PIE Magazine Issue 02: The ebook version

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ASIA-PACIFIC’S FIRST MAGAZINE ON THE POSTERIOR SEGMENT

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EAST MEETS WEST ISSUE June/July 2017

magazine posterior segment • innovation • enlightenment

Role of Photoreceptor Cells in Retinal Vasculature Disease Page

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Saving Sight with Fundus Phone Imaging Page

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Retinal Reattachment Stent Page

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The

Macula Gang is in Town to Drop

Knowledge

SNEC Medical Director, Prof. Wong Tien Yin

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Inside this issue...

Posterior Segment

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Treating Diabetic Macular Edema From the Other Side of the World – Welcome to Telephotocoagulation Keeping an Eye Out for Post-Typhoid Fever Retinitis

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27-Gauge Vitrectomy Surgery “Small” is the New “Big” for Eye Care

COVER STORY

The Macula Gang is in Town The ‘Gang’ descends on the Macula Symposium in Singapore strapped with insight and slinging knowledge on imaging modalities, lasers and anti-VEGFs. Read on to see what other ‘trouble’ these optical gangsters (O.G.s) are causing…

The Untold Link Between Photoreceptor Cells and Retinal Vascular Disease Correlation of GCL Damage and Diabetic Macular Ischemia using OCTA and their Relationship with Visual Acuity in Diabetes

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Innovation

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page Matt Young

CEO & Publisher

Hannah Nguyen CFO

From Selfies to Saving Sight Smartphone Imaging System Provides Accessible and Affordable Eye Health Screening

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Putting Computers to Work The Pushing Approach in Retinal Detachment Treatment

Fixing the Challenges of Pediatric Fixation Screening and Detection of Amblyopia

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Gloria D. Gamat Chief Editor

Brooke Herron Associate Editor

Ruchi Mahajan Ranga Project Manager

Timmo Gunst

Publications & Digital Manager

Winson Chua Patalina Chua

Graphic Designers Writers

April Ingram Helin Räägel Olawale Salami

Published by

Media MICE Pte. Ltd.

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

Enlightenment

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Pharmaceutical Regulation for Patient Protection

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Rolling out the Red Carpet for Celebrity Patients

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The Role of Photo Documentation in Ophthalmology

ASCRS 2017

Posterior Segment Highlights

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Posterior Segment Tidbits from ASCRS 2017 Posters

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Quality of Vision in YAG Vitreolysis for Treatment of Floaters: Are Patient-Reported Outcomes Enough?

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

A Nano Approach to Posterior Segment Drug Delivery in DME Patients

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


PIE MAGAZINE LETTER TO READERS When East Meets West in Posterior Segment

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Matt Young (center), CEO & Publisher of PIE Magazine, in his usual monkey suit at an ophthalmology meeting in Kuching, Malaysia.

here does Asia-Pacific end and the rest of the world begin? It depends on who, or what, you ask. Consult the general Wikipedia page on Asia-Pacific and you get as far away as Afghanistan, as part of Central Asia. Ok. Consult the Daniel K. Inouye Asia-Pacific Center for Security Studies, a U.S. Department of Defense institute in Hawaii (which is highly ranked in Google when searching “Asia-Pacific countries”), and both Canada and the United States are part of the Asia-Pacific region. Consult the Asia-Pacific Economic Cooperation (APEC) countries, and countries go beyond even Canada and the U.S, to even include Peru and Mexico. So what are Asia-Pacific countries? In short, whatever you want them to be, so long as you are a powerful enough organization to make it so. Given that we are PIE Magazine, Asia-Pacific’s first magazine on the Posterior Segment, we won’t go as far to say that Asia-Pacific is the entire world. However, in this issue, we will salute Daniel K. Inouye, whoever the hell he was, and APEC, and adopt the United States as part of Asia-Pacific for the purpose of our East-West Issue. There’s just too much posterior segment innovation going on in the U.S. to ignore of late, even at places like the ASCRS – a traditionally anterior segment meeting. But very importantly – and this is the crux for us here – The Macula Society, a prestigious U.S.-based group for new research in retinal vascular and macular diseases, had its annual meeting in Singapore this past June. U.S. and international members had flocked here. We have no idea what they discussed, as it was a closed meeting, something akin to a Sean Spicer press conference with even less news forthcoming. But then, many of those members also attended the proximal Macula Symposium Singapore at Singapore National Eye Centre (SNEC), open to the press. To say the least, we salute you SNEC, and especially Medical Director Prof. Wong Tien Yin, for agreeing to appear on our cover, all tatted up. Prof. Wong, if you’re ever in prison, we’ll visit. We promise. Especially if you get a retina tat. Legit. Meanwhile, we’d like to extend a fist bump to our new Advisory Board members, featured on the next page. We had a few criteria: A criminal record was a plus, they had to have a pulse, they had to reside within Asia-Pacific (real Asia-Pacific), and they had to be renowned retinal specialists. Each fit at least 75% of our criteria, which is great because for a while we were thinking we might need to change the criteria and dig six feet under to get some willing board members. Besides being alive, these guys are great because they have agreed to help guide coverage in upcoming 2017 issues. Thanks, guys, because 15,000+ ophthalmic readers checking out PIE per issue in Asia-Pacific don’t want to be let down. Or at least, Dear Reader, if you are let down, now you know who to troll. Just kidding. Be nice to them. Peace,

Matt Young CEO & Publisher PIE (Posterior Segment-Innovation-Enlightenment) Magazine

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

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

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).

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POSTERIOR SEGMENT RETINAL TELEPHOTOCOAGULATION

Treating Diabetic Macular Edema From the Other Side

Welcome to Telephotocoa by April Ingram

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elemedicine strategies represent a booming trend in the delivery of effective eye care to underserved regions around the globe. The associated technology has allowed for an evolution of telemedicine applications from research to clinical use, most often addressing screening challenges and access to an expert referral. In eye care, teleophthalmology targets either diseases for which there is lack of available expertise, such as retinopathy of prematurity, or diseases that cause overwhelming burden, such as diabetic retinopathy or glaucoma. Within peer-reviewed literature, there are hundreds of publications referencing teleophthalmology approaches. The most common approach is the “store-and-forward” method, where digital images are taken and then forwarded for interpretation and appropriate follow-up. In addition, real-time examinations are starting to take place digitally. These are great steps forward in patient diagnostics, but there can be specialist accessibility issues. For example: What can be done if a patient’s required treatment is identified, but they are far away from any specialist that can deliver it? Addressing this “now what?” challenge would typically spiral into a flurry of expedited logistics and funding requests to transport the patient to the specialist or surgeon. But what if the equipment was in place for the patient to be effectively treated at their local facility, and then linked to the specialty care? Is teleophthalmology treatment feasible? Dr. Igor Kozak, a clinical lead at the Moorfields Eye Hospital Centre in Abu Dhabi, and his colleagues believe

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it is thanks to the concept of retinal telephotocoagulation. They have taken the concept of teleophthalmology beyond the scope of a diagnostic screening tool, and applied it to the actual treatment of patients with diabetic macular edema (DME). This is a critical study – an estimated 285 million people have diabetes mellitus worldwide and approximately 31 million have visionthreatening diabetic retinopathy, including DME. The study by Kozak et al., recently published in Graefe’s Archives of Clinical and Experimental Ophthalmology, introduces the idea that actual treatments can be performed between or among distant clinical sites. “This, for the first time, moves teleophthalmology up to therapeutic level. It utilizes the concept of image transfer and alignment, along with retinal laser photocoagulation, using navigation and eye tracking. With this concept, clinical sites can exchange pre-programmed treatment plans which can be applied to patients at any location,” explained Dr. Kozak. The authors stress that there are two essential components of successful retinal telephotocoagulation: image registration and transfer. Image registration is the transformation of images acquired at different time points, or with different imaging modalities, into the same coordinate system. This allows the images to be combined, while maintaining important structural and functional details. A minimum of three corresponding landmarks must be identified by the operator in both images to calculate a multidimensional transformation matrix for registration.

The study involved 16 eyes of 10 subjects diagnosed with DME, that underwent navigated focal laser photocoagulation using their novel teleretinal treatment plan. At King Khaled Eye Specialist Hospital in Riyadh, Saudi Arabia, patients underwent retinal imaging and fundus fluorescein angiography, which were registered using the NAVILAS Contact registration software (NAVILAS®, ODOS Inc. Berlin, Germany). The images were then transmitted to a second clinic in an encrypted format.


of the World

agulation Photocoagulation world map diagram [Image source: Dr. Kozak]

Investigators looked at the feasibility of image transfer and performing navigated laser photocoagulation for subjects at two distinct clinics. Additionally, the patients’ eyes were followed for three months after treatment, to assess changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) by spectral-domain optical coherence tomography. Kozak and colleagues were able to successfully execute the treatment plan in all 16 eyes. No adverse events occurred and all eyes demonstrated improvement in the area of retinal edema: BCVA remained stable and CRT improved from 290.1 ± 37.6 μm at baseline to 270.8 ± 27.7 μm (p = 0.005) after three months. This has been the first study to apply a therapeutic teleophthalmology approach, rather than strictly

At the second clinic, Palmetto Retina Center in West Columbia, South Carolina, USA, retina specialist and co-investigator, Dr. John Payne, created image-based treatment plans from the original imaging, targeting leaking microaneurysms and placement of computerized grid patterns in areas of diffuse leakage. The treatment plans were then transmitted back-toback to King Khaled Eye Specialist Hospital where the macular laser photocoagulation was performed, using the same NAVILAS system.

diagnostic. It demonstrates safety and feasibility of telephotocoagulation to perform navigated retinal laser treatments, regardless of geographical distance. This novel concept has the potential to open a new chapter in ophthalmic care, as described by Dr. Kozak, “This can be executed online or as a step-wise process. Furthermore, it provides ability to standardize retinal laser treatments at multiple sites for the purpose of clinical trials research as well as improving access and enhancing patient care.” This standardization could address inter-operator variability in conventional laser photocoagulation, which could potentially impact comparison to other treatments. Additionally, the concept of retinal tele-navigation could be applied to vitreoretinal and robotic surgical procedures guided by image-based navigation.

Reference: Kozak I, Payne JF, Schatz P, et al. Teleophthalmology image-based navigated retinal laser therapy for diabetic macular edema: a concept of retinal telephotocoagulation. Graefes Arch Clin Exp Ophthalmol. 2017 [Epub ahead of print].

About the Contributing Doctors Dr. Igor Kozak, M.D., Ph.D, M.Sc., 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. 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]

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POSTERIOR SEGMENT TYPHOID RETINOPATHY

Keeping an Eye Out for

Post-Typhoid Fev by April Ingram

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n some parts of the world, particularly in developing countries, there has been a resurgence of typhoid or enteric fever recorded. Typhoid fever is a systemic disease and characterized by fever and abdominal pain, but it has a little known symptom: in rare cases, it can manifest in the eyes, leading to blindness and other complications if left untreated. Typhoid fever is caused by the gram-negative bacteria Salmonella typhi, and is transmitted by contaminated food or water, likely from fecal contamination by patients with active fever or by asymptomatic chronic carriers. Approximately 2-5% of people become chronic carriers, harboring S. typhi in their gall bladder, making disease control extremely difficult. Salmonella paratyphi A, B and C causes the similar, but often less severe, paratyphoid fever. The risk factors for contracting typhoid are similar to those of cholera and other epidemic prone diarrheal diseases – they are mainly correlated to access, or lack thereof, to safe, clean water; functionality of sanitation systems; and food safety. During an outbreak, healthcare providers face serious challenges. It can be difficult to confirm diagnoses, as well as manage the outbreak as a public health crisis. Current guidelines, released by the World Health Organization (WHO), provide clear management strategies, including anticipated manifestations (common to extremely rare) of typhoid within the

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different systems of the body during all phases of the disease. Within these documents, there is no mention of eye-related manifestations of typhoid. This is concerning, because although considered rare, ocular manifestations of typhoid fever can occur, whether caused by direct invasion of the organisms into the ocular tissue, or from a hypersensitivity reaction such as vitreous hemorrhage following typhoid vaccination.

Recently, in the International Journal of Retina and Vitreous, Dr. Mahalingam Prabhushanker and colleagues from Sankara Eye Centre in Coimbatore, India, reported their clinical experience with a patient with post-typhoid retinopathy, a not very well recognized sequalae of the disease. They describe a 59-year-old male patient that presented with sudden, painless vision loss in his right eye, four weeks after recovering from typhoid fever.


ever Retinitis

The clinical examination found no abnormal finding in the anterior segment, however the fundus examination of the patient’s right eye showed “white fluffy lesions” along the superior and inferior arcades, with superficial hemorrhages in and around the macula, with a macular star suggestive of retinitis. Optical coherence tomography (OCT) clearly showed a macular serous retinal detachment.

Although the patient did not demonstrate any visual acuity changes in the left eye, fundus examination also found a few dispersed retinitis lesions with superficial hemorrhages along the superior arcade with intact foveal reflex. In order to confirm that the ocular findings were related to the previous typhoid fever, the investigators performed blood tests to rule out Venereal Disease Research Laboratory (VDRL) and human immunodeficiency virus (HIV) status. X-cyton analysis (XCyton Diagnostics Limited, Bengalaru, Karnataka, India) of the anterior chamber aspirate was also completed and found to be negative for organisms including Mycobacterial Tuberculosis, Toxoplasma Gondii, Herpes Simplex Virus, Cytomegalovirus and Varicella Zoster Virus. Polymerase chain reaction (PCR) by X-cyton analysis (XCyton Diagnostics Limited, Bengaluru, Karnataka, India) of the aqueous is key because it provides rapid diagnosis and detection of multiple organisms and sight threatening bacterial and viral infections can be ruled out. More importantly, initiating steroid therapy in the presence of infectious retinitis could exacerbate any non-immune mediated retinitis. This patient was put on a regimen of oral prednisolone 1 mg/kg body weight, tapered over a period of two months, and followed every two weeks

for three months. After two months of treatment, visual acuity had been restored and maintained in the right eye, and lesions in both eyes had started to resolve. In addition, the serous retinal detachment in the right eye demonstrated resolution on OCT. The authors noted that, “Immune mediated retinitis is a clinical diagnosis most often when there is past history of infection a few weeks or days prior to the onset of ocular manifestations.” “It can be managed with steroids followed by good resolution of the lesions,” they concluded. In addition to post-typhoid retinopathy, reported ocular manifestations of typhoid may include lid edema or abscess, dacryoadenitis, conjunctival petechiae or chemosis, corneal ulceration, uveitis, vitreous haemorrhage, retinal haemorrhage and detachment, stellate maculopathy, pigmentary retinopathy, optic neuritis, internal or external ophthalmoplegia, orbital haemorrhage or abscess. Although post-typhoid fever eye complications are rare, they may be more common in other parts of the world, according to these authors. These ocular findings can have devastating outcomes, and future revisions to management guidelines should perhaps consider including ocular sequalae in the listing of systemic manifestations of the disease.

Reference: Prabhushanker M, Topiwalla TT, Ganesan G, Appandaraj S. Bilateral retinitis following typhoid fever. Int J Retina Vitreous. 2017; 3: 11.

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POSTERIOR SEGMENT VITRECTOMY MACHINES

27-Gauge Vitrectomy Surgery

“Small” is the New

by April Ingram

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n 2010, publications confirmed the safety and feasibility of 27-gauge surgery. Since then, more data describing its use – in even the most complex vitreoretinal surgical procedures – has been published. As interest grows, and the noted learning curve becomes less daunting to vitreoretinal surgeons, the makers of the retinal surgery platforms have taken notice and are stepping up to meet the increasing need. Alcon (Fort Worth, TX, USA) has released the Constellation Vision

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System; Dutch Ophthalmic Research Center (DORC, Zuidland, Netherlands) has made 27-gauge vitrectomy packs available for the EVA vitrectomy system; and Bausch + Lomb (Rochester, NY, USA) is also developing a 27-gauge platform for its Stellaris PC Vision Enhancement System. So, what’s the big deal with 27-gauge, and why would we make the switch? Well, one of the major criticisms of 23- or 25-gauge vitrectomy is that the resulting sclerotomies do not seal

completely, potentially leading to an increased risk of hypotony, choroidal detachment, or endophthalmitis. By decreasing the gauge size, the risk of these complications can also possibly be lowered. Reduced risk of complications is a definite benefit, but smaller instruments also mean removal of the vitreous will take longer. However, even though it may take more time, these 27-gauge cutters have shown that they can remove half of the nucleus from the posterior segment, eliminating the need for a fragmatome.


“Big” for Eye Care The learning curve that most vitreoretinal surgeons refer to is related to the rigidity, or lack thereof, with the 27-gauge instrumentation. The increased flexibility of the 27-gauge over the 25-gauge instrument may present some challenges initially, but surgeons have reported that the smaller tip is more beneficial for membrane dissection, even allowing epiretinal membranes to be peeled without forceps. So, what technology is currently available? Alcon’s Constellation Vision System continues to deliver advanced technologies and the latest tools to meet the needs of vitreoretinal surgeons. The company’s 27+ Vitrectomy Packs and Instrumentation for use with the Constellation includes a full range of instruments designed for complex, micro-incision vitrectomy procedures. Alcon has focused on providing surgeons with exceptional access to the small tissue areas of the eye, while also providing a probe stiffness experience similar to the 25+, by using a proximal sleeve that stabilizes the instrument at the trocar interface, allowing for better control during procedures. Alcon has also addressed a way to reduce traction that may lead to iatrogenic tears and postoperative complications, and delivers high speed 7500 cpm dual pneumatic drive technology with 27+, consistent with their 20, 23, and 25+ series. This dual pneumatic vitreous cutter, relies on independent airflow to drive the closing and opening of the cutter, while the port location has been optimized by placing it closer to the tip. Surgeons using Alcon’s Constellation Vision System also have the freedom to modify duty cycle to control flow independent of vacuum

and cut rate. They have the ability to select from three different duty cycle options at any given cut rate, Port Biased Open, 50/50, or Port Biased Closed. The Constellation also continuously monitors infusion pressure through the IOP compensation feature, resulting in better control and more stable IOP. Finally, the Constellation delivers state-of-the-art illumination technology for visualizing ocular tissues, including the ENGAUGE Radio Frequency Identification Device Technology (RFID). This recognizes light probe gauge size and automatically adjusts light intensity. In addition, the Xenon Illuminator is designed to provide longlasting high brightness illumination. EVATM, from Dutch Ophthalmic Research Center (DORC) is another retinal surgery system, (actually a cataract and vitrectomy system), that has stepped up to meet the need for 27-gauge surgery. DORC recognizes that smaller instruments can enhance wound construction, reducing the need to suture, making vitreoretinal surgery less invasive than ever before. The challenge of flexibility with the 27-gauge instrumentation was addressed by the rigid shaft design to optimize performance during core and peripheral vitrectomy. EVA includes a LEDStar illumination system, which is a three port light emitting diode (LED) illumination and has the added benefit of constant lumen output. This means that there is no degradation of light

output over the +10,000 hour life of the LED. Unique to EVA is the TDC, a two-dimensional cutter which delivers a cut speed of up to 8000 cpm and is designed to facilitate cutting tissue on the return of each stroke of the vitrectome, effectively doubling the cut speed to up to 16,000 cpm. The Stellaris PC Vision Enhancement System from Bausch + Lomb accommodates instrumentation ranging from 23- to 25-gauge, with a 27-gauge in the pipeline. Also, of note, is the VersaVIT 2.0 vitrectomy system from Synergetics (O’Fallon, MO, USA), which is carving out its place as a small, portable vitrectomy platform. This “size of a suitcase” vitrectomy platform has a maximum cute rate of 6000 cpm and will soon have VersaVIT procedures packs for 20- and 27-gauge available. So, is smaller better? Small gauge vitrectomy, is intended to be transconjunctival, self-sealing, and sutureless. It has the potential to reduce complications and to be better suited to smaller, pediatric eyes. All great benefits, but the confines of instrument diameter and lumen may be limiting on instrument flexibility, efficiency, and performance – thus, making it best suited for specific cases. As we know, instrumentation for vitreoretinal surgery is continuously evolving, and companies are eager to address challenges to meet the needs of surgeons. So the better question might be: How small can we go?

References: Lin X, Apple D, Hu J, Tewari A. Advancements of vitreoretinal surgical machines. Curr Opin Ophthalmol. 2017;28(3):242-245. Mohamed S, Claes C, Tsang CW. Review of Small Gauge Vitrectomy: Progress and Innovations. J Ophthalmol. 2017;2017:6285869

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POSTERIOR SEGMENT PHOTORECEPTOR CELLS

Untold Link Between Photoreceptor Cells and Retinal Vascular Disease The

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he retina relies on a wellfunctioning blood supply through the retinal vasculature to do its precious work. In a number of retinopathies, such as diabetic retinopathy (DR), age-related macular degeneration, and other retinal vascular diseases, the retinal vasculature is adversely affected, causing the retinal capillaries to be damaged or degenerated. This, in turn, has shown to further impede the function of the retinal tissue, including the photoreceptor cells, causing impairment of vision in affected eyes. “The main research focus in retinal vascular diseases to explain the visual dysfunction has been on the vasculature itself; however, the potential contribution of photoreceptor cells to the disease has largely been overlooked,” said Prof. Timothy Kern from the Case Western Reserve University, who recently published a review article discussing the possible causal links between photoreceptor cell damage and retinal capillary degeneration. The article lays out a number of evidence supporting that link. For instance, laser photocoagulation, a laser therapy directed at destroying and thus limiting the number of photoreceptor cells, has been shown to inhibit

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by Helin Räägel

progression of advanced retinopathies, including DR. Another significant piece of evidence comes from studies with rhodopsin deficient animal models. Rhodopsin is a light-sensitive pigment found in photoreceptor cells, and is necessary for normal vision, particularly in low-light conditions. Studies with rhodopsin-deficient animals illustrate that when photoreceptor cells produce mutated or no rhodopsin at all, the photoreceptor cells can initiate the dysfunction and degeneration of retinal capillaries. As a result, Prof. Kern hypothesizes that because the photoreceptors in those animal models are present but not functioning properly, the “sick” or stressed photoreceptor cells are the ones contributing to the development of the vascular damage and the subsequent retinal vascular disease. So, how can we combat the effects of this? Aside from the laser photocoagulation approach mentioned above, scientists have applied a light-based therapy called

photobiomodulation, where patients are treated with a specific series of illumination to inhibit early DR. Using light as therapy, especially in the night when light-sources are sparse, has shown to significantly improve vision, contrast sensitivity, and the overall microstructure of the eye. The theory behind the light-based therapy is that in the dark, the metabolic activity and the accompanying oxygen by the photoreceptor cells increases drastically. This creates a hypoxic environment that might compromise the retinal capillaries, bringing about or accelerating the retinal vascular disease. However, as not all cases of retinopathies show existence of hypoxia, other factors may also contribute to the demise of the retinal vasculature. Possible factors include oxidative stress, inflammatory response, or soluble factors like cytokines that activate a cascade of molecular mechanisms that result in the damage of the retinal microvessels. Several studies have also demonstrated a protective and possibly therapeutic effect of vascular endothelial growth factor (VEGF) overexpression in photoreceptor cells that causes new blood vessels to form in the photoreceptor layer. VEGF is a growth factor that stimulates vasculogenesis and angiogenesis, and therefore may potentially trigger neovascularization in the retina. Recent research highlights the necessity to further investigate the potential therapeutic avenues discussed in the article, but Prof. Kern also speculates that more research focusing on photoreceptor specific gene-modification therapies could be the next step in combating the pathogenesis of retinal vascular diseases.

Reference: Kern TS. Do photoreceptor cells cause the development of retinal vascular disease? Vision Res. 2017; pii: S0042-6989(17)30065-2.


POSTERIOR SEGMENT OCTA Correlation of GCL Damage and Diabetic Macular Ischemia using OCTA and their Relationship with Visual Acuity in Diabetes by Gloria D. Gamat

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t is well recognized that a healthy foveal avascular zone (FAZ), containing metabolically active photoreceptors, is essential for central vision. However, diabetic eyes have enlarged FAZ – which has been shown to correlate with reduced visual acuity. Early microvascular damage in diabetes can now be quantified with OCT angiography (OCTA). Studies have also correlated FAZ size and vessel density with severity of diabetic macular ischemia. In addition, the ganglion cell layer-inner plexiform layer complex (GC-IPL) and retinal nerve fiber layer (RNFL) thinning, indicating retinal neurodegeneration, have been shown to be associated with diabetic retinopathy (DR). This neurodegeneration could be the earliest indicator of functional damage in diabetic eye disease preceding vascular changes. With this background, Dr. Dilraj S. Grewal, from Duke Eye Center in Durham, North Carolina, USA, and Drs. Manpreet Brar and S.P.S. Grewal, from the

Grewal Eye Institute in Chandigarh, India, conducted an investigation to evaluate the correlation between diabetic macular ischemia and retinal neurodegeneration. They used OCTA to examine 195 eyes of 105 diabetic patients and acquired 3x3 mm scans using Zeiss Angioplex OCTA (Carl Zeiss Meditec, Dublin, CA,USA) centered on the fovea. Superficial (SCP) and deep capillary plexus (DCP) FAZ horizontal (H) and vertical (V) greatest linear diameter were calculated using ImageJ (NIH, Bethesda, MD, USA). The GCL thickness was generated from the Macular Cube 512×128 scan protocol centered on the fovea. OCTA facilitates study of the link between microangiopathy and neurodegeneration in DR as it can allow simultaneous visualization of microvascular abnormalities and quantitative analysis of the inner retinal layers. In diabetic patients without DME, there is a significant correlation between the neurodegenerative component in the inner retinal layers measured using GCL thickness and

diabetic macular ischemia in the SCP and DCP FAZ, and these are both significantly correlated with VA. These results confirm the relationship between retinal neurodegeneration and microvasculopathy in diabetic eyes and also demonstrate that neurodegeneration may precede microvasculopathic changes in such eyes. In conclusion, using OCTA to quantify early microvascular and neurodegenerative changes in diabetic eyes may help optimize patient management – both for evaluation of future neuroprotection and microvascular network reconstitution therapeutic strategies where these changes may serve as a biomarker. However, further work is needed on this topic and assessment of the relationship between the capillary network and retinal neurodegeneration in diabetes is the subject of an ongoing investigation.

Reference: ASRS 2017 and AAO 2017 Meeting Presentation by Dr. Dilraj S. Grewal, Duke Eye Center, Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA.


COVER STORY

The

Macula Ga

is in Town

The Macula Symposium Singapore was held 10-11 June, 2017, courtesy of Singapore National Eye Centre (SNEC). International retinal specialists turned up in the island nation to beat down retinal vascular and macular diseases.

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by Matt Young and Gloria D. Gamat

Transforming Science to Reality with Aflibercept

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n the evolution of anti-vascular endothelial growth factor (antiVEGF) agents for the treatment of neovascular age-related macular degeneration (AMD), aflibercept was the last drug on the market. However, as heavily reported in literature, it appears to have theoretical advantages over other anti-VEGFs: it

had a much greater binding affinity to VEGF-A; it binds to placental growth factor (PGF) 1 and 2, and all isoforms of VEGF-A and VEGF-B; and the vitreous half-life for aflibercept (4.8 days) was estimated longer than that for ranibizumab (3.2 days). Ophthalmologists have been using aflibercept for a while now and in the


There is no treatment “ yet for MacTel Type 2. While conventional management of subretinal neovascularization with anti-VEGF responds well, there is no established treatment for nonproliferative disease.

- Prof. Mark Gillies, Director of Research, Save Sight Institute alias: Needles

Gang

process have further understood its novel mode of action. At the recently held Macula Symposium Singapore, aflibercept took center stage once more. “We have seen how aflibercept performed superiorly in multiple studies compared to other anti-VEGF agents,” said Quan Dong Nguyen, M.D., M.Sc., professor of ophthalmology at the Byers Eye Institute, Stanford University School of Medicine, California, USA. Every retinal specialist who has reported on the benefits of aflibercept has emphasized that the true value of this “VEGF-trap” is in its unique molecular design.

Specifically designed for strong, broad, and durable activity, aflibercept is a novel recombinant fusion protein for intravitreal injection that binds all isoforms of VEGF-A, VEGF-B, and PGF. “It binds more tightly to VEGF than the native VEGF receptors,” emphasized Dr. Nguyen. While all commonly used anti-VEGF agents inhibit all VEGF-A isoforms, noted Dr. Nguyen, aflibercept blocks VEGFinduced activation of VEGFR-1/2 with up to 92 times greater potency than ranibizumab and bevacizumab. In mathematical models, reported Dr. Nguyen, the intravitreal activity of aflibercept is extended almost 3-fold compared with ranibizumab, suggesting that biological activity of aflibercept 2 mg at 83 days is comparable to that of 0.5 mg at 30 days. Also, aflibercept has a strict 1:1 binding ratio, it binds or traps both sides of the VEGF dimer. Hence, it does not form multimeric conglomerates, which may aggregate and induce an immune response. “It is these unique properties of aflibercept that explain its bioactivity and efficacy against various retinal vascular diseases. It is not just a ‘VEGFtrap’ but also binds to PGF which is another promoter of angiogenesis,” Dr. Nguyen added. Together, these chemical properties support clinical finding of aflibercept’s efficacy, emphasized Dr. Nguyen.

Since its approval by the U.S. Food and Drug Administration (FDA) in November 2011 for the treatment of nAMD, aflibercept is also currently indicated for diabetic macular edema (DME), macular edema secondary to all types of retinal vein occlusion (branch or central RVO) regardless of perfusion status, and myopic choroidal neovascularization (CNV). Presenting about a proactive approach with aflibercept, Dr. Peter Kaiser, M.D., from the department of ophthalmology of the Cleveland Clinic in Ohio, USA, highlighted the need for real life data to compare with results of randomized clinical trials (RCTs). There is a need for real-life evidence to complement the data provided by RCTs, as most often there is a disparity between the outcomes observed from these two settings. In RCTs, patients are homogenous and are pre-selected. On the other hand, clinical patients are very diverse. Dr. Kaiser presented RCTs involving ranibizumab (and aflibercept as well) and noted that “ranibizumab did not demonstrate RCT-like effectiveness in a large population of nAMD patients in over three years.” The vision gains seen in RCTs of ranibizumab have not been reflected in clinical practice, noted Dr. Kaiser. “In some cases, 83% of the patients even after 5 years of treatment continue to have retinal fluid,” he observed.

15


COVER STORY

(L-R). Dr. Quan Dong Nguyen and Dr. Peter Kaiser

alias: Snake Eyes Spaide

is “nowColorthe photography gold standard for AMD classification in all major studies. OCT is likely to replace/augment color photography.

- Dr. Richard Spaide, Vitreous Retina Macula Consultants of New York

16

Aflibercept has a longer durability of action, as shown in RCTs such as the VIEW studies. Looking at the real life outcomes with aflibercept, these compare favorably to the results from pivotal aflibercept clinical trials. “Aflibercept real-life outcomes in nAMD compare favorably to those seen in RCTs,” reported Dr. Kaiser, Evidence accumulated in aflibercept came from across the globe, representing diverse patient populations. “In these studies, we don’t see the drop in gain of vision through time as seen in ranibizumab outcomes,” said Dr. Kaiser. The treat-and-extend regimen, according to Dr. Kaiser, is the better regimen among all anti-VEGFs , not just aflibercept. “You get the vision gain and maintain that vision gain through time in the treat-and-extend regimen,” he explained. “In addition, the treat-andextend regimen enables a lower injection burden (and reduced number of doctor visits) to patients over time.” Good outcomes can be achieved and maintained with the licensed aflibercept posology in year 1, with treatand-extend enabling a lower injection burden in year 2, noted Dr. Kaiser. “Real-life evidence is important to look at and compare to RCTs. Long term real-life studies seem to demonstrate that the ‘as needed’ treatment regimen in ranibizumab is not as good as the treat-and-extend regimen in aflibercept,” he said.

“It appears that aflibercept is working well in real-life studies as in RCTs. Aflibercept delivers effectiveness in real-life settings due to its unique mechanism of action that delivers both efficacy and durability,” concluded Dr. Kaiser. Furthermore, results of key trials of aflibercept in polypoidal choroidal vasculopathy (PCV), a sub-type of nAMD have been discussed as well at the Macula Symposium in Singapore. Being more common in Asia, it is important to talk about polypoidal choroidal vasculopathy (PCV), noted Prof. Wong Tien Yin, MBBS, MMed(Ophth), MPH, FRCS(Ed), FRANZCO, FAFPHM, PhD(Johns Hopkins), Medical Director of the Singapore National Eye Centre (SNEC) and senior consultant ophthalmologist sub-specializing in medical retina. “It presents somewhat differently from the typical AMD and choroidal neovascularization (CNV). However, a lot of evidence suggests that PCV is a variant of type 1 CNV. The question therefore is, how do we now treat PCV?,” reported Prof. Wong. In the ophthalmic community, there are concerns surrounding the treatment of CNV with PDT (photodynamic therapy) in terms of safety, efficacy and cost. In his presentation, Prof. Wong also elaborated on the practical considerations of aflibercept monotherapy compared to alternative treatment options for PCV and noted that issues remain in the long-term outcomes of PDT in PCV. Then Prof. Wong presented outcomes of the PLANET study, a multi-centered study which primarily investigated the efficacy and safety of aflibercept monotherapy compared to aflibercept with rescue PDT in the treatment of PCV, and determined whether aflibercept monotherapy is noninferior with rescue PDT (as indicated), based on best corrected visual acuity (BCVA) in PCV patients. The study’s secondary objectives were to estimate the proportion of PCV patients who require rescue PDT therapy and to determine to what extent rescue PDT therapy is beneficial in PCV patients who


have suboptimal responses to aflibercept monotherapy. “At 52 weeks, aflibercept monotherapy leads to gain of more than 10 letters from baseline, high rates of polyp inactivation (over 80% of patients showed no evidence of active polyps) and over 85% of patients needed no rescue PDT treatment,” reported Prof. Wong. What about in the <15% of patients requiring PDT rescue? “The VA gains were similar in monotherapy versus active PDT rescue,” he said. Hence, there is no significant difference in BCVA gains between the monotherapy and active PDT, regardless of need for rescue requirement, highlighted Prof. Wong. Aflibercept monotherapy protocol demonstrated similar outcomes to aflibercept combined with rescue PDT – suggesting that aflibercept monotherapy can be established as a first line treatment option for patients with PCV. “Aflibercept monotherapy leads to favorable vision gains and high rates of polyp inactivation. Results of the PLANET study are consistent with aflibercept monotherapy studies, including real-life studies,” said Prof. Wong. “Whether treat-and-extend regimen is suitable in the treatment of PCV, we have to wait for the second year PLANET study data,” concluded Prof. Wong. The second year of PLANET study will assess the efficacy of aflibercept treat-and-extend protocol in PCV, potentially leading to extended treatment intervals and a reduced injection number.

Of Lasers and Anti-VEGFs Prof. Dr. med. Frank G. Holz of the Department of Ophthalmology, University of Bonn, Germany, while discussing new perspectives in imaging and functional assessment of dry AMD, delivered the most interesting statement: “The holy grail of AMD therapy is prevent late-stage manifestation.” Whether through the use of lasers or anti-VEGFs, the intention is to retard the progression of AMD. Prof. Robyn Guymer, MBBS, PhD, FRANZCO, deputy director of

the Centre for Eye Research Australia and a professor of ophthalmology at University of Melbourne, Australia, presented results of a pilot study on the use of nanosecond laser to retard AMD progression. Results from the said study concluded that resolution of drusen continued over a 12-month period, and greatest functional improvement occurred in the treated eyes between 3 and 6 months. According to Prof. Guymer, a good question to ask would be: “Is the improvement in sensitivity really an indication that we are reversing the defect that leads to advanced AMD?” “The explanation for the bilateral effect is not yet known but being explored,” she noted, referring to the LEAD (Laser intervention in Early Agerelated macular Degeneration) study. The LEAD study is an investigation of the safety and efficacy of subthreshold nanosecond laser treatment to slow the progression of intermediate age-related macular degeneration (AMD). The study has a time frame of 36 months and is still on-going. “Based on initial results, the nanosecond 2RT laser warrants ongoing evaluation as an early intervention,” said Prof. Guymer. Speaking of laser in a separate session, Prof. Wong Tien Yin of SNEC posed a very important question: “In the era of anti-VEGF therapy, is there still a role for laser in the treatment of diabetic retinopathy (DR) and diabetic macular edema (DME)?” We have seen the changing management in DME, from laser in the 80s, intravitreal steroids in early 2000s to intravitreal anti-VEGF agents in recent years. In proliferative diabetic retinopathy (PDR), on the other hand, are we going to see the change in management from panretinal photocoagulation (PRP) to anti-VEGF therapy? “However, for 50 years now, laser PRP remains the first line of treatment in PDR, with excellent structural and functional long -term outcomes and significant combined global clinical experience,” said Prof. Wong.

alias: Ophtha-Dog

is to “takeOurcaremission of anyone in Singapore who needs eye care. Every patient who walks through our door will receive good quality evidence-based care.

- Prof. Wong Tien Yin, Medical Director, SNEC

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COVER STORY As reported in by Olson, et al. in JAMA (2015), highlighted Prof. Wong: “Clinicians with decades of experience observing and managing the long term complications of PDR understand that most patients with adequate PRP have stable retinopathy for many years.” “As far as PDR treatment is concerned, anti-VEGF is not superior to PRP; anti-VEGF is not cost-effective compared to PRP. Also, PRP has fewer visits and is less resource intensive,” explained Prof. Wong. “Most patients with diabetes have at least one comorbid disease, and 40% have 3 or more. Thus, going for a monthly doctor visit with “eye injection” for PDR is not a priority,” he added. Why focal/grid laser in PDR? It has robust, long-term level 1 evidence in preserving vision, is overall safe, and is less resource intensive. Besides, noted Prof. Wong, anti-VEGF therapy requires compliant knowledgeable patients. “There are significant gaps in knowledge and awareness among patients with DR and PDR,” he said. DME is a different story altogether, highlighted Prof. Wong. For DME with central involvement and vision loss, antiVEGF therapy is now the gold standard. For DME without central involvement and good vision, there is a role for focal/grid laser. For DME with central involvement but good vision, clinicians can observe anti-VEGF versus focal/grid laser. “In eyes with PDR, laser PRP

Based on findings of the “ Asian AMD Phenotyping Study [which we conducted at SNEC], two subtypes of PCV can be classified based on choroidal vascular features. These provide further understanding of different AMD and PCV sub-types.

alias: The Degeneration Duchess

remains the standard of care, with long-term efficacy and safety results, and is a widely available, cost-effective treatment,” Prof. Wong concluded.

On Imaging Modalities At the recently held Macula Symposium in Singapore, updates in imaging modalities abound in all sessions. Generally, in the management and treatment of ocular diseases, imaging plays a critical role – from diagnosis to monitoring of efficacy of treatment. In recent years, there has been an exponential development in ophthalmic imaging. As much as anterior segment

- Dr. Ranjana Mathur, Senior Consultant, Medical Retina Department, SNEC

ophthalmologists are benefiting from the technology, retinal specialists have apparently more reason to be excited about it. The back of the eye has never been this much visible as it is today with innovations in wide-field flourescein imaging and in OCT technology, to name a few. In inflammatory eye diseases, these imaging updates have become more useful than ever, noted Dr. Vishali Gupta, M.D., professor of ophthalmology at Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. “Wide angle flourescein angiography is useful in examining the periphery in uveitis patients. Fundus autoflourescence is a useful noninvasive imaging modality for monitoring choroiditis,” reported Dr. Gupta. The advancements in Optical coherence tomography (OCT), spectral domain (SD) and swept source (SS), emphasized Dr. Gupta, are very useful for studying the vitreo-retina interface, the intra-retinal pathologies, retinal pigment epithelium (RPE) and choroid. “Optical coherence tomography angiography (OCTA) is a very useful non-invasive imaging modality with a newer view of the retina,” she added. Macula Symposium Singapore was held on 10-11 June 2017 courtesy of Singapore National Eye Centre (SNEC).

18


INNOVATION IMAGING SYSTEM

From Selfies to

Saving Sight

Smartphone Imaging System Provides Accessible and Affordable Eye Health Screening by April Ingram

A

ccording to the World Health Organization (WHO), there are nearly 285 million visually impaired people worldwide – and 80 percent of those cases could have been avoided with early detection. In addition, 90 percent of those affected live in low-income areas. These statistics illustrate why effective, accessible and affordable screening strategies are critical for early detection of disease and overall eye health. Dr. Ramachandran Rajalakshmi, the Head of Medical Retina at Dr. Mohan’s Diabetes Specialities Centre in Chennai, India, recognizes the importance of preventative screening. “India is challenged by the burden of diabetes and its complications. Blindness due to diabetes is preventable, and early detection and treatment is the key,” Dr. Rajalakshmi explained. “Easy-to-use, lower-cost devices would overcome barriers to [allow patients to receive] regular diabetic retinopathy screening in lower and middle-income countries like India.”

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INNOVATION IMAGING SYSTEM

Remidio’s Fundus on Phone (FOP NM-10) in action

So, how can we provide more accessible and affordable screening instruments to patients in need? Thankfully, the answer lies in our pockets (or purses): our smartphones. We’ve long known that these devices are more than simple telephones – and they have the ability to do things we have yet to imagine. Now thanks to Remidio Innovative Solutions, our smartphones have one more use: preventing eye disease and visual impairment. Remidio Innovative Solutions (Bengaluru, Karnataka, India) has developed the world’s first and the only smartphone-based non-mydriatic (no pupillary dilation required) retinal imaging system, the Fundus On Phone (FOP NM-10). With its cutting-edge optical design and simplicity of use, the device can be applied to screen for a variety of ocular conditions including: diabetic retinopathy, macular edema, vitreous hemorrhages and anterior segment diseases. In addition, the compact optical design allows for extremely low flash intensities, which means there is no pupil dilation required, resulting in lower patient stress and discomfort. This puts Remidio in a unique position to make a huge impact on the

Mild – Moderate NPDR

Severe NPDR with DME

TOPCON

REMIDION – FOP

Comparison of Topcon and Remidio FOP in an eye with severe NPDR with DME. [Image source: Dr. Sabyasachi Sengupta]

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visual health of diabetics, and others suffering from vision loss, around the globe. Remidio’s R&D team hails from the Massachusetts Institute of Technology (MIT) in Cambridge, Mass., USA. These engineers are using technological innovations to improve the imaging capabilities of the smartphone-based fundus camera. The company utilizes hardware that has been developed for more than half a decade, and is well-recognized for delivering unmatched quality in terms of image acquisition without requiring pupillary dilatation. The camera is easy to use, portable, low-cost, relatively lightweight, and is based on simple point-and-shoot technology. These features enable technicians in clinics, and the in field, to be easily trained to acquire excellent images. Additionally, Remidio has established a reading center of highly skilled retina specialists trained from reputable national and international centers such as Sankara Nethralaya (Chennai, India) and Johns Hopkins Medicine (Baltimore, Maryland, USA). These retina specialists provide “real time” grading of retinal images via telemedicine solutions. According to Dr. Sabyasachi Sengupta, an ophthalmologist, retina

TOPCON

REMIDION – FOP

Comparison of superotemporal quadrant images from the Topcon and Remidio FOP in an eye with moderate NPDR. [Image source: Dr. Sabyasachi Sengupta]


specialist and head of Sengupta’s Research Academy, based in Mumbai, India, “The addition of the Remidio FOP and the ‘software’ – which can provide instant grading of images by retinal specialists obtained over cloud based software – makes this DR screening solution a complete package. It can be easily employed by ophthalmologists, diabetologists and other health care organizations on a large scale to achieve the mission of preventing blindness due to diabetic retinopathy.” Dr. Sengupta has no financial interest in the technology, but has been very involved in validating the FOP NM-10. “We imaged more than 200 eyes with various severity of DR using the FOP as well as the gold standard Topcon fundus camera and found that the FOP was more than 90% sensitive and specific for detecting all forms of DR,” he shared. “Mobile phones offer connectivity. Images obtained can be instantly sent to an esteemed colleague and the best opinion sought for patients, irrespective of geographic barriers. Hence, I see tremendous potential in mobile phone based screening solutions for timely and early DR detection,” he added. Dr. Rajalakshmi and colleagues at Dr. Mohan’s Diabetes Specialities Centre have been extensively using the Remidio FOP, and feel that the device is both sensitive and specific in detecting retinopathy of varying severity which provides sharp image quality both in the mydriatic and the nonmydriatic versions. They previously published a study in the journal PLoS One*, comparing the Remidio FOP to a traditional Zeiss FF450 desktop imaging system and found the clinical sensitivity to be 93% and specificity to be 98%. “The combination of affordability, portability of the device, easy transmission of images and other

Retinal color photography of diabetic macular edema taken using REMIDIO FUNDUS ON PHONE CAMERA. [Image source: Dr. Ramachandran Rajalakshmi]

features of this Fundus On Phone system provides a platform not only for physician’s in-clinic use, but it’s also invaluable for teleophthalmology purposes. Remidio FOP is a good option for cost-effective regular repetitive retinal assessment in people with diabetes,” shared Dr. Rajalakshmi. Remidio has installed more than

Retinal color photography of diabetic retinopathy taken using REMIDIO FUNDUS ON PHONE CAMERA. [Image source: Dr. Ramachandran Rajalakshmi]

500 of the FOP units in the Asia-Pacific region, including India, SAARC region, Southeast Asia, Australia and some initial units in the US market. The technology is protected with patents granted in the US, Europe, China and South Africa. The device is CE marked, TGA registered, HSA (Singapore) approved and USFDA registered.

Reference: *Rajalakshmi R, Arulmalar S, Usha M, et al. Validation of Smartphone Based Retinal Photography for Diabetic Retinopathy Screening. PLoS One. 2015; 10(9): e0138285.

About the Contributing Doctor Dr. Sabyasachi Sengupta is an ophthalmologist and retina specialist based in Mumbai, India. He completed his ophthalmology residency from Aravind Eye Hospital, Pondicherry, vitreoretinal fellowship at Sankara Nethralaya and a postdoc research fellowship at Wilmer Eye Institute, Johns Hopkins. He has published more than 65 articles in peer reviewed journals and is currently the Associate Editor of the Indian Journal of Ophthalmology. He has pioneered Sengupta’s Research Academy (www.senguptasresearchacademy.com), a comprehensive research portal offering e-Learning modules and manuscript editing and data analysis services. In addition to patient care and research, Dr. Sengupta enjoys music and is a trained singer. [email: info@senguptasresearchacademy.com] Dr. Ramachandran Rajalakshmi, MBBS, DO, MRCS, PhD, is the Head of Medical Retina at Dr. Mohan’s Diabetes Specialities Centre in Chennai, India, a center recognized as WHO Collaborating centre for Non-communicable Diseases Prevention & Control. She recently published her paper, Validation of Smartphone Based Retinal Photography for Diabetic Retinopathy Screening, which evaluated the sensitivity and specificity of a smartphone based retinal imaging system, as a screening tool for diabetic retinopathy (DR) detection and DR severity. [email: drraj@drmohans.com]

21


INNOVATION PEDIATRIC VISION SCREENER

Fixing the Challenges of

Pediatric Fixation and Detection of Amblyopia by April Ingram

N

early four percent of children develop poor vision in one eye – known as amblyopia, or more commonly, “lazy eye” – simply because one eye was suppressed or not adequately used during early childhood. This suppression is usually the result of a misalignment of the child’s eyes, such as crossed eyes, or a difference in image quality or focus between the two eyes. Eventually one eye becomes stronger than the other, and over time the weaker eye may become useless. Because amblyopia can be reversed if found and treated early, this is a major public health concern and effective childhood screening needs to take place. As with most screening programs, finding an assessment that is reliable,

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cost-effective and that can be performed by non-physician personnel is essential in addressing the large number of individuals who need to be screened. In order to reliably diagnose amblyopia, the detection of reliable central fixation is essential. Yet there remains a need for a commercially available and widely accepted automated screening instrument that can reliably detect strabismus and defocus in young subjects. The latest contribution on the topic of pediatrics vision screening comes from Dr. Boris Gramatikov, with the Laboratory of Ophthalmic Instrument Development in the Zanvyl Krieger Children’s Eye Center at the Wilmer Institute (Johns Hopkins University School of Medicine), who recently

published his work in the journal, BioMedical Engineering OnLine. This laboratory continues to be on the cutting edge of vision screening, with achievements including numerous publications, and four issued or allowed U.S. patents. The work has been supported by an R01 grant from the National Institutes of Health (NIH), an Individual Biomedical Research Award from The Hartwell Foundation, as well as a number of private donors. Everyone knows that vision assessments in children, like teasing out lack of fixation from simple lack of attention, can be particularly challenging. Dr. Gramatikov’s work discusses how depending on the direction of gaze and the instrument design, the screener produces several


Screening signal frequencies that can be utilized in the detection of central fixation. The article also describes how the use of artificial neural networks can allow for a more reliable detection of central fixation and eye alignment, which is essential in diagnosing amblyopia (lazy eye). To further explaining neural networks, Dr. Gramatikov said: “They are multilayer decision-making mathematical structures that resemble the organization of the neurons in the human brain. They have an input layer that accepts the available data, hidden layers that can be trained (or taught) to represent the interconnections between the neurons at different levels, and an output layer providing the decisions made based on the input data and the network structure and training.” “This particular network has four inputs, representing normalized spectral powers at four signal frequencies generated by our screening device during retinal birefringence scanning for each eye. The hidden layer contains four neurons. The output suggests presence or absence of central fixation,” he added. Dr. Gramatikov used the method of backpropagation to train the network, which is a method that calculates the gradient of the loss function with respect to the weights in an artificial neural network. Once the network was trained, validated and tested on a set of controlled calibration data, obtained from 600 measurements from 10 eyes in a previous study, it was tested again on a clinical set of 78 eyes, which were independently diagnosed by an ophthalmologist. Four inputs for each clinical

subject were fed to the artificial neural network, then the output was compared each time with the target, a step in the process which in fact was the doctor’s decision. This allowed for the calculation of the sensitivity and specificity of the artificial neural network when applied to the clinical data. The results of the tests on the clinical set demonstrated a sensitivity of 0.9851 and specificity of 1.0000, with no false positive decisions and only one false negative decision. Importantly, these results were slightly better than those obtained from the same device and the same signals in their earlier study using statistical methods, including discriminant analysis. “This work builds upon intensive development work in this field performed in our lab in the past 20 years under the guidance of Dr. David Guyton, a prominent pediatric ophthalmologist, a physicist, and an

inventor. Other team members in the past included Drs. David Hunter, Kristi Irsch, Kurt Simons, just to name a few, “ shared Dr. Gramatikov. “We have developed an improved pediatric vision screener (PVS) that can reliably detect central fixation, eye alignment and focus. The instrument identifies risk factors for amblyopia, namely eye misalignment and defocus. It uses the birefringence of the human fovea (the most sensitive part of the retina),” he explained. Birefringence is the property of media (in this case the tiny Henle fibers surrounding the fovea) that change the polarization state of light upon reflection of a beam of polarized light from the fundus in a double pass scanning system. The optics have been reported in more detail in 2014 in the Journal of Biomedical Optics. Dr. Gramatikov notes that circular scanning, as performed by this instrument, generates signals of four distinct frequencies, whose amplitudes are indicative of central fixation or lack thereof. Although this initial sample size may be considered relatively small, this pediatrics vision screening instrument, in its design and analysis methods, will undoubtedly prove to be incredibly valuable in effectively screening large numbers of children and identifying eye misalignment.

Reference: Gramatikov BI. Detecting central fixation by means of artificial neural networks in a pediatric vision screener using retinal birefringence scanning. Biomed Eng Online. 2017;16(1):52.

About the Contributing Doctor Dr. Boris Gramatikov obtained his Dipl.-Ing. degree in Biomedical Engineering from the Technical University of Ilmenau, Germany, and his Ph.D. from the Technical University of Sofia, Bulgaria. He has completed a number of postdoctoral studies in Germany, Italy and the United States. He joined the faculty of Johns Hopkins University in 1996, and has worked in the Laboratory of Ophthalmic Instrumentation Development since 2000. He is an active member of the IEEE, having chaired the Baltimore Section in 2006, and being the Section’s Director for Continuing EE Education ever since. Dr. Gramatikov’s areas of expertise are electronics (both digital and analog), optoelectronics, computers, computer modeling, signal/ image processing, data analysis, electronic instrumentation design, biophotonics, ophthalmic optics, and biomedical optics, all applied to the development of diagnostic methods and devices for ophthalmology and vision research. He serves as a reviewer and editorial board member with a number of high-impact peer-reviewed journals. [Email: bgramat@jhmi.edu]

23


INNOVATION RETINAL REATTACHMENT STENT

Putting Computers to Work by Helin Räägel

The Pushing Approach in

Retinal Detach

The force of pushing is effective both in reattaching retinas and camel wrestling.

T

hanks to technological advances in computer imaging, an idea to treat retinal detachment is gaining ground. The retina of the eye is comprised of mostly photosensitive cells. Damage to the retina, from mechanical impact, excessive straining of the eye, or diabetes, can lead to retinal detachment resulting in partial or total loss of vision, if left untreated. There are already a number of treatments for retinal reattachment: laser surgery (tissue scarring), cryopexy

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(freeze treatment), scleral buckling, or inserting fluid into the eye. Regardless of the method, the main idea behind the treatments is to increase the force pushing on the detached retina to facilitate reattachment between the tissues in the eye. Retinal repair procedures have been shown to have a high success rate; however, loss of vision is still a frequent setback after surgery for a number of patients. “Sight is inevitably the most important sense for anyone and its impairment has a negative effect

on both the individual and on society,” said Dr. Razvan Rusovici, one of the authors of a recently published paper on a novel surgical procedure that takes a more patient-focused approach to treating retinal detachment. This new surgical procedure involves inserting a stent into the patient’s eye to create pressure, allowing the retina to reattach, an idea that was designed and patented by Dr. Ganiban and his company OptiStent (Rockledge, FL, USA). Of course, any new development in healthcare must


chment Treatment undergo rigorous testing before it can be considered as a viable treatment option, and Dr. Rusovici and a team of scientists at Florida Institute of Technology are doing just that. This new approach utilizes a titanium alloy stent that is surgically inserted into the patient’s eye. The insertion of the stent itself is facilitated by a medical catheter-like device that acts as an expandable pressurized balloon inside the eye to gently press the retina back into contact with the choroid and sclera. As opposed to a self-expanding stent, it would allow more accurate control over the applied pressure, as research has shown that self-expandable stents may continue to slowly expand post-implantation, and thus induce too much strain on the sclera – which could permanently damage the eye. Fortunately for doctors, like Dr. Rusovici, with innovative ideas for improvements to patient care and surgical procedures, computers can be used to create models to design medical devices and anticipate problems before they arise in an actual patient. In this new approach, designing a stent that would serve its purpose, and not damage the eye in the process, is key – and there are a number of factors to consider: too much pressure on the retina could lead to irreversible retinal damage at the stent-retina interface; or insufficient pressure, on the other hand, could potentially allow the stent to lose contact and move within the eye cavity. Furthermore, since eye tissue properties, including intraocular

pressure may vary significantly between patients, but also within the eye of a single patient throughout a day, the design of an “ideal stent” is a challenging task. To overcome this hurdle, Dr. Rusovici and colleagues have used a 3-dimensional computational model to identify a given stent configuration (diameter and specific geometric shape) that would induce high enough additional intraocular pressure, but not exceed the maximum allowable threshold that would lead to permanent retinal damage. The study showed that the maximum strain occurred at the contact between retina and the apex of the loops of the stent, making it a feasible strategy for retinal reattachment procedure, and providing a theoretical basis for the experimental

implementation of the new procedure. Despite the proof of concept, the authors strongly emphasize the importance of careful stent design and analysis for proper patient treatment, as certain combinations of stent geometry and intraocular pressure could lead to retinal strains too close or above the permanent damage threshold. With these results, the retinal repair procedure has a strong theoretical starting point and will hopefully continue experimentally. “I feel fortunate if my research could bring a small contribution to the understanding and treating of eye injuries”, shared Dr. Rusovici, who is personally invested in this research due to family history of ophthalmic diseases.

Reference: Rusovici R, Dalli D, Mitra K, et al. Finite element modeling, validation, and parametric investigations of a retinal reattachment stent. Int J Numer Method Biomed Eng. 2017 Mar 27. [Epub ahead of print]

About the Contributing Doctor Dr. Razvan Rusovici is an associate professor of Aerospace and Biomedical Engineering in the College of Engineering, and an associate professor of Aviation Science in the College of Aeronautics at the Florida Institute of Technology (Melbourne, Florida, USA). Initially trained as an aerospace engineer, he has always held a deep appreciation and love for medicine. He has slowly gravitated toward biomedical research by employing his knowledge held from structures and structural dynamics to analyze ophthalmologic and orthopedic procedures. Dr. Rusovici was also awarded one patent in turbomachinery research (USPTO 9394804). He holds a diploma engineer degree (Dipl. Eng.) in aerospace engineering, a master’s degree in aerospace engineering, and a doctoral degree in mechanical engineering. His research is and has been funded by the U.S. Department of Defense, NASA and industry since 2000. He has published several scholarly publications and numerous technical reports and is the 2000 international winner of the ASME/ Boeing Structures, Structural Dynamics and Materials Award, which is the highest international award for structural dynamics during a calendar year in a joint AIAA/ASCE/ASME/AHS conference. Dr. Rusovici is a member of the AIAA Technical Committee on Structural Dynamics. He is also an FAA-certified Airline Transport Pilot (ATP) multi-engine pilot and an instrument/advanced ground instructor, and a passionate higher education teacher. [Email: rrusovic@fit.edu]

25


ENLIGHTENMENT REGULATORY AFFAIRS

Pharmaceutical Regulation

Patient

by Brooke Herron

W

ith increased regulation, pharmaceutical companies are turning away from sales representatives to promote their products and instead looking toward medical affairs professionals to provide quality information to ensure patient safety. We spoke with Dr. Sushil Panda, M.D., the Regional Scientific Expert – Retina (APAC) for Allergan in Singapore, to learn more about how medical affairs is now becoming the trusted voice for the industry. He began by explaining that it’s a common misconception that

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medical affairs professionals are just amped-up (or super) pharmaceutical sales representatives. “Medical affairs professionals are not the super heroes of pharmaceutical sales. They do not have a sales target – and their salaries are not dependent on the commercial success of a product,” said Dr. Panda. “Salespeople have one job: to sell. That is not the goal of medical affairs. We do not say, ‘this drug is the best,’ instead we are focused on what is best for the patient,” he continued. In order for medical affairs professionals to be a trusted source of information, they must be unbiased.

If the pharmaceutical company they work for has a medication that is shown to have unfavorable results, it is their job to communicate that information. Medical affairs professionals communicate with three main entities: external healthcare providers (doctors), internal stakeholders and healthcare organizations (governmental bodies). Those who focus on external affairs, will work to ensure that doctors get the right information to prescribe the correct medicines and dosages. “Of course, doctors know many things. However, they may not be upto-date on all the possible medicines


for

Protection or treatments available – this is where medical affairs can step in to provide responsible advice that has the best interest of the patient in mind,” added Dr. Panda. “Again, they are not there to sell to the doctor, but to provide accurate information based on facts, safety and efficacy.” Medical affairs professionals also relate critical information to internal stakeholders. “With internal stakeholders, we have to play a strategic role. This requires planning and scientific evidence, and must be done within a standard operating procedure to be compliant,” he explained. “For example, if a new drug is being released, we will ensure that the correct dosage is promoted, as well as the correct intended use. That distinction must be made based on scientific evidence.” Medical affairs personnel also work closely with healthcare providing organizations or regulating governmental bodies. They provide research and evidence to give a fair and balanced opinion, without any commercial intent.

“Someone who reports to a healthcare organization might help answer questions like: ‘what diseases are most prevalent?’ or ‘what are right guidelines for this medicine?’” said Dr. Panda. Working with so many different teams within an organization requires collaboration on all sides. “It’s important for medical affairs professionals to work well with others, and to be firm: a yes is a yes, and a no is a no,” he added. And like everything concerning the healthcare industry, this is an evolving field as well. “This isn’t the way it used to be… there are more checkpoints, and we’re getting better results. That is

the benefit of an unbiased view.” Much of this regulation has come into effect because of drug misuse, incomplete testing, or a focus on sales figures over patient safety. Those in the healthcare industry may be familiar with the Sulfanilamide Disaster, which was responsible for more than 100 deaths in 1937. Before this tragedy the drug had been used in the tablet and powder form without any ill-effect. Then, a salesman reported that there was a need to have the drug in liquid form. The company’s chemist created it… and tested it for flavor, fragrance and appearance. But, what they didn’t test it for was toxicity – because at that time, they didn’t have to. While selling toxic drugs could damage a company’s reputation, it wasn’t illegal. Thankfully, we’ve come a long way… but there is still more that can be done. “Following this disaster, among others, clinical trials are now mandated from Phase I to Phase IV,” said Dr. Panda. “There’s always a right way to do things. What we want to do is a good thing, in the right way… and that’s by being responsible and providing unbiased scientific evidence to ensure the safety of patients and the efficacy of the medicine.”

About the Contributing Doctor Dr. Sushil Panda, MBBS, M.D., brings along with him over 16 years of comprehensive experience in clinical, medical teaching and pharma-medical affairs. He has past experience as a clinician in the Department of Surgery of Tata Hospital, India, and subsequently worked as an assistant professor in the Department of Pharmacology, J N Medical College, India. Before joining Allergan, Dr. Panda worked at Bayer as medical advisor for ophthalmology and oncology. He later joined Allergan as India lead for retina therapy of the company’s eye care portfolio. Currently he is based at the regional office of Allergan in Singapore and works as its Regional Scientific Expert-Retina-(APAC), Medical and Scientific Affairs, Eye Care.

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ENLIGHTENMENT VIP PATIENTS

Rolling out

Celeb

by Brooke Herron

C

elebrities are used to getting the red carpet treatment, and they expect the same from their medical care and doctors. Often VIPs (very important people) and MIPs (the most important people) require special handling: reduced (or no) waiting times, separate entrances, secrecy and the best technology available. And for the doctors who treat them, there can be big reward for the additional headache. To understand the lengths doctors and medical facilities must go to in order to treat VIPs and MIPs, we spoke with Dr. Mohan Rajan, the chairman and director for Rajan Eye Care Hospital in Chennai, India. His clinic treats a large number of VIP clients, and in order to keep them happy (and healthy), he follows some general guidelines.

Timing, Technology and Pampering The first thing Dr. Rajan mentions is technology. “We have a huge number of VIPs coming into our clinic. Mainly because they know we have the most advanced technology available,” he said. Just like any other person, celebrities want the best possible treatment. But that’s where the similarities between the VIPs and the non-VIPs end. “The main thing VIPs want is special treatment – that is number one. When they arrive at my clinic, I

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the Red Carpet for

brity Patients personally receive them at the entrance of the hospital and take them to my chambers right away. A regular patient will have to wait for one or two hours,” explained Dr. Rajan. “They want to be pampered, and a lot of doctors don’t know how to handle that.” Another reason for this special service is secrecy. “Celebrities don’t want to be recognized when they are receiving medical care – it’s a very personal thing,” he added. Image plays a big role in the career of VIPs and MIPs. “If they are seen to have a medical problem, like cataracts, it could negatively affect their career.” Because of this, VIP and MIP patients are usually seen before or after normal operating hours. “I ask them to come in for consultations at the end of the day, usually 30 minutes to one hour after my last patient leaves,” explained Dr. Rajan. “And if they need surgery, I schedule them early in the morning, well before my first regular patient arrives.” And it’s not just about secrecy from other patients, celebrities’ identities are protected from the staff as well. He says only a selected few will know the VIPs are coming – usually six to eight people at maximum are on-site when a VIP or MIP arrives. In addition, those employees are instructed to not bother them or take photos. Dr. Rajan knows that if the celebrities feel embarrassed, they will not return.

Have Back-Ups of Back-Ups Even under normal circumstances, performing surgery can be stressful, and Dr. Rajan admits that performing it on VIPs or MIPs adds extra tension. He recommends having plenty of back-up machines, just in case one fails – which has happened to him before. “Back in 2006, I was operating on a VIP patient and my phaco machine conked out… I wasn’t sure what to do. Fortunately, we had another back-up machine then. Today we have 7-8 backups,” he explained. For a normal patient, the hospital will have three back-up machines ready to go… for celebrities, they have up to 10. “You have to anticipate problems and complications before they occur, whether it’s a normal patient or VIP,” he added. Dr. Rajan admits the extra tension can be challenging. “You might be doing the same procedure you’ve done 100 times… but then something like a posterior capsule rupture might occur with a VIP patient. Mentally, it can be difficult.”

Extra Trouble Means Extra Reward With the extra lengths doctors and hospital staff have to go to in order to treat VIPs and MIPs, it’s natural to question whether the additional hassle is worth it. For Dr. Rajan, it is. “I tend to be very socially active, so I know many of the VIPs and MIPs personally. They know me, and they trust me...that’s important,” he said. “Plus, they know that we are going to extra trouble for them, and they are willing to pay more for that kind of attentive and upscale service.” And often, VIP and MIP patients return the favor for Dr. Rajan’s efforts. “If I have an eye donation rally and fundraiser, one of my famous clients will sing at the event free of charge,” he said.

About the Contributing Doctor Dr. Mohan Rajan, MBBS, D.O., Dip. NB Ophthalmology, FMRF, MNAMS, M. Ch Ophthalmology, FACS, D.D., FRCS, Ph.D., is the chairman and medical director of Rajan Eye Care Hospital, Chennai, India. Dr. Rajan is a distinguished ophthalmic surgeon in both anterior and posterior segment surgeries. He is a specialist in phacoemulsification, foldable IOLs and vitreoretinal procedures. At the helm of Rajan Eye Care Hospital and Rajan Eye Bank, Dr. Rajan’s mission is to provide people of all socio-economic backgrounds the benefits of total eye care. His surgical skills and experience has touched thousands of patients throughout his professional life. [Email: drmohanrajan@gmail.com]

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ENLIGHTENMENT TELEOPHTHALMOLOGY

The Role of by Ruchi Mahajan Ranga

Photo Documentation in Ophthalmology

‘P

hotography in Ophthalmology’ is a highly specialized branch of medical imaging dedicated to the study and treatment of disorders of the eye. This broad-spectrum branch of photography takes on its true identity by use of specialized equipment aimed at documenting ocular parts such as the iris, cornea and retina. Teleophtahalmology specifically refers to eye care using digital media devices and telecommunications technology. In a poster presented at the recently held American Society of Cataract and Refractive Surgery (ASCRS) 2017 meeting in Los Angeles, California, USA, entitled Clinical photos for diagnosis, treatment and teleophthalmology, Dr. Clifford Terry of Terry Eye Institute in Fullerton, California, USA, highlighted why it’s imperative to incorporate clinical photography in every ophthalmic practice. In addition to diagnosis and treatment, patient photographs are routinely used in presentations, documentation of surgical outcomes, as well as teaching. In the advent of technology that has touched every area of ophthalmology treatment options, taking high-quality images has become very simple, and there is no need to invest in expensive equipment or employ a professional photographer. In fact, any ophthalmologist can take clinical photographs in their office setting with minimal technical skill. In 2011, the first clinical slit lamp adapter for iPhone made its debut, and brought with it the sophistication of high quality images, ease of use for ophthalmologists. In addition, it also had the advantage of portability, and could be brought into every exam room. “Compared to slit lamp examination, which offers only a few degrees of field, this camera [slit lamp adapter for iPhone] allows the view of entire posterior pole. With the camera,

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Just a minute Betty, I'm sending patient photos to the clinic...

photo documentation of the findings is feasible,” said Dr. Terry. The fundus slit lamp camera for routine ophthalmology exams allows the clinician to photograph the retina while examining it. It has the benefits of being inexpensive and portable, plus it has provisions for image enhancement in cloudy media and light amplification for photophobic eyes. It’s also quick and easy to send photos to Electronic Health Records (EHRs) with the advancements in slit lamp and retinal cameras. “Photo documentation enables clinicians to easily compare and track the progress of treatment plans and/or effectiveness of treatment modalities. This helps to document all retinal morphological findings,” Dr. Terry explained. Over the past two decades, digital photography has been widely accepted in teleophthalmology for its significant advantages over conventional photography. In addition to the economic advantage of immediate visualization, the digital format of the pictures allows easy deletion of undesired or unneeded images, thus eliminating the costs of unnecessary prints – as was the case with traditional photography.

Dr. Terry also extolled the benefits of photo documentation in regard to patient communication. “It makes it easier for the clinician to explain diagnosis and treatment to the patient. Patients can also understand pictures better than the ophthalmic terms,” he shared. Where digital photography in ophthalmology has made storage and editing of photographs easier, it has also facilitated the movement of these pictures to electronic medical records and provided the ability to upload the photographs with patient data. The most common forms of storing digital images are JPEG (Joint Photographic Experts Group) and TIFF (Tag Image File Format), and it is imperative for clinicians to backup copies of the photographs regularly on CD-ROMs or external hard disks, which are economical and readily available. These advancements allow ophthalmologists to not only offer highresolution photography to patients, but to also create an organized and efficient approach to ophthalmology treatment practices.

Reference: ASCRS 2017 Eposter #34482-0431: Clinical Photos for Diagnosis, Treatment and Teleophthalmology by Dr. Clifford Terry, M.D., Terry Eye Institute, Fullerton, California, USA.


ASCRS 2017 POSTERIOR SEGMENT HIGHLIGHTS

Posterior Segment Tidbits from

by Olawale Salami and Timmo Gunst

ASCRS 2017 Posters PVD Patients Without New Symptoms Do Not Require Early Routine Follow-up

P

osterior vitreous detachment (PVD) is common in older patients, particularly after cataract surgery. Currently, there is a paucity of published prospective follow-up data on PVD post-cataract surgery as patients are only typically followed 4-6 weeks after the initial presentation. Therefore, it remains unknown if routine, early follow-up appointments are necessary for patients without new symptoms. To help address this issue, Dr. Michael Ross, M.D. and his colleagues from the Department of Ophthalmology at McGill University in Alberta, Canada, investigated this and presented their findings in a poster entitled Posterior Vitreous Detachment and Incidence of Delayed Retinal Breaks: A Retrospective, Multi-Site Study at an Academic Center, at the recently held ASCRS 2017 meeting in Los Angeles. Dr. Ross and colleagues performed a retrospective chart review of all patients presenting to the emergency departments of the McGill University

Health Center over a two-year period who were subsequently diagnosed by ophthalmology with a Schaeffer negative PVD, (in the absence of any other vitreoretinal pathology including retinal tears, detachments, or vitreous hemorrhage). They recorded patient demographics, past ocular surgery, and retinal findings at the first and second exams, as well as the examiner’s identity. The primary outcome measure of the study was the absence of new retinal tears or pathology on the second follow-up visit, while secondary outcome measures included age, past ocular surgery, and training level/specialty of the initial and secondary examiner. At the end of the review, 166 patients were identified, and 105 patients were present for both an initial and routine scheduled followup examination. The median interval between the initial and follow-up examination was 6 weeks. It was striking to note that none (0%) of the patients had any new pathology discovered

on the follow-up exam. One patient returned early because of increased symptoms, but no pathology was discovered. Most patients (n=62) were seen initially by one of 15 residents alone, and most patients (n=80) were seen at follow-up by one of ten comprehensive and subspecialist staff in uveitis, neuro-ophthalmology, cornea and retina. The remaining 25 patients’ follow-ups were completed by residents. “To our knowledge this is the first study on the incidence of delayed retinal breaks with the exam performed by a variety of residents and comprehensive and subspecialist staff. Our results suggest that PVD patients without new symptoms, even those followed by nonretina ophthalmologists, do not require early routine follow-up,” highlighted Dr. Ross and colleagues. “These findings could help ophthalmologists better manage healthcare resources,” they concluded.

Forget 0.01%. Sometimes 0% is on the money.

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ASCRS 2017 POSTERIOR SEGMENT HIGHLIGHTS Macula Capillary Perfusion Evaluation and its Correlation to Diabetes Mellitus

Q

uantitative retinal vascular perfusion density mapping has been proposed as an objective method for monitoring disease progression in diabetic retinopathy. Comparative noninvasive evaluation of macula blood flow changes in diabetes mellitus may significantly aid clinicians in assessing progress and prognosis of diabetic retinopathy. Dr. Gregory Pamel, M.D. and colleagues from New York University Medical School evaluated macula capillary perfusion in relation to clinical and laboratory parameters. Their findings were presented at the ASCRS 2017 meeting in a poster entitled Macula Capillary Perfusion Evaluation

with Spectral Domain OCT and Its Correlation to HbA1C Levels and Clinical Duration of Diabetes Mellitus. The team evaluated 95 consecutive patients with known diabetes mellitus. Both eyes of each patient were imaged with the angioflow software of the AngioVue Imaging System (Optovue, Fremont, CA, USA). A correlation of the capillary macula plexus was made in association with the duration of clinical diagnosis and HbA1C levels. Within the patient population, they found that 6 of the 95 cases (6.3%) showed significant macula capillary angioflow changes that correlated closely with HbA1C levels over 8% in more than five years

of clinical diagnosis, with one case with uneven contralateral eye findings. Based on these findings, Dr. Pamel and colleagues concluded that “vascular macula flow pathology, such as capillary dropout, micro aneurysms, macula edema was evident in routine evaluation of diabetics with this non-invasive vascular flow study.” The investigators highlighted that no intravenous dye was used, which increases safety and facility of the exam. “This reinforces patient compliance with such routine such checks and this data may significantly aid clinicians in the progress and prognosis of diabetic retinopathy,” they added.

Fractal Analysis for Objective Assessment of Microvasculature in Diabetic Retinopathy

O

ptical coherence tomography angiography (OCTA) is becoming an increasingly popular approach by clinicians to qualitatively assess disease. The role of OCTA in the assessment and management of retinal diseases has become significant in understanding the vitreoretinal relationships and the internal architecture of the retinal structure. Fractals are patterns found in nature and biological systems that demonstrate the same level of complexity and general pattern, regardless of the scale on which they are measured. Fractal analysis of the retinal vasculature in color fundus photographs and fluorescein angiographic images has been attempted with limited success by researchers as early as 1990. Although OCTA remains a promising new modality, OCTA images have thus far been largely interpreted qualitatively. Given the more detailed imaging of each retinal vascular layer possible with OCTA compared to fundus photographs and flourescein angiography, these images are well-suited for fractal analysis and may shed new insights and quantifiable

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parameters for microvascular diseases. To investigate this further, Dr. Suruchi Bhardwaj, M.D. and colleagues utilized fractal analysis to investigate retinal vascular disease patterns in patients with various stages of nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR) using spectraldomain (SD) optical coherence tomography angiography (OCTA). The team conducted a retrospective study of 49 eyes from 26 control subjects and 58 eyes from 35 patients with diabetic retinopathy. Of the 58 diabetic eyes, 31 exhibited NPDR (13 mild, 9 moderate and 9 severe) and 27 were categorized as PDR. OCTA images were acquired using the RTVue XR Avanti (Optovue, Fremont, CA, USA). They obtained automated segmentation through the superficial and deep capillary plexuses for each eye and grayscale OCTA images were standardized and binarized. Fractal box-counting analyses were performed using Fractalyse. Fractal dimensions (FD) and correlation coefficient (CC) of the superficial and deep capillary plexuses were compared

between control eyes diabetic eyes using two-tailed t-tests and ANOVA analyses. Based on the analyses of the superficial and deep plexuses from diabetic and control eyes, Dr. Bhardwaj and colleagues found that a statistically significant average FD for diabetic eyes was significantly reduced in comparison to those of control eyes in the superficial plexus (p= 2.4 x10^-6) and deep plexus (p= 1.87x10^-12). The team therefore concluded that the OCTA FD is significantly reduced in both the superficial and deep capillary plexuses in eyes with all stages studied of diabetic retinopathy. Presenting their findings at the recent ASCRS 2017 meeting in a poster entitled Fractal Dimensional Analysis of OCTA in Various Stages of Diabetic Retinopathy, Dr. Bhardwaj and colleagues highlighted that “utilization of fractal analysis provides objective parameters to assess microvascular disease burden in diabetic retinopathy.”


ASCRS 2017 POSTERIOR SEGMENT HIGHLIGHTS Quality of Vision in YAG Vitreolysis for Treatment of Floaters

Are Patient-Reported Outcomes Enough?

Floats are great. Floaters, not so much.

by Olawale Salami

C

urrently, systematic assessments of post-treatment quality of vision in patients treated for symptomatic vitreous floaters have relied upon patient-reported satisfaction tools, which use self-rated numeric scales of improvements in daily function. However, these patient-reported responses are subjective, and therefore highly prone to inter-patient variability. This has underscored the need for more research into the development and validation of new methods, which can objectively analyze post-treatment quality of vision. In a poster presented at the recently held American Society of Cataract and Refractive Surgery (ASCRS) 2017 meeting in Los Angeles, California, USA, entitled An Objective Analysis of Quality of Vision in Patients Undergoing YAG Vitreolysis for the Treatment of Symptomatic Floaters, Dr. I. P. Singh of the Eye Centers of Racine and Kenosha in Wisconsin, USA, investigated the effect of YAG laser floater treatment (vitreolysis)

on quality of vision by measuring internal aberrations using wave front aberrometry. In the study, Dr. Singh utilized the i-trace system, which combines corneal topography with a ray tracing aberrometer to objectively measure quality of vision in patients. This was a retrospective, observational study of 36 eyes of 28 consecutive patients. All patients had documented “amorphous� cloud-like floaters in their visual axes. During the study, patients underwent one session of YAG Vitreolysis with the Ellex Ultra Q Reflex laser. Following this, preoperative undilated iTrace scans were performed on the day of the procedure. Further assessments were made using postoperative scans one month after treatment. Dr. Singh compared preoperative and postoperative measurements of

dysfunctional lens index (DLI) and higher-order aberrations (HOA). At follow-up, 91.6% of eyes (33 out of 36) noted improvements in either DLI or HOA. The mean pre- and post-operative DLI were 5.2 and 8.3, respectively, with an average DLI improvement of 3.1. At the follow-up evaluation, mean observed improvement in postvitreolysis HOA was 0.16, with Trefoil aberrations demonstrating the biggest difference. Furthermore, measurement of modulation transfer function (MTF) curves showed a 0.217 average change in curve heights. In addition, Dr. Singh compared different patient populations and found no significant difference in post-vitreolysis improvements in vision quality between phakic and pseudophakic eyes. The study showed that the average number of required laser shots was 516, with a mean power setting of 6.6 MJ. Snellen visual acuity remained stable: eight eyes did improve one line postoperatively. Safety signals were monitored postoperatively, and no adverse events were recorded in all 28 patients. In addition to objective measurements of vision quality, patient-reported outcomes were also evaluated. One month after YAG vitreolysis, 92% of patients reported visual improvements. "This pilot study on objective analysis using wave front aberrometry demonstrates that YAG vitreolysis has the potential to improve quality of vision in patients experiencing symptomatic floaters," reported Dr. Singh. A larger study is currently being conducted to corroborate these findings in a larger patient population, and hopefully, address more critical questions regarding the management of floaters in symptomatic patients.

Reference: ASCRS 2017 Eposter #32086-0217: An Objective Analysis of Quality of Vision in Patients Undergoing YAG Vitreolysis for the Treatment of Symptomatic Floaters by Dr. I.P. Singh, Eye Centers of Racine and Kenosha, Wisconsin, USA

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ASCRS 2017 POSTERIOR SEGMENT HIGHLIGHTS

A Nano Approach to Posterior

Segment

Drug Delivery in DME Patients

by Olawale Salami

D

iabetic macular edema (DME) is a leading cause of vision loss. Intravitreal corticosteroids remain important options for patients who fail to respond to anti-VEGF agents. These are two known facts in the ophthalmic world. However, their use [intravitreal costicosteroids] in DME patients has been limited by increased risks of infectious and non-infectious endophthalmitis. Since most patients are treated with a series of intravitreal injections, the cumulative per-patient risk of endophthalmitis is higher than the per-injection risk. Reducing this lifelong cumulative risk by decreasing the number of injections represents one of the major benefits of extended-release drug preparations. Therefore, an extended release biodegradable intravitreal implant, which delivers a decreased dose of dexamethasone in a linear manner over approximately six months while still achieving efficacy, could reduce cataract and intraocular pressure (IOP) elevation rates associated with current therapies. At the recently held American Society of Cataract and Refractive Surgery (ASCRS) 2017 meeting in Los Angeles, USA, Dr. Benjamin Yerxa and colleagues from Envisia Therapeutics (in Durham, North Carolina, USA) presented a poster entitled Nonclinical Development of An Intravitreal Extended Release Implant for the Treatment of Diabetic Macular Edema. In that poster, Dr. Yerxa reported that ENV1105 was designed for intravitreal delivery using a novel nano and microparticle precision implant

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Endophthalmitis ain't cute

manufacturing (PRINT) technology to release dexamethasone over a long period (approximately six months). In ENV1105, according to Dr. Yerxa, implants were fabricated using dexamethasone and polymers designed to produce a linear release rate, and content and release were measured by reversed-phase high performance liquid chromatography (RP-HPLC). “These extended release dexamethasone implants were fabricated with a focus on two key features: a high degree of mass and drug content uniformity, and a low degree of implant to implant variability in drug release. In vitro data demonstrated a near zero-order release rate over six months,” explained Dr. Yerxa and colleagues. In a proof of concept study, the team characterized the pharmacokinetics and tolerability

following a single, bilateral, intravitreal administration of ENV1105 in an albino rabbit, with analyses performed at week 1, month 1 and month 3 timepoints. At these timepoints, dexamethasone concentrations were measured in ocular matrices, remaining implants, and plasma by LC-MS/MS (liquid chromatography-mass spectrometry). The rabbits were examined via slit lamp biomicroscopy and indirect ophthalmoscopy. In this study, Dr. Yerxa and colleagues demonstrated that following the administration of ENV1105, therapeutically relevant dexamethasone concentrations were present in target tissues of retina, choroid, and vitreous up to the third month after administration. More importantly, anterior and systemic exposure was not quantifiable. This has important implications for patients, as the side effects of intravitreal corticosteroids could be eliminated by minimizing anterior segment and systemic exposure. However, with ENV1105 administration, posterior segment tissue concentrations following administration were generally not quantifiable at month 3, and dexamethasone was quantifiable in aqueous humor and plasma through month 1. According to Dr. Yerxa and colleagues, “Intravitreal administration of a dose sparing, uniformly releasing dexamethasone implant produced extended delivery to the posterior target tissues with no anterior or systemic exposure and excellent ocular tolerability, and may thus decrease the risk of adverse effects.”

Reference: ASCRS 2017 Eposter #32392-0234: Nonclinical Development of An Intravitreal Extended Release Implant for the Treatment of Diabetic Macular Edema by Dr. Benjamin Yerxa, et.al.