, but this is the most common,” he shared. He also said that fluorescein angiography (FA) is not as helpful for diagnosis. “It tends to be more nonspecific, but it can show leakage,” he explained. “I think it’s more useful in follow-up where you can see leakage that either goes away or comes back depending on the treatment. So, it can demonstrate disease activity.” In addition to the diagnostic variances seen in imaging platforms, there are ethnic differences as well. The prevalence of PCV in Asians is higher than in Caucasians and African Americans (although Dr. Jaffe mentions this could be underdiagnosed in the West due to lack of ICGA systems). In Asians, PCV is more common in males, it appears in a macular location and it’s primarily unilateral. In other ethnicities, it’s more common in females, with a papillary location and is primarily bilateral. In any case, once a diagnosis is made, Dr. Jaffe notes that treatment is key: “More than 50 percent of untreated patients will lose two lines of visual acuity (VA) over 12 months.”

Determining treatment regimens Just as the definition of PCV is still in flux, so are the management and treatment regimens. Various clinical trials have reported that treatment with anti-VEGF alone or in combination with photodynamic therapy (PDT) is showing promise in managing PCV. During the symposium, Dr. Min Kim, assistant professor at Gangnam Severance Hospital and Yonsei University College of Medicine in Korea, discussed some of these study results and their implications. Regarding anti-VEGF monotherapy, several studies (like VIEW 1, VIEW 2 and APOLLO) show that patients treated with aflibercept monotherapy either maintained or improved visual gains. In addition, the APOLLO study

showed that 54.8 percent of patients had complete regression of polypoidal lesions at month 6; and by month 12 the number increased to 72.5 percent. The VAULT study is another example of aflibercept monotherapy, where patients with PCV gained an average of 9 letters at month 12 and showed an improvement in their central macular thickness. In the same study, 67 percent of patients had polyp regression after 12 months. Dr. Kim also highlighted results from first year of the PLANET study which looked at the safety and efficacy of intravitreal aflibercept (IVT-AFL) monotherapy for treatment of PCV. In this study, all patients received a three-loading dose of IVT-AFL. At three months, participants were randomized into two groups: one with an active rescue PDT arm, the other with a sham arm. At 52 weeks, there was an option for treat-and-extend (T&E). In the first year, investigators found that patients gained an average of 10 letters and only 15 percent of participants required rescue PDT. At the end of year one, they concluded that IVT-AFL monotherapy was noninferior to IVT-AFL plus PDT. In addition, real world studies are corroborating this clinical trial data. In two different post-marketing studies (PMS) in Japan and Korea, patients with PCV treated with IVT-AFL achieved vision gains similar to the PLANET study.

Exploring PLANET’s year two results Adding to the conversation on aflibercept monotherapy was Dr. Tien Yin Wong from Singapore National Eye Centre (SNEC), who discussed year two results from the PLANET study. “The idea behind the PLANET study was to show the non-inferior qualities of monotherapy,” explained Dr. Wong. “So, if indeed it [PCV] is what we’re now thinking, that it’s a type 1 CNV AMD, what would you expect PLANET to show over two years?” Dr. Wong says that from 52 to 96 weeks, patients maintained a nine to 10 letter gain – and this is a good outcome

for patients. In addition, 94 percent of study participants avoided a loss of vision and more than 80 percent had a dry retina at 52 weeks and up to 96 weeks. “Basically, this fits with our clinical experience of treating PCV like nAMD,” said continued Dr. Wong.

Polyp activity versus regression Another outcome of PLANET assessed polyp regression. At 96 weeks, about 30 percent of patients had complete polyp regression – suggesting that two-thirds of patient had some sort of polyp. But are they active polyps? Not necessarily, in fact more than 80 percent did not have active polyps. This is where Dr. Wong makes an important distinction between polyp activity and regression. “Sometimes, polyps are seen (on ICGA) without any activity – meaning there’s no fluid or impact on function. You may not need to treat if those polyps have not regressed, and if there is no activity” he said. “An active polyp is not the same of having one that’s just still there.” Dr. Wong says that longer term data is needed to determine if aflibercept monotherapy is sufficient for complete polyp regression, noting that patients who received rescue PDT did not have any additional polyp regression.

So, what about PDT? Studies, like those mentioned above, have shown that IVT-AFL monotherapy has several benefits over PDT combination therapy. It provides meaningful outcomes in diverse disease subtypes; it’s a simple regimen with no need to purchase specialized equipment; and it avoids the potential long-term side effects associated with PDT. So, with that said, what role should PDT play in the future? Dr. Kim warns against mandating PDT at baseline – this could result in overtreatment for many patients, noting that at week 12 of the PLANET study, only 6 percent of patients qualified for rescue PDT treatment. “Anti-VEGF monotherapy is a simple regimen, and there is no need

to access special equipment,” said Dr. Kim, explaining that PDT requires more preparation, is more time-consuming to perform, is costlier to acquire and maintain, and requires specific training. There are also side-effects associated with long-term use of PDT. “Treating these patients repeatedly with PDT could result in the occlusion of the choriocapillaris which may lead to RPE atrophy,” said Dr. Kim. He also mentioned other studies concerning long-term PDT use – one of which found a 64 percent recurrence of polypoidal lesions and an abnormal branching vascular network (BVN) in all patients. Thus, the PLANET study is setting the stage to enable PDT to be reserved as a rescue treatment. Dr. Kim notes that this combination therapy (IVT-AFL plus rescue PDT) could be considered in the following cases: if there’s a loss, no change or insufficient VA gains; if persistent fluid is showing on OCT; or if active polyps are observed on ICGA. Dr. Wong also mentions that PDT does not help non-responders: “We know that in all AMD cases, there is a group that will not respond . . . the fluid will be there and it will be difficult to improve their vision.” And he says that patients who don’t respond to monotherapy likely won’t respond to PDT either: “The small group that’s not responsive – even if you want to do PDT, it doesn’t help that much anyway. This group just doesn’t respond.” Overall, results from PLANET (and other studies) have shown that IVT-AFL is non-inferior to combination PDT therapy. In addition, the average number of injections was reduced in the second year of PLANET (where there was a treat-and-extend option), from about 8 injections to 4.6 – which can help ease the treatment burden on both patients and doctors. And, indeed, these results certainly pave the way for improvement in diagnosis and treatment for patients with PCV. Editor’s Note: The APVRS 2018 Congress was held in Seoul Korea, on December 14-16, 2018. Reporting for this story also took place at APVRS 2018.

CONFERENCE HIGHLIGHTS RISHI-VRSI 2018 COVERAGE

RISHI at VRSI 2018 Highlights the Crucial Role

of Imaging in Retinal Diseases

Uncovering insights into dome shaped maculopathy.

by Olawale Salami and Gloria D. Gamat

Media MICE Pte Ltd, the parent company of PIE Magazine was the official media partner at the annual conference of the Vitreo Retinal Society of India held in Jaipur (VRSI 2018). The Retinal Imaging Symposium in the Hills of India (RISHI) was held prior to VRSI 2018. Below are some of the highlights from PIE Magazine’s coverage of the RISHI event.

OCT angiography: In search of the next ocular vital sign With improvements in “interpretation software, OCTA could become one of the ocular vital signs,” said Dr. Glenn Jaffe. Optical coherence tomography angiography (OCTA) is becoming an integral part of vitreoretinal examination. Dr. Glenn Jaffe from Duke University Eye Center in the United States provided critical insights into the applications of OCTA in both routine clinical and research setting. He noted: “When you consider the advantages and disadvantages of this technology, it really brings to life the utility of using it in the clinic and also highlights some of its unmet needs.”

OCTA has a lot of key advantages including its ability to see depth-resolved blood flow, show retinal vasculature and the absence of confounding leakage. In addition, OCTA is non-invasive and image acquisition is fast. However, OCTA has peculiar disadvantages, which include its long interpretation time, absence of information on leakages (which could be useful in some situations), small field of view and presence of artifacts. Therefore, to overcome the disadvantages of OCTA, automatic algorithms and deep learning approaches have been deployed to speed up the interpretation time. In addition, integrated artifact removal software and faster scanning time have led to remarkable advancements in image quality and resolution, while image montaging has helped overcome the small field of view.

For vitreoretinal surgeons who are not fully familiar with OCTA, there is one important question: How would I use that technology in the clinic? “One can think of OCTA as a fluorescent angiogram that can be used when it helps with the diagnosis and monitoring,” advised Dr. Jaffe. “OCTA is particularly helpful for multimodal assessment,” he added. Furthermore, Dr. Jaffe noted that artifact recognition is an important consideration of regular OCTA. These artifacts come in a variety of forms: shadowing, signal attenuation, segmentation artifacts and motion artifacts. In addition, false negative blood flows and projection artifacts are particularly associated with OCTA use. So, how can we recognize these myriad OCTA associated artifacts? The secret, according to Dr. Jaffe, lies in cross sectional scans with flow overlay, and he elegantly demonstrated this to the audience, using multimodal images from five clinical cases. “In selected cases, the multimodal approach will allow the use of OCTA in the recognition of artifacts,” he concluded.

Dense B-scan OCTA, to the rescue in AMD-related type 3 neovascularization Dense B-scan OCTA can help “show the implantation of Muller cell processes and vascular elements into the basal laminar deposits, which defines type 3 neovascularization and distinguishes it from other lesions with similar multimodal imaging features,” explained Dr. Bailey Freund. About one-third of newly diagnosed Caucasian patients with neovascular AMD present with type 3 (intraretinal) neovascularization (NV), and these patients are at a high risk for bilateral involvement and atrophy. Currently, there is limited knowledge on the characterization of these type 3 NV lesions. However, dense B-scan OCT has emerged as a technique to get

better quality structural B-scans with flow overlay. Dr. Bailey Freund from the New York University School of Medicine in the United States explained that the clinical findings of type 3 NV are intraretinal hemorrhage, hyperpigmentation, drusen and/or subretinal drusenoid deposits; while OCT findings are intraretinal fluid and intraretinal hyperreflective lesions. But how do these lesions appear on OCTA? Dr. Freund highlighted that type 3 NV lesions are visible in the mid retinal layers and are both fed and drained by retinal vessels. Particularly, he noted that these lesions do not contain retinochoroidal anastomoses. Over the past few years, Dr. Freund and colleagues have evaluated the clinicopathological correlation of anti-vascular endothelial growth factor (anti-VEGF)-treated type 3 NV in AMD, and their findings are quite interesting. They showed that in these patients, the intraretinal complex was associated with the splitting of the retinal pigment epithelium and Muller cells’ deposition into the basal lamina, leading to adhesions. According to Dr. Freund, the identification of type 3 NV has significant connotations for monitoring patient outcomes, especially monitoring response to anti-VEGF treatment.

Understanding dome-shaped maculopathy As far as we know, serous “retinal detachment associated with DSM is refractory to anti-VEGF; spironolactone reported to be successful in one case, and some cases may require no treatment,” said Dr. Adrian Koh. Dome shaped maculopathy (DSM) is not a new entity. However, it has received little attention from retinal surgeons, according to Dr. Adrian Koh from Eye & Retina Surgeons, Camden Medical Centre in Singapore. There is no consensus among vitreoretinal surgeons concerning the best treatment of DSM. Several treatment modalities

have been tried, such as anti-VEGF agents (i.e. aflibercept), spironolactone and micropulse laser therapy (MPLT), but with generally poor outcomes. Dr. Shrinivas Joshi from M.M. Joshi Eye Institute, Hubballi, Karnataka, India, presented the case of a 66-yearold male myopic patient who presented with an eight-year history of diminution of vision in the left eye. Prior to presentation, he had been treated with a single dose of anti-VEGF, without improvement. Examination revealed a dome shaped macula and significant amounts of subretinal fluid. At onemonth follow-up, the patient showed little or no improvement based on OCTA. Further insights into the pathogenesis of DSM were provided by Dr. Koh. He summarized that currently, DSM is described as an inward convexity of the macula occurring in highly myopic eyes within the convexity of the posterior staphyloma. Dr. Koh stated that not all DSMs have the classic dome shaped configuration; therefore, radial scans are needed to detect them. He added that several complications may arise from DSM, and of these, choroidal neovascularization is the most common, occurring in about 41 percent of patients. Other complications include diffuse chorioretinal atrophy, serous retinal detachment, macular hole and extrafoveal retinal schisis.

Dengue virus infection can cause DIIFOM of the fovea Intravitreal signs may show “resolution, but resolution of ischemic damage may be incomplete even three months after dengue infection,” noted Dr. Vishali Gupta. A new clinic-pathological syndrome of dengue maculopathy has been described and it’s called DIIFOM, which stands for Dengue-induced ischemic inflammatory foveolitis and outer maculopathy. Dr. Vishali Gupta and colleagues at the Postgraduate Institute of Medical Education and Research (PGIMER) in

CONFERENCE HIGHLIGHTS RISHI-VRSI 2018 COVERAGE Chandigarh, India, described dengue maculopathy in a cohort of 16 patients who were diagnosed based on positive dengue serology. General clinical features at presentation were consistent with dengue fever and anterior chamber inflammation was absent in all patients. Dr. Gupta noted that about 1 in 3 eyes showed superficial retinal hemorrhages in the macular area, while no evidence of retinitis was observed. The authors of this study went further to evaluate the macula using swept-source OCT and OCTA. They found foveolitis in 69 percent of eyes and all eyes showed edema of the outer plexiform layer and external limiting membrane (ELM) disruption. At the three-month follow-up, Dr. Gupta and colleagues observed complete resolution of foveolitis and outer plexiform edema in all eyes. However, focal disruption of the ELM was persistent in about 20 percent of patients, and these patients continued to experience scotomas. In addition, persistent flow deficit in both superficial and deep plexuses were seen, which correlated with visual acuity. Two pathophysiological mechanisms were proposed by Dr. Gupta and colleagues: an ischemic and an inflammatory mechanism. So, what will be the impact on outcomes to patients with dengue maculopathy? Dr. Gupta noted that while steroids can be used to control the ischemic component of DIIFOM, the outcome of ischemia following steroid therapy remains unknown.

Doing big things with big data in retinal diseases Big data is driving the machine “learning revolution and is helping to validate it,” said Dr. Adnan Tufail. According to a recent report from IBM, about 90 percent of the world’s information has been created in the last two years and we generate 2.5 quintillion bytes of data every day. There’s not enough space to fit all the zeros in that number! And this will only increase, as it’s estimated that 30 to 50 billion devices will be connected

to the internet by 2020. Therefore, it’s important to understand how to use this data to address challenges in retinal disease diagnosis and treatment. According to Dr. Adnan Tufail from Moorfields Eye Hospital in the United Kingdom (UK), big data could be useful in understanding the effectiveness of new treatments when introduced into real life populations, outside the tightly controlled environment of clinical trials. In settings like the UK, the availability of structured AMD data from electronic medical records was an opportunity to analyze outcomes of patients receiving anti-VEGF. Therefore, Dr. Tufail and colleagues, designed a study with the aim of providing real world outcome data, providing benchmarks for therapy and establishing predictive models. Following ethical approval, Dr. Tufail and colleagues had access to records of more than 11,000 wet AMD patients who received approximately 90,000 injections at 333,000 follow-up visits across 16 centers in the UK. Overall, the authors analyzed 2.8 million data items. One key outcome of this study was that following anti-VEGF injections for AMD, visual acuity state – and not visual acuity change – was what patients found most meaningful. It is an exciting field and there are many data useful data sources out there. Dr. Tufail explained recent attempts towards multimodal data sources like sensors, devices, internet searches, bio-banks and the linkage of these data sources. An example of this is the use of a new, home-based OCT, equipped with an artificial intelligence (AI) algorithm that interprets retinal images and sends a message to the patients’ physician. So, can big data help reduce physician workload and cost of managing retinal diseases? Dr. Tufail described the RETMARKER and EYEART machine learning algorithms which have been used on more than 30,000 patients. “These algorithms have identified 100 percent of referable diseases and have saved costs of around 10 million GBP per year,” said Dr. Tufail. There is a plan to roll this out to all centers in the UK. “A wealth of big, real world data

is available to benchmark outcomes. In addition, big data can inform personalized medicine approach with the totality of the data,” concluded Dr. Tufail.

Counting what matters: Retinal biomarkers from OCT OCT biomarkers can “helpQuantifiable predict outcomes based on baseline characteristics, response to anti- VEGF and natural history,” said Dr. Faisal Beg. Modern OCT imaging scanners provide high quality images of the human retina. However, pretty images aren’t enough. Retinal surgeons need quantifiable markers to classify disease, decide on optimal treatment strategies and monitor treatment response. According to Dr. Faisal Beg, Professor, School of Engineering Science, Simon Fraser University, Canada, to be clinically useful and available for decision making in a timely manner, the whole process of quantification of retinal OCT images needs to be automated. He provided examples of critical OCT image parameters for which algorithms for quantification have been developed. These are measurements of retinal layer segmentation and thickness measurements, microvasculature segmentation and density, fluid segmentation and area measurements. On the other hand, Dr. Koh provided an insight into the use of retinal biomarkers for disease prognostication. Biomarkers such as the length of retinal ellipsoid zone restoration have been used to assess response to anti-VEGF therapy and visual acuity in AMD. Other retinal biomarkers, such as hyperreflective foci have been studied as quantifiable markers of retinal diseases, and according to Dr. Koh, are associated with poor outcomes in AMD and correlate with severity of diabetic maculopathy. Choroidal thickness decreases progressively with age and AMD patients have thinner choroids. Dr. Koh noted that baseline choroidal thinness is a negative prognostic factor for VA gains.

“OCT has become an indispensable diagnostic tool in modern ophthalmology and has facilitated the treatment of macular diseases with antiVEGF agents. Today there is a paradigm shift towards specific morphological changes relevant for visual function, treatment outcomes and disease management,” Dr. Koh concluded.

AMD and masquerades: Don’t get fooled again Beware of these genetic “dystrophies that can be misdiagnosed as AMD and CSCR and consider genetic testing to avoid unwarranted injections and laser therapy without a proper diagnosis,” noted Dr. David Sarraf. Retinal surgeons need to be aware of diagnostic entities that can masquerade as AMD. These include geographic atrophy (GA), macular detachment, and others. Dr. David Sarraf from the Stein Eye Institute, University of California Los Angeles, United States, discussed several cases where retinal surgeons need to be on the lookout. “In one of our patients presenting with what appeared to be geographic RPE atrophy, further evaluation revealed that the patient had spinocerebellar ataxia 7,” he said. In some cases, GA may be associated with a golden tapetal fundus. In this instance, think of a prgR mutation. In addition, a variety of other genetic mutations associated with cone rod dystrophy may present as geographic atrophy. “Watch out for Stargadt’s disease, in which there is complete loss of choriocapillary, so dark atrophy is seen with indocyanine green angiography (ICGA), whereas in AMD, there is incomplete loss, so you’ll see hyperfluorescent geographic atrophy on ICGA. On OCTA, there is fulminant loss of choriocapillary and intact surrounding areas in Stargadt’s, whereas it’s thin, with attenuated edges in AMD,” Dr. Sarraf warned. “Best disease (vitelliform macular degeneration) is one of those rare diseases that can present with macular detachment and masquerade as AMD

Don't get fooled: Other pathologies can masquerade as AMD.

or central serous chorioretinopathy (CSCR),” explained Dr. Sarraf. “There is associated retinal pigment epithelium channelopathy, leading to apical microvilli disruption. This can be further driven by thick choroids, especially in older patients causing fluid to accumulate in the subretinal space,” he said. Furthermore, Dr. Sarraf noted that in patients who are chronically unresponsive to currently available antiVEGF and laser therapy, doctors should consider Best disease.

Are two retinas on the same person exactly the same? Assessing symmetry of the foveal avascular zone in OCTA No significant differences were “observed between two eyes of the same subject using FAZ area, when corrected for axial length,” said Dr. Judy Kim. When it comes to the eyes, it is generally assumed that two eyes are symmetric – and in many patients with retinal diseases, the contralateral eye is often used as the control. Therefore, it’s important to understand if indeed the two eyes in the same patient are truly symmetric. To answer this, Dr. Judy Kim and colleagues from the Medical College of Wisconsin looked at the foveal avascular zone (FAZ). There are many ways to quantify the FAZ. These include the area, the axis ratio, acircularity and the major horizontal axis. Dr. Kim and

colleagues aimed to provide an answer to the question of symmetricity of the FAZ and the comparability of the various published FAZ metrics. To do this, they studied data from 170 subjects with no known ocular or systemic diseases aged between 7 and 77 years. They imaged both eyes in each subject and measured axial lengths. Each image was segmented twice by the same observer to reduce segmentation errors and metric underwent multivariant component analysis. What were the results of this interesting study? The authors found that the FAZ area captured individual differences in FAZ morphology. However, no significant differences observed between the two eyes on the same subject using FAZ area, when corrected for axial length. Therefore, Dr. Kim concluded that two eyes on the same subject are symmetric when assessed using the FAZ area. Next, they evaluated the use of axis ratios, and found that there was no asymmetry in both eyes on the same subject due to the high degree of variation in the shape of the FAZ. Furthermore, Dr. Kim reported low overall variance in acircularity between eyes of the same subject. “FAZ area seems to be the best measure of inter subject variability. More studies of combinations of FAZ metrics may be needed to identify most clinically relevant combinations,” she concluded.

CONFERENCE HIGHLIGHTS COPHy AA 2019 COVERAGE

Acknowledging the Role of

Steroids in RVO Treatment by Gerardo D. Sison III

teroids are becoming an integral part of the management of retinal vein occlusion (RVO). And as a result, new parameters have been reviewed regarding which steroid(s) to use and when to use them. At the recently held 5th Annual Congress on Controversies in Ophthalmology: Asia-Australia (COPHy AA 2019) which took place in Shanghai, China, a panel of experts and specialists revealed their thoughts and conclusions on steroids in ophthalmology. In this article, we’ll go over the nuances of steroid use in RVO and what, if any, place they have in practice.

Not all steroids are the same Potency and overall utility differs across the many steroids available. For instance, triamcinolone is five times more potent than cortisol, whereas dexamethasone is 25 times more potent. But there are more differences to note. What actually distinguishes one steroid from another? According to Dr. Barry Kupperman from University of California-Irvine, USA, every steroid has their own mechanism of suppressing cytokines. Due in part to their unique structures, steroids can also up-regulate and alter the expression of thousands of genes.

From his own laboratory, Dr. Kupperman found that steroids exhibit their own toxicities that can often be masked by apparent benefits. He explained that, “while triamcinolone causes some toxicity to retinal cells in cultures, dexamethasone and fluocinolone do not appear to”. All steroids, to varying degrees, can cause cataracts and intraocular pressure (IOP) issues. From cell culture work, Dr. Kupperman described how the affinity of dexamethasone to the human trabecular meshwork is much less than that of triamcinolone and fluocinolone. “This may explain the

All steroids are not the same...

CONFERENCE HIGHLIGHTS COPHy AA 2019 COVERAGE slightly lower rate of cataracts from dexamethasone, as well as the easier management of IOP issues associated with it compared to triamcinolone and/ or fluocinolone,” he said. Water solubility also differs within each steroid, with dexamethasone having the highest solubility. Dr. Kupperman explained that this can be a double-edged sword. Because solubility indicates a shorter half-life in the eye, the drug can leave the eye faster without inducing lingering effects. However, it may have a shorter active effect. He also stated that, despite their differing efficacies, the risk for intraocular hypertension is still associated with the use of steroids. The incidence of intraocular hypertension was 15% in dexamethasone versus 30 to 40% in triamcinolone and 60% in fluocinolone. Clinical applications of steroids therefore have their own caveats. Regardless of treatment used, Dr. Kupperman advised to treat early for RVO. The dexamethasone implant can work rather quickly with initial effects seen within 24 hours and dramatic effects apparent within 1 week. Because IOP and cataracts can be easily managed with dexamethasone implants, it may be the more preferred steroid from a pressure elevation standpoint.

Outcomes in clinical trials As exemplified in the GENEVA study, dexamethasone intravitreal implants exhibited improvements in mean visual acuity compared with sham treatment (P≤0.006). The percentage of eyes with a ≥15-letter improvement in visual acuity was higher in the implant groups although there was no significant

difference in the occurrence of cataracts or cataract surgery compared to sham groups. In regards to the RVO natural course, the initial visual acuity is closely related to the final prognosis of the patient. As presented by Dr. Sun Xiaodong from China, 87% of patients with ischemic CRVO have a final visual acuity of less than 0.05. This is distinguishable from the fact that half of those patients with BRVO can maintain visual acuity above 0.5. Dr. Xiaodong explained that RVO treatment mainly lies in the treatment of complications. Visual impairment in patients with RVO is typically caused by macular edema (ME) which is the most common complication, among others such as retinal neovascularization and neovascular glaucoma. Fortunately, there are currently approved RVO-ME treatments such as laser photocoagulation, ranibizumab, aflibercept and dexamethasone implants. Further results were emphasized by Dr. Xiaodong where he compared the GENEVA study with an identical phase 3 study based in China. This trial evaluated the safety and efficacy of dexamethasone intravitreal implant compared with sham treatment in Chinese patients with ME due to BRVO or CRVO. While mean IOP peaked at 2 months, Dr. Xiaodong mentioned that no accumulated effect was observed after retreatment. The results of the China registration study showed that dexamethasone improved visual acuity in both BRVO and CRVO during the first 3 months where similar improvements

were also seen with CRT in both BRVO and CRVO. Dexamethasone implants overall provided long-lasting and significant anatomical and functional improvements in Chinese patient populations with RVO. Dr. Xiaodong also reviewed another study based in China comparing intravitreal dexamethasone with intravitreal ranibizumab for ME. Both dexamethasone and ranibizumab reduced CMT while also improving visual acuity at each follow-up. Although dexamethasone was accompanied with more side effects such as IOP, it required a lesser mean number of injections due to its sustained release.

How real-world data in RVO can affect actual practice While clinical results may prove to be informative, there is still something to be said for ophthalmologists who practice and report real-world data. This data often begs questions like, “what is going to provide sustained visual improvement for my patient in the long run?” and “what are my options for patients who are non-responsive to particular treatments?” As a supplement to the discussion, Dr. Marc De Smet from Canada, went over current practices in ophthalmology regarding RVO treatment. He stated that anti-VEGF treatment is certainly effective based on clinical trials with 40 to 50% of patients achieving a 20/40 vision or better. However, he also stated that “there is a drop-off over time” with those who require sustained injections becoming a problem in the long run.

In contrast with anti-VEGF treatment, Dr. De Smet noted that dexamethasone (Ozurdex, Allergan, Dublin, Ireland) is released over a long period of time, with maximized release at 1 month followed by stabilized release for 2 months. Depending on how severe the occlusion might be in an RVO patient, low drug release after this period may be sufficient enough for those who do not have severe ME or ischemia. Otherwise, for severely affected patients, Dr. De Smet recommends retreating due to the need for more steroids. It is also important to consider patients who have had a vitrectomy as the release of Ozurdex will be sustained over a prolonged period of time. Dr. De Smet clarified that those who had a delay in treatment never reach the sort of recovery seen in those patients who were initially treated with a steroid. “With each month of delay, there is less chance of improved vision and recovery,” he said. Dr. De Smet also explained that 15 to 20% of patients with less severe BRVO will respond with one or two injections and be fine. “Although age is not much of a predicting factor of resolution, naive and early treatment can determine the number of injections needed,” he added. Some patients will require more injections depending on the degree of ischemia present or whether the patient is tackling a more severe situation.

When asked about treatment parameters in the conversion to ischemic RVO, Dr. De Smet affirmed the use of steroids to prevent inflammation. Thus, while the prognosis may be altered, he did not indicate a change in treatment in these cases. He concluded that anti-VEGF response is limited in many patients. A less than 25% decrease in CMT on anti-VEGF with the first injection can often elicit a poor response long term. Therefore, Ozurdex can be considered for both early and late treatment as well as a first line therapy, he said.

Defining early use in RVO Results from the pivotal GENEVA study can at times obscure the shortcomings of the study, such as longer duration of ME and less optimal injection frequency. Patients were retreated at 6 months, although real-world data often indicates use of injections as early as 3 to 4 months as needed. In highlighting results from the COBALT study, Dr. Young Hee Yoon, a clinician from South Korea, answered the question of early use in RVO. The COBALT study modified the GENEVA study design and implemented

an early treatment strategy in naive patients of less than 3 months duration. It also modified the treatment interval to every 4 months. Consequently, these changes resulted in 65% of participants achieving a ≥15 letter gain at month 6, as well as a mean gain of 18.6 letters in BCVA at month 6. Overall, Dr. Yoon expressed that early treatment of BRVO-associated ME with dexamethasone implant significantly and safely provides BCVA and CRT improvements. As early as 1 week, treatment with dexamethasone implant can show a 12.6 letter improvement. Although an IOP of ≥25 mmHG was experienced by 18% of patients, all were managed with IOP-lowering medications. In total, 36% of patients showed progression of lens opacity. Dr. Yoon noted an optimal retreatment interval of 5 months according to the study. Re-treatment with 4 month intervals was required in eyes with high CRT and a large area of macular nonperfusion at baseline. Editor’s Note: Reporting for this story took place at the 5th Annual Congress on Controversies in Ophthalmology: Asia-Australia (COPHy AA 2019) in Shanghai, China.

Before selecting steroid treatment, doctors should review the most recent parameters.

This is

Laser-ablated micro-surface is designed to easily facilitate initiation of the ILM peel 1 Optimized grasping platform* and angled tip closure to help mitigate membrane shredding 2

Finesse™ Sharkskin™ ILM Forceps ILM Peeling Internal Limiting Membrane (ILM) peeling is one of the most common surgical procedures and is carried out in the majority of vitreoretinal cases. Yet it is a challenging surgical step with potentially significant complications to the patient. The following are indications for ILM peeling:

• Macular Hole • Epiretinal Membrane • Vitreomacular Traction Syndrome • Vitreomacular Schisis and Myopic Foveoschisis

• Proliferative Vitreoretinopathy

p Figure 1: ILM denoted as “a”

What makes ILM peeling so challenging? The ILM is a 3 μm transparent thick membrane overlying the retinal nerve fiber layer, and representing the basement membrane of the retinal Muller cells. The ILM is intrinsically related to the nerve fiber layer and has a convoluted margin on its retinal side. During surgery its removal may be made more challenging by respiratory and other inadvertent patient movements. Given its transparent nature a variety of surgical stains have been used to enhance the visualization of the ILM. Therefore, successful peeling of the ILM is dependent on a combination of surgical skills and instrumentation (Fig. 2). Later in the document Dr. Steve Charles1 shares some of the surgical pearls he found helpful in his practice to increase likelihood of successful outcomes.

p Figure 2: Surgical view of ILM peeling with Brilliant Blue staining

ILM peeling has several potential advantagesi: • Reduces recurrence rates of epiretinal membrane by removing the scaffold for recurrent ERM formation

• Increased likelihood of macula hole closure and decreases reopening rates • Increases likelihood of complete removal of epiretinal membrane and/or residual posterior vitreous cortex

Dr. Steve Charles is a paid consultant to Alcon

David Steel et.al. “INTERNAL LIMITING MEMBRANE PEELING IN MACULAR HOLE SURGERY; WHY, WHEN, AND HOW?”, RETINA 0:1–13, 2017

Engineers interviewed many vitreoretinal surgeons and condensed their feedback to the need of resolving two main challenges: improving grasping of the membrane, especially initial grasping to create an edge in the ILM and minimizing amount of pressure applied to the retina. Most surgeons initiate ILM peeling by what is p Figure 3: Alcon Grieshaber 25 Ga ILM forceps called ‘pinch peeling’. They use the forceps to directly grasp a section of ILM, lift it from the retinal surface to initiate a tear and then start peeling. To initially engage the ILM the surgeon has to push the open forceps into the retina by a few microns and then close the tips to grasp the ILM, hoping to avoid inadvertent retinal trauma. The amount of force applied to do this optimally is difficult to judge. By increasing the friction between instrument and ILM the intent is to reduce need for this normal force (Fig. 4). Repeated grasping and/or excessive force exerted on the retina during procedure are known to result in complications, including nerve fiber layer trauma resulting in paracentral scotomata and reduced visioni. These innovative forceps attempt to mitigate both challenges. Until now the most preferred ILM forceps were Alcon® Grieshaber® 25G DSP Revolution™ ILM Forcepsii, iii (Fig. 3).

p Figure 4: New forceps hypothesis is to significantly reduce or eliminate need for normal force to accomplish grasping

Approaches to facilitate grasping belong to two main categories – applying coating and modifying surface structure. Surprisingly, all surface coating resulted in deterioration of the force, however laser ablated microstructure proved promising and resulted in almost two-fold increase of the grasping abilityiv (Fig. 5).

p Figure 5: All surface coatings actually hurt grasping ability

Market Scope®, LLC. 2017 Retinal Surgical Device Report: A Global Market Analysis for 2016 to 2022 Alcon internal data on file. Grieshaber Market Evaluation Prepared by Andrew Stokes, Morten Andersen and Silvia Bodini 5th October 2017 iv Alcon internal data on file. Alcon Grieshaber “Slipless Forces” project, document number TR-0322 “Design Selection Slipless Forceps (Funnel screening)” ii

iii

The surface structuring by laser ablation using specific pattern of 10 x 10 x 5 micron teeth pointed toward grasping edge at 30 degrees as shown in figure 6, tested clearly superior to the reference forceps as well as to all other surface modifications.

p Figure 6: 23/25 Ga. SEM picture of the laser ablated microstructure. Numbers in the right photo denote geometry of the teeth: 1 - 10 μm, 2 - 10 μm, 3 - 30º, 4 -5 μm

In the concept evaluation phase, the minimum force required to grasp a model membrane was measured. For this experiment the rabbit lens capsule including the rabbit lens was used as a test model. The test was done by comparing the Laser structured ILM forceps to unstructured ILM forceps. The forceps were mounted on a lab setup recording the minimal force for successful grasping. Although the Laser structured forceps showed a lower force than the unstructured one, these test results are highly variable due to the nature of the rabbit lens. Unstructured forceps had average force of 130.0 mg while Laser structured forceps had statistically lower force – 79.3 mg (p<.0001) – with a sample size of 27 tests per arm. To further confirm this advantage, tribological, friction measuring tests were performed on several models. The new concept was trademarked as “SHARKSKIN™” and compared to the current market leader Grieshaber Revolution® ILM forceps (Fig. 7).

p Figure 7: Reference Revolution and Sharkskin ILM forceps with structured surface were tested for friction on contact lens and rabbit eye lens as models

Three different models were considered - Air Optix® Aqua (AOA) contact lenses (Alcon), rabbit eye cornea and rabbit eye lens capsule. The latter model turned out to be highly variable like in the grasping test, however the Contact Lens and rabbit eye cornea models both showed highly consistent and superior friction coefficient for the SHARKSKIN™ ILM Forceps design (Fig 8, 9 and 10).v

p Figure 8: Examples of friction force measurements (lateral force FL vs. Distance) for non-structured (left) and structured (right). Air Optix® Contact Lens used as a model. Positive force values stand for one sliding direction, negative values for opposite direction. Different colors indicate different normal forces. 23/25 Ga.

p Figure 9: Average Coefficient of Friction, CoF values for the Grieshaber Revolution® (left) and SHARKSKIN™ ILM (right) forceps when tested on Air Optix® Contact Lens used as a model. Three samples were tested two times each of the forceps type. The difference between the two groups is statistically significant (p-value<0.005).

p Figure 10: Average Coefficient of Friction, CoF values for the Grieshaber Revolution® (left) and SHARKSKIN™ ILM (right) forceps when tested on Rabbit Cornea used as a model. Three samples were tested two times each for the forceps types. The difference between the two groups is statistically significant (p-value<0.005).

Alcon internal data on file. Alcon Grieshaber “Slipless Forces” project, document number TR-0370 “Tribological investigations of ophthalmic ILM forceps tips”

A masked wetlab study was performed by 13 surgeons who were asked to attempt grasping of the rabbit lens capsule model using the same control and test forceps. They were asked to fill out a questionnaire evaluating the relative ease by which they could grasp the lens capsule between the two forceps types. These results showed a statistically lower grasping force for the SHARKSKIN™ ILM forceps (p<.0001) (Fig. 11).vi

Indentation Force Grieshaber Revolution® Forceps

Indentation Force SHARKSKIN™ ILM Forceps

p Figure 11: 13 Surgeons in a masked wetlab study on rabbit lens capsules indicated statistically lower grasping force required

To address varying surgeons preferences, SHARKSKIN™ ILM forceps come in 23, 25+® and 27+® gauges. Further improving on prior best in class design, 27+® SHARKSKIN™ ILM forceps have been developed with an enlarged grasping platform, with the area almost equal to that of the 25+® gauge forceps (see Figure 12 and 13). It is 59% larger than the prior 27 gauge platform and thus proportionately reduces pressure on the membrane thereby minimizing likelihood of it being shredded by excessive pressure, a complaint mentioned by some surgeons with the current 27g forceps. Additionally the new 27+® SHARKSKIN™ ILM forceps brings the same conformal grasping platform shape as the 23 and 25+® gauge versions compared to the current 27+® gauge which has a more rectangular shape. This may reduce the risk of pinching into the sensory retina with the edge of the grasping platform when grasping in an angled configuration.

p Figure 13: 23/25+ Ga SHARKSKIN™ ILM Forceps

p Figure 12: 27+ Ga SHARKSKIN™ ILM Forceps

Alcon internal data on file. Alcon Grieshaber “Slipless Forces” project, document number TR-0330 “Wetlab Test”

Dr. Steve Charles2: Surgeons’ Challenges Surgical Technique Suggestions by Dr. Steve Charles

• Visualization is crucial for ILM peeling; I found that the NGENUITY® 3D visualization system

provided improved visualization by increasing depth of field allowing increased magnification. A plano or aspheric contact lens improves visualization compared to non-contact visualization (BIOM3, ReSight4) because it eliminates all corneal asphericity and increases lateral and axial resolution.

• The surgeon must approach ILM very slowly, and scaled up position means velocity must be scaled down.

• Initial grasp should be at the epicenter of striae (radial slight folds), the place where the membrane is most obvious, not at some standard location and definitely not temporal to the macula. If nerve fiber layer is grasped, release and start again; do not keep pulling. Peeling motion is similar to rhexis; circular and tangential to the retinal surface.

• Finesse® flex loop is an appropriate tool to make an edge. Pics or MVR blades are too sharp in my experience.

• ILM staining is mandatory. I only use Brilliant blue. In my opinion it is the only optimal stain and it can and should be reapplied; ICG has toxicity and shouldn’t be reapplied; trypan blue stains epiretinal membrane not ILM; triamcinolone is a particulate marking agent not a stain and not specific for any tissue, definitely not ILM. Surgeons should check regulatory approval status and availability of various stains in their locale.

• The larger the macular hole, the greater the wrinkling in an epimacular membrane case or the more extensive the schisis; the wider the diameter of ILM that must be peeled because the ILM is elastic, think Y term in Hookes Law (F=-kY).

Dr. Steve Charles is a paid consultant to Alcon Trademarks are the property of their respective owners 4 Trademarks are the property of their respective owners 2 3

References: 1. Abdelkader, Ehab, and Noemi Lois. “Internal Limiting Membrane Peeling in Vitreo-Retinal Surgery.” Survey of Ophthalmology, vol. 53, no. 4, 2008, pp. 368–396., doi:10.1016/j.survophthal.2008.04.006. 2. Semeraro, Francesco, et al. “Current Trends about Inner Limiting Membrane Peeling in Surgery for Epiretinal Membranes.” Journal of Ophthalmology, vol. 2015, 2015, pp. 1–13., doi:10.1155/2015/671905. 3. Gelman, Rachel, et al. “Retinal Damage Induced by Internal Limiting Membrane Removal.” Journal of Ophthalmology, vol. 2015, 2015, pp. 1–10., doi:10.1155/2015/939748. 4. David Steel et.al. “INTERNAL LIMITING MEMBRANE PEELING IN MACULAR HOLE SURGERY; WHY, WHEN, AND HOW?”, RETINA 0:1–13, 2017 5. Market Scope®, LLC. 2017 Retinal Surgical Device Report: A Global Market Analysis for 2016 to 2022 6. Alcon internal data on file. Grieshaber Market Evaluation Prepared by Andrew Stokes, Morten Andersen and Silvia Bodini 5th October 2017 7. Alcon internal data on file. Alcon Grieshaber “Slipless Forces” project, document number TR-0322 “Design Selection Slipless Forceps (Funnel screening)” 8. Alcon internal data on file. Alcon Grieshaber “Slipless Forces” project, document number TR-0370 “Tribological investigations of ophthalmic ILM forceps tips” 9. Alcon internal data on file. Alcon Grieshaber “Slipless Forces” project, document number TR-0330 “Wetlab Test” *Trademarks are the property of their respective owners.

GRIESHABER® DSP Important Product Information Caution: Federal (USA) law restricts this device to sale by, or on the order of, a physician. Indications for Use: GRIESHABER® DSP instruments are a line of single-use vitreoretinal microinstruments, which are used in ophthalmic surgery, for cases either in the anterior or the posterior segment. The GRIESHABER® Advanced Backflush Handles DSP are a family of instruments for fluid and gas handling in vitreoretinal surgery. Warnings and Precautions:

• Potential risk from reuse or reprocessing GRIESHABER® DSP instruments include: foreign particle introduction to the eye; reduced cutting or grasping performance; path leaks or obstruction resulting in reduced fluidics performance.

• Verify correct tip attachment, function and tip actuation before placing it into the eye for surgery. • For light fiber instruments: Minimize light intensity and duration of exposure to the retina to reduce risk of retinal photic injury. The light fiber instruments are designed for use with an ALCON® illumination source.

• Good clinical practice dictates the testing for adequate irrigation and aspiration flow prior to entering the eye. If stream of fluid is weak or absent, good fluidics response will be jeopardized.

• Use appropriate pressure supply to ensure a stable IOP. • If unwanted tissue gets engaged to the aspiration port, it should be released by interrupting aspiration before moving the instrument. Attention: Please refer to the product labeling for a complete listing of indications, warnings, and precautions.