PIE Magazine Issue 12X: The ebook version (The 'Stand-Up Issue', AIOC 2020 Edition)

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12X THE STAND-UP ISSUE December/January 2020


AIOC 2020 Edition www.piemagazine.org

posterior segment • innovation • enlightenment

Cover Story

‘Stand-up’ to Complications in

Posterior Segment Surgeries Page 20



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magazine posterior segment • innovation • enlightenment



Inside this issue...

Posterior Segment Matt Young

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Robert Anderson



Media Director

Vitreoretinal Lymphoma Masquerading as Infectious Retinitis

Hannah Nguyen

Production & Circulation Manager Chief Editor

Associate Editor

Ruchi Mahajan Ranga

On Macular Edemas, Diabetic Eyes and Anti-VEGFs . . .


Rare and Interesting Cases Abound in Posters from APVRS 2019


Gloria D. Gamat Brooke Herron





Revolutionizing the Way Eye Surgeons See with NGENUITY

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‘Stand-up’ to Complications in


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PIE MAGAZINE LETTER TO READERS Seriously, This is No Laughing Matter


ver the past 16 years ‘operating’ in the ophthalmology industry, I’ve had some of the most enjoyable moments of my life. The people in our industry are warm, polite, caring, devoted – and ultimately, changing the world of eye care for the better. They also are funny. Sometimes bawdy. But, they are funny typically in the private parts of conversations in the nooks and crannies of the show floor and conference hotels. They are not typically funny on the podium, at dinner symposia, in posters, or at booth lectures – outside of the occasional lighthearted introductory remark. It makes sense. Saving sight is serious. And the bottom line is critical. At the same time, we also see ‘Humor’ poking his head out when he can. Or perhaps he’s a she. Either way. This past year, we saw the ‘punny’ ophthalmic movie poster section at ASRS in Chicago. We have seen funny slides introduced in ophthalmic lectures in India. And there is the very occasional lighthearted abstract – even if it’s only a funny title. If you’re searching through a myriad of electronic posters, your eyes will land on a title that makes you giggle. When industry laughter happens, there is immense benefit. First, the speaker or author, becomes memorable. The scientific merit of what has been said is not merely politely listened to, only to be forgotten – it is conveyed. Therefore, the speaker or author has a real chance to make a difference in our ophthalmic universe. The product has a better chance of being recalled later during a purchase decision. And overall, the spirits of countless delegates have been lifted for a moment, perhaps creating an overall feeling that yes, it’s been a good day after all. But there are other forces constantly combating humor in our industry, and most people don’t think twice about that. Pride – which sometimes makes its way into the upper echelons of our industry – is one such force. How often have we seen pride – often irrationally believing that one is better than others – end up the butt of many a joke? Pride and humor aren’t easy bedfellows. Lack of creativity is another issue. Our industry is extremely adept at device and drug innovation, but less so with innovative communication. Whether that is because we’re an industry dominated by left brains instead of right brains, or whether it is because math is not poetry, there is a dryness in the collective psyche of the ophthalmic industry. There’s no eye drops that can solve this problem; if only there were PIE Drops . . .


Well, on Friday, Nov. 8, two days before my 40th birthday, Media MICE achieved our revenue target for the entire year of 2019 with the help of PIE and CAKE Magazines. We had already hit our record revenue in the third quarter, and it was our fifth straight year of revenue growth. We do so, not by being the laughingstock of industry, but by emulating Humor’s older brother Wit, and of course his good friend, Metaphor. In this issue of PIE, for example, we explain how the use of “Improv” – or improvisation – in comedy also applies to that need to improvise (or spontaneously invent something in the midst of changing circumstances) in the OR. So, the next time you get up on the podium, or develop a poster headline, consider inserting a little humor into your delivery. Or go all out and pretend you’re John Belushi in The Blues Brothers while delivering free-paper methodology. (I resemble that remark!)

All the best,

Matt Young CEO & Publisher PIE (Posterior Segment - Innovation - Enlightenment) Magazine P.S. This letter is not indicated for laughter. It has been fully vetted by Media MICE regulatory staff, which did not laugh. The approval code for this article is: 911911911. For complaints, please email the Food and Laughter Administration (FLA). Please include samples that are no laughing matter.

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

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

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



Vitreoretinal Lymphoma Masquerading as

Infectious Retinitis by Konstantin Yakimchuk


asquerade syndromes are known in ophthalmology to mimic eye infections. One of these diseases, vitreoretinal lymphoma (VRL), a subtype of B-cell lymphomas, affects the retina and vitreous body and represents an example of clinical mimicry as there are developed similarities between the features of this lymphoma and infectious retinitis. Common symptoms of VRL include blurred vision and floaters. The characteristic features of VRL are retinal white lesions, necrosis, vitreitis and punctate yellow-white infiltrates in subretinal pigment epithelium.1 However, VRL may be associated with several symptoms, which mimic viral retinitis or retinal vasculitis, and is therefore recognized as a masquerade syndrome. As a consequence, the diagnosis of lymphoma is often substantially delayed, leading to unnecessary exposure to anti-viral or antiinflammatory drugs and lymphoma dissemination, instead of a timely start of chemotherapy. Why is it so important to promptly verify the etiology of retinitis? The fast destruction of retinal tissue demands immediate diagnosis in order to commence the appropriate therapy and impede the progression of retinitis. An effective approach to distinguish features and patterns of the lesions observed in VRL from the features of viral and protozoal retinitis has recently been found in a novel study by Marchese et al., published in a recent issue of Ocular Immunology and Inflammation.2 The leading authors of the paper, Dr. Alessandro Marchese from the University Vita-


The fast destruction of retinal tissue demands immediate diagnosis in order to commence the appropriate therapy and impede the progression of retinitis. Salute San Raffaele, Milano, Italy, and Dr. Aniruddha Agarwal from the Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India, were invited by PIE magazine to comment on their paper. Since no central database for VRL is established, it is difficult to measure the incidence of this rare form of lymphoma. Nevertheless, about 380 cases of VRL are diagnosed in the United States annually.3 Dr. Agarwal believes that “the total incidence of vitreoretinal lymphoma is increasing”. This might be explained by improved diagnostic methods, such as vitreous biopsies, serum interleukins, flow cytometry, targeted next generation sequencing, MYD88 oncogene detection and retinochoroidal biopsies. Moreover, according to Dr. Agarwal, “there is also an increase in central nervous system (CNS) lymphomas all over the

world. The involvement of the eyes is approximately 20% of CNS lymphoma”. He also added that in their settings of more than 600 uveitis patients per month, they diagnose VRL in at least two new patients every month. How often can retinitis-like lesions be detected in patients with VRL? The authors indicated that these lesions were observed in 6 eyes out of 76 eyes of 38 patients, involved the peripheral retina, and masqueraded as infectious retinitis. Earlier studies have reported retinal infiltrates formed by atypical B-lymphocytes.4 Furthermore, a clinical case of VRL manifested with blurry vision in the right eye and accompanied by retinal hemorrhages has also been published. Although infectious retinitis was originally suspected, PCR testing disproved infectious genesis of the eye disorder.5

What are the key imprints specific to VRL revealed by Marchese et al.? The most prominent feature was massive retinal thickening in the areas resembling retinitis. Furthermore, the infiltrates in the subretinal space and retinal pigment epithelium also distinguished VRL from other types of retinitis. In contrast to the VRLinitiated lesions, anterior uveitis and iris atrophy were found in patients with viral retinitis. Moreover, the authors observed more intraretinal cysts in viral retinitis than in VRL lesions. Also, toxoplasmic lesions showed less hemorrhages in the retina and were associated with chorioretinal scars. Why does VRL mimic viral retinitis? Could viruses be the triggers, which induce VRL development? The authors of the article stated that VRL has been associated with several infectious agents, such as herpes viruses, as metagenomic deep sequencing detected viral pathogens, which may potentially be involved in the development of VRL.6 In particular, the Epstein-Barr virus has been recognized as a risk factor for the development of VRL. Besides, VRL has been strongly associated with immunodeficiency and immunosuppression. There are several methods for VRL characterization with non-imaging techniques, such as optical coherence tomography (OCT).7 Typical imaging features include hyper-reflective infiltrates in inner retinal and subretinal layers, deposits in pigment epithelium and agglomerates of vitreous cells. In particular, the structure of hyperreflective infiltrates has been suggested to be highly specific for VRL. Besides, vitreous cells in sheets and the absence of cystoid macular edema also indicate towards VRL. Moreover, OCT analysis helps to distinguish between VRL and choroidal lymphoma, since the cellular infiltrates are detected between the RPE and Bruch’s membrane in VRL patients, while they are located deep to Bruch’s membrane in the cases of choroidal lymphoma. In the current paper, the authors strongly advocate the use of OCT, a highly sensitive and non-invasive

VRL has been associated with several infectious agents, such as herpes viruses, as metagenomic deep sequencing detected viral pathogens, which may potentially be involved in the development of VRL. technique, which allows high-resolution analysis of retinal tissue and detection of retinal structural and ultrastructural alterations and intraretinal microangiopathic lesions. The OCT scanning, which was described in the current paper, has not been performed earlier for distinguishing VRL from microbial retinitis. Furthermore, VRL lesions, which resemble retinitis, have never been compared to viral retinitis. Notably, all patients with VRL included in the study showed negative for viral and Toxoplasma PCR. Are there other imaging techniques that may help to diagnose VRL in addition to OCT? Earlier clinical studies have applied fluorescein to detect punctate hyperfluorescent defects, hypofluorescent loci and granularity. In addition, indocyanine green angiography detects hypofluorescent lesions. As Dr. Marchese pointed out, the authors “have not analyzed other multimodal techniques to differentiate retinitis lesions of VRL from other causes. However, on fundus photographs, sharp edges of retinitis were significantly associated with viral forms and not VRL”. Also, Dr. Agarwal noted that in addition to OCT, “fluorescein angiography is a traditional tool that demonstrates the important features of VRL such as leopard skin appearance. On the other hand, viral retinitis appears highly hyperfluorescent with associated arteritis on fluorescein angiography. Toxoplasma chorioretinitis also appears hyperfluorescent with central hypofluorescence, and has associated phlebitis, such as Kyrieleis arteritis, which can also be evaluated on indocyanine green angiography”. Another study, recently published by Marchese et al., has revealed several features of vitreous haze using ultrawide-field imaging, ophthalmic ultrasonography and slit-lamp

photography.8 The observations in eyes of patients with VRL included an aurora borealis pattern, which was represented by cell conglomerates aligned along the vitreous fibrils, and a string of pearls pattern. Furthermore, medical scientists from Northwestern University, Chicago, have reported hyperreflective lesions in all retinal layers in VRL patients.9 The observed lesions would usually appear prior to pigment deposits and surrounded retinal vessels and vanished mostly without scarring after the start of treatment. In addition to diagnostic applications, the authors of the current study followed the healing patterns in both VRL lesions and infectious retinitis using CT analysis. According to Dr. Marchese, the most common treatments for VRL are intravitreal rituximab and methotrexate. Other treatments include radiotherapy, intravitreal melphalan, systemic chemotherapy with high-dose methotrexate or cytarabine. Additional or alternative treatments are performed in the case of the involvement of central nervous system. Intravitreal chemotherapy led to the decrease of sub-RPE lesions and partial regeneration of the retina. In contrast to VRL, patients with viral and toxoplasmic retinitis revealed retinal destruction and necrotic lesions during the healing process. In conclusion, the authors suggest that attentive analysis of the OCT scans would provide clear benefits for patients, especially in cases of suspected VRL versus infectious retinitis. This diagnostic method helps to distinguish VRL from viral or toxoplasmic retinitis. However, clinicians should beware of unspecific OCT features detectable in both VRL and infected retina. Thus, early diagnosis of VRL and appropriate treatment strategy would help to prevent retinal deterioration.


POSTERIOR SEGMENT VRL MASQUERADE References: Aronow ME, Singh AD. The use of imaging in the diagnosis and management of intraocular lymphoma. Int Ophthalmol Clin. 2012 Fall;52(4):199-208. 2 Marchese A, Agarwal A, Miserocchi E, et al. Features of Retinitis-like Lesions in Vitreoretinal Lymphoma. Ocul Immunol Inflamm. 2019;30:1-8. [Epub ahead of print] 3 Chan CC, Rubenstein JL, Coupland SE, et al. Primary vitreoretinal lymphoma: a report from an International Primary Central Nervous System Lymphoma Collaborative Group symposium. Oncologist. 2011;16(11):1589-1599. 4 Albadri ST, Pulido JS, Macon WR, et al. HISTOLOGIC FINDINGS IN VITREORETINAL LYMPHOMA: Learning From Enucleation Specimens. Retina. 2019: [Epub ahead of print] 5 Reddy V, Winslow R, Cao JH, et al. Vitreoretinal lymphoma, secondary to non-CNS systemic lymphoma, masquerading as an infectious retinitis. Am J Ophthalmol Case Rep. 2019;16:100545. 6 Gonzales J, Doan T, Shantha JG, et al. Metagenomic deep sequencing of aqueous fluid detects intraocular lymphomas. Br J Ophthalmol. 2018;102(1):6-8. 7 Barry RJ, Tasiopoulou A, Murray PI, et al. Characteristic optical coherence tomography findings in patients with primary vitreoretinal lymphoma: a novel aid to early diagnosis. Br J Ophthalmol. 2018;102(10):1362-1366. 8 Marchese A, Miserocchi E, Giuffre C, et al. Aurora borealis and string of pearls in vitreoretinal lymphoma: patterns of vitreous haze. Br J Ophthalmol. 2019 Nov;103(11):16561659. 9 Deak GG, Goldstein DA, Zhou M, et al. Vertical Hyperreflective Lesions on Optical Coherence Tomography in Vitreoretinal Lymphoma. JAMA Ophthalmol. 2019;137(2):194-198. 1

About the Contributing Doctors Dr. Alessandro Marchese is a fellow of the European Board of Ophthalmology (FEBO) currently working at the Ocular Immunology and Uveitis Service, Department of Ophthalmology, University Hospital San Raffaele Milan, Italy, where he also received his residency training, after graduating in Medicine and Surgery at the University of Turin. He underwent short term training in uveitis and retina at the Post Graduate Institute of Medical Education and Research (PGIMER) Chandigarh, India, with Prof. Vishali Gupta and Dr. Aniruddha Agarwal. He has authored more than 50 publications in peer-reviewed international journals and his main areas of interest are inflammatory eye disorders and vitreoretinal diseases. He is serving as Editorial Assistant of the European Journal Ophthalmology (January 2018-present). He is a member of the Italian Society of Ophthalmology (SOI) and Uveitis Society of India (USI). [Email: amarchese@hotmail.it] Dr. Aniruddha Agarwal is currently working as an assistant professor in Vitreoretina and Uveitis in the Department of Ophthalmology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India. He has completed his Clinical Research Fellowship (subspecialty of vitreoretina and uveitis) in the Ocular Imaging Research and Reading Center, Stanley M. Truhlsen Eye Institute, Omaha, Nebraska, USA, between 2014 to 2016. He did his ophthalmology residency and Surgical Vitreoretina and Uveitis Fellowship at the PGIMER, Chandigarh, India. He is the recipient of prestigious awards such as the Bayer Global Ophthalmology Association Project (GOAP) Fellowship, Carl Camras Best Researcher Award, J.M Pahwa Award by Vitreoretina Society of India (VRSI), Narsing Rao Award by Uveitis Society of India (USI), and the Carl Herbort Award by the USI. In 2015, he was felicitated by the Hon. Prime Minister of India for his excellent contribution. He has authored more than 150 publications and 36 book chapters. His areas of interest include uveitis, as well as medical and surgical diseases of the retina. He is an expert in ocular imaging and has numerous international presentations and collaborations for the same. [Email: aniruddha9@gmail.com]

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POSTERIOR SEGMENT 3D IMAGING Revolutionizing the Way Eye Surgeons See with NGENUITY by Brooke Herron


he NGENUITY 3D Visualization System from Alcon provides unprecedented 3D visualization of the back of the eye, with greater depth and detail during surgery than traditional microscopes. In fact, a theoretical assessment by Lu Yin, Data Science and Digital Solutions, Alcon, compared three analog microscopes with NGENUITY. He found that NGENUITY can provide 26% to 48% higher total magnification; up to 5-fold greater instantaneous depth of field; and 11% to 42% better depth resolution than scopes. Additionally, NGENUITY provides this higher level of magnification, without compromising depth of field. According to Dr. Shrinivas Joshi from the MM Joshi Eye Institute in India, NGENUITY is also superior to analog scopes for peripheral work thanks to the illumination provided by the chandelier. “It gives fantastic visualization, even when working at the periphery, an area where the analog microscope is lacking,” he explained, adding that this particular advantage of NGENUITY has proven to be a gamechanger for him and his practice – and is the reason he uses NGENUITY. Dr. Joshi also presented findings from a study that compared the high magnification performance in NGENUITY to an analog microscope. Results showed that the conventional microscope scored 79%, while NGENUITY received 89% for best performance, with a P-value that was statistically significant.

NGENUITY: An Intraoperative Advantage For complicated or delicate procedures like cannulation or transplantation, Dr. Kazuaki Kadonosono from Yokohama City University in Japan, says the NGENUITY is exceptional: “The contact lens gives higher magnification, which allows for better (and higher) resolution than under a conventional microscope.” Further, Dr. Lim Kian Seng, an international specialist at Eye Center Malaysia, says that “understanding

the system is very, very important for surgeons to see its capabilities and great potential”. To illustrate this point, he presented a case of a combined cataract with macular hole – and his first use of a cannula. “With more experience, I began to understand the system better,” said Dr. Lim. “The valve cannula allowed better control of intraocular pressure before the commencement of the phaco surgery; and by optimizing elimination, I could actually see the continuous-tear curvilinear capsulorrhexis extremely well, in real time.” From there, Dr. Lim showed how easy it is to stain the internal limiting membrane (ILM) with NGENUITY; and how to use an extrusion cannula to properly control intraocular pressure (IOP) while gas is injected into the eye. “This results in a very controlled combined phaco and vitrectomy for macular hole surgery,” he concluded.

Settings for Success Maximizing the view on the NGENUITY system involves visual resolution, depth of field and depth of resolution. Depth of resolution is particularly important for peeling ILMs or epiretinal membranes, and during macular hole surgery. For optimum visualization, Dr. David Chow from the University of Toronto, Toronto Retina Institute, Canada, recommends a viewing distance of 1.2 meters and a camera aperture of 30% (to allow for maximum depth of field). Dr. Chow adds that “maximal macular magnification should be used whenever possible, while a light pipe power of 20% should increase safety without sacrificing visibility benefits”.

Vision for the Future Not only has NGENUITY shown superiority over conventional microscopes, its functionality – and versatility – has provided further benefits to both patients and surgeons alike. “NGENUITY as used in the clinical setting has a series of benefits, from clearer views of surgery, improved surgery ergonomics, to its teaching capabilities,” said Dr. Joshi. “Enhanced depth of field enabled with NGENUITY has resulted in both a clearer front and back view of the eye during surgery, and the underexposed and the overexposed images both blend together to provide exceptional image systems,” he continued, adding that with NGENUITY surgical ergonomics have also improved. “Nearly 70% of ophthalmologists have experienced neck, back or shoulder injuries,” said Dr. Joshi. NGENUITY is also an excellent teaching tool, enabling fellows, residents and technicians to watch a surgery while it’s being performed. It’s clear that digital technology like NGENUITY is revolutionizing the way retina surgeons operate – and these advances will continue to drive improved patient outcomes. Editor’s Note: Reporting from this story took place at amplifEYE, an Alcon-sponsored event to share user experience with NGENUITY, in Hong Kong on March 4, 2019.




Macular Edemas, Diabetic

Highlighting the best treatment strategies for the diseased retina data from studies which showed that quantitative OCT-A metrics strongly correlate with severity of retinal changes in patients with diabetes mellitus. “OCT-A provides useful information in diabetic retinopathy screening, macular ischemia evaluation and risk stratification. However, its use in clinical practice remains limited due to artifacts, wide variations in patients and lack of consensus on quantitative metrics,” he summarized.

The diabetic retina: When AI takes the wheel

by Olawale Salami and Gloria D. Gamat


ast fall, all roads led to Paris, where the rock stars of the posterior segment subspecialty convened to discuss the latest trends – not in fashion, but in the management of retinal diseases. Below is a brief summary of the most notable presentations from experts across the globe at EURETINA 2019 in Paris . . .

Diabetic eyes: Who cares about OCT-A anyway? In diabetic retinopathy (DR), the evaluation of retinal vascular changes such as FAZ enlargement, capillary abnormalities and neovascularization is central to diagnosis, management, treatment monitoring and prognosis. During his presentation, Dr. Francesco Bandello, professor and


chairman, Department of Ophthalmology, University Vita-Salute, Ospedale San Raffaele of Milan, Italy, highlighted the emerging relevance of OCT-A in patients with retinal changes in diabetes. He explained that OCT-A is useful in evaluating macular ischemia and has shown excellent results in delineating micro infarction of surrounding vascular arcades and FAZ area, which strongly correlates with visual acuity. “Several studies have shown that OCT-A provides better assessment of macular ischemia than fluorescent angiography. It is also a vital tool in screening patients with diabetes and no retinopathy, shown by subtle OCT-A alterations present in diabetic patients with no retinopathy,” said Dr. Bandello. Furthermore, Dr. Bandello discussed

“Machine learning algorithms are able to identify, localize and quantify pathological features in almost every macular and retinal disease,” Dr. Ursula Schmidt-Erfurth, professor and chair of the Department of Ophthalmology at the University Eye Hospital, Vienna, Austria, told conference delegates. Indeed, new advanced diagnostic technologies are expanding the frontiers of our understanding of the pathophysiology of the retina. “Digital images providing millions of morphological datasets can be rapidly analyzed using artificial intelligence and methods based on machine learning and deep learning,” she added. In supervised machine learning, the intricate pathways of the human brain that recognize objects can be mimicked by convolutional neural networks through learning of distinct pathological features from training sets, while extrapolation from independent pattern recognition can help fine tune machine learning independently. Artificial intelligence (AI) could potentially enhance retinal disease screening, diagnostic grading as well as guidance of therapy with automated detection of disease activity, recurrences, quantification of therapeutic effects and identification of relevant targets for novel therapeutic approaches.

Eyes and Anti-VEGFs . . . According to Dr. Schmidt-Erfurth, fully automated AI-based systems have recently been approved for screening of diabetic retinopathy. “In 2018, we witnessed the first FDA clearance of an autonomous AI based diagnostic system, to automatically detect more-than-mild diabetic retinopathy (mtmDR),” she said. Furthermore, several studies have demonstrated that AI is as accurate as or better than the human eye in the analysis of digital fundus images, resulting in EC certifications in the EU as a class II medical device. “Published studies have shown excellent results of the usability of AI in retinal fluid volume quantification in OCT images from patients with diabetic macular edema (DME). AI-based image analysis offers rapid, cost effective, precise, reliable screening and monitoring method for diabetic retinopathy and DME,” reported Dr. Schmidt-Erfurth.

What you should know about the management of DME and PDR in 2019 Treatment of DME has undergone a paradigm shift over the last decade. Anti-VEGF therapy has replaced laser photocoagulation as the mainstay of treatment. “In patients with noncenter-involving DME and good visual acuity (VA), the best management strategy is to observe,” said Dr. Sobha Sivaprasad, professor and consultant ophthalmologist, Moorfields Eye Hospital, London, United Kingdom. A key dilemma faced by retinal surgeons is how to treat patients with center-involved DME whose visual acuity is 20/25 or better. The options available include observation, focal/grid laser (with anti-VEGF if VA reduces) or anti-VEGF treatment alone. The Protocol V study aimed to resolve this dilemma. In this

randomized controlled trial, patients were randomly allocated to the 3 treatment strategies. According to Dr. Sivaprasad, after 2 years of follow-up, 19% of patients in the observation only group had ≥ 5 letter loss, which was similar to 17% in the laser treatment group and 16% in the aflibercept treated group. Therefore, subsequent secondary subgroup analyses may be needed to unravel any differences in the outcome between groups. What about the DRCR Protocol T? Dr. Sivaprasad narrated that study compared the results of three antiVEGF drugs: 2.0mg aflibercept, 1.25mg bevacizumab or 0.3mg ranibizumab, in the management of center-involved DME. After 2 years of follow-up, the data showed superiority of aflibercept over bevacizumab, and not with ranibizumab (which was seen at 1 year), with regards to mean change in VA (ETDRS letters: 18.3 vs 13.3 vs 16.1, respectively) in those who had baseline VA of 20/50 or worse. However, if the baseline VA was between 20/32 and 20/40, no difference was observed among these three anti-VEGF drugs. To summarize the treatment options available today for patients with DME, Dr. Sivaprasad said: “In those patients with no visual impairment, observation will suffice. Secondly, with mild visual impairment of between 20/30 to 20/40, any anti-VEGF agent can be used. When DME patients present with VA of 20/50 or worse, aflibercept is recommended.” For patients with proliferative diabetic retinopathy (PDR), Dr. Sivaprasad highlighted that panretinal photocoagulation remains the standard of care for patients with PDR. AntiVEGF therapy is also recommended if good surveillance programs are in place to provide rescue therapy.

Patients with center-involved DME with good VA: Don’t rock the boat! Exciting results from the DRCR Protocol V study: Treatment-naïve patients with good visual acuity (but who have center-involved DME) that are treated by observation can maintain good vision, with outcomes comparable to patients treated with intravitreal injections or laser photocoagulation. These results were presented by Dr. Mathew MacCumber, professor and associate chairman for research, Department of Ophthalmology at Rush University Medical Center in Chicago, Illinois, USA. Dr. MacCumber and his team demonstrated that there was no significant difference in VA loss at two years of follow-up, regardless of whether the patient was treated with intravitreal drugs (16%), laser photocoagulation (17%) or observation alone (19%). Furthermore, he noted that the percentage of eyes with VA >20/20 was significantly greater with aflibercept than observation, but not laser photocoagulation. The randomized controlled study enrolled patients with center-involved DME and VA >20/25; 702 participants completed 2-year follow-up. All three management strategies resulted in mean VA at 2 years of 20/20. According to Dr. MacCumber, the proportion of eyes with 20/20 or better was significantly greater with aflibercept (77%) as compared to observation alone (66%). Also, Dr. MacCumber emphasized that the study did not compare monotherapies, rather it compared three different management strategies. Eyes were followed-up carefully and aflibercept was initiated in the laser and observation groups if vision decreased by 1 line at 2 consecutive visits or 2 or


POSTERIOR SEGMENT RETINAL DISEASE MANAGEMENT more lines at 1 visit. Changes on OCT did not trigger aflibercept initiation. He explained that the primary outcome of the study, which was loss of 5 or more letters, is likely clinically relevant in eyes with good vision and unlikely due to chance variation. “Among eyes with center-involved DME and good VA, there were no significant differences in VA loss at 2 years, whether eyes were initially managed with aflibercept, laser photocoagulation or observation, and given aflibercept only if VA worsened. And given the cost and risk associated with interventions, observations without treatment unless VA worsens may be a reasonable strategy in these eyes,” concluded Dr. MacCumber.

In treating patients with macular edema: Do you know your anti-VEGFs? These are exciting times for ophthalmologists treating patients with macular edema due to central retinal vein occlusion (CRVO). Results of the LEAVO study, presented by Dr. Philip Hykin, consultant ophthalmic surgeon from Moorfields Eye Hospital, London, United Kingdom, provided insights into the cost-effectiveness and efficacy of some of the most popular anti-VEGF treatments for patients. LEAVO was a phase 3, multicenter, double-masked, randomized, controlled, non-inferiority trial which evaluated the clinical and cost-effectiveness of 3 anti-VEGF treatments over the course of 2 years. Dr. Hykin and colleagues enrolled a total of 463 patients in the study, who were subsequently randomized in a 1:1:1 ratio to receive treatment with aflibercept, bevacizumab or ranibizumab. Based on the analyzed data from the trial, Dr. Hykin reported that: “Bevacizumab may or may not be worse than ranibizumab or aflibercept. For patients managed as in this study, we would have low confidence in recommending bevacizumab treatment as equivalent to ranibizumab and aflibercept over 100 weeks.”


The primary endpoint measure of the study was change in best corrected visual acuity (BCVA) ETDRS letter score from baseline to 100 weeks in the study eye. Secondary endpoints included proportion of patients gaining 10 or more and 15 or more letters, the proportion of patients losing < 15 or 30 more letters at week 100, change in OCT central subfield thickness (CST) from baseline to week 52 and 100 weeks, the number of injections performed in the study eye at 100 weeks, and local and systemic side effects. A total of 155 patients were randomized to receive ranibizumab, 154 received aflibercept, and 154 received bevacizumab. Baseline characteristics were similar across all 3 arms of the study. At 100 weeks, the mean gain in BCVA with ranibizumab was 12.5 compared to 15.1 with aflibercept and 9.8 with bevacizumab. In the intent-to-treat analysis, investigators found bevacizumab was not non-inferior to ranibizumab (95% CI: -1.73 [-6.12, 2.67]). Additionally, investigators noted aflibercept was noninferior to ranibizumab, but it was not superior either (95% CI: 2.23 [-2.17, 6.13]). “There were less injections at week 100 among those who received aflibercept (9.8) compared to bevacizumab (11.5) and ranibizumab (11.8),” noted Dr. Hykin.

Shining star: Ranibizumab is a ‘preferred’ treatment option in patients with DME The effectiveness of ranibizumab in the treatment of diabetic macular edema has been proven with large clinical trials. However, there is paucity of clinical data on the clinical outcomes from a headto-head comparison of the efficacy of ranibizumab and bevacizumab. Dr. Reinier Schilgemann, professor of Ocular Angiogenesis in the Faculty of Medicine (University of Amsterdam) and head of the Ocular Angiogenesis Group (University of Amsterdam Academic Medical Centre), the Netherlands, and his colleagues, compared the effectiveness and costs of 1.25mg of bevacizumab to

0.5mg ranibizumab given as monthly intravitreal injections during 6 months in patients with DME. The study team hypothesized that bevacizumab would be non-inferior to ranibizumab regarding its effectiveness. They conducted a randomized, controlled, double-masked, clinical trial in 246 patients with DME and BCVA of ≥ 24 letters and ≤ 78 in ETDRS charts, and central area thickness on OCT > 325µm. The primary outcome measure was the change in BCVA in the study eye from baseline to month 6. Secondary outcomes were the proportions of patients with a gain or loss of 15 letters or more or a BCVA of 20/40 or more at 6 months, the change in leakage on fluorescein angiography and the change in foveal thickness by OCT at 6 months, the number of adverse events in 6 months, and the costs per quality adjusted life-year of the 2 treatments. When the team analyzed the primary outcome data, they found that ranibizumab performed significantly better than bevacizumab and the noninferiority threshold set was not attained. “Based on our results, the noninferiority of bevacizumab to ranibizumab cannot be confirmed. Therefore, we show in this study that ranibizumab is better than bevacizumab in the treatment of DME,” concluded Dr. Schlingemann. “In patients with a BCVA of < 20/40 and DME, consider ranibizumab 0.5mg rather than bevacizumab 1.25mg,” he recommended.

Retinal vascular diseases: On the trail of VEGF Vascular endothelial growth factor (VEGF) and placental growth factor (PGF) modulate vascular permeability, inflammation and neovascularization – and intraocular VEGF and PGF levels are significantly elevated in patients with diabetic eye disease. According to Dr. Aude Ambresin, from RetinElysée, Lausanne, Switzerland, VEGF and PGF act together through VEGF receptors to play a critical role in vascular permeability inflammation and neovascularization. In addition, VEGF and PGF both drive the development of retinal vascular leakage in diabetic eye disease.

Dr. Ambresin explained that evidence exists to suggest an important role for both VEGF and PGF in the breakdown of the blood brain barrier seen in both DR and retinal vein occlusion (RVO). The activation of proinflammatory cells in the retina, which mediates chronic inflammatory damage in the retinal pigment epithelium, can be linked directly to the elevated expression of VEGF and PGF; and binding of VEGF and PGF to the VEGF receptor on microglia results in a pro-inflammatory and pro-angiogenic response. Even with complete VEGF blockade by some anti-VEGF agents, PGF would still be available to bind to the VEGF receptor, allowing, for example, further escalation of the inflammatory signals and secondary vascular remodeling in DME. According to Dr. Ambresin, aflibercept represents a unique multi-target agent designed for high-affinity binding to VEGF and PGF. The innovative multi-target trap of aflibercept is the only anti-VEGF that blocks all VEGF receptor-1 ligands, including VEGF and PGF. “There is convincing evidence to show that aflibercept has a higher VEGF-A binding affinity than all available anti-VEGF agents and its native receptors. For example, aflibercept has a VEGF-A binding affinity 100 times that of ranibizumab,” said Dr. Ambresin.

The high binding affinity of aflibercept has important clinical advantages. “Aflibercept has been shown to have a longer lasting mean VEGF-A suppression; twice as long as that of ranibizumab in patients with neovascular age-related macular degeneration,” shared Dr. Ambresin. What about patients with impaired retinal perfusion? “Data from the VIVID and VISTA studies have demonstrated that aflibercept specifically targets underlying diseases in patients with DME while improving retinal perfusion. This improvement in retinal perfusion was associated with improvement in the diabetic retina severity score (DRSS),” explained Dr. Ambresin.

DME: Optimized management with intensive, early treatment The efficacy of aflibercept in DME treatment is supported by evidence from three important clinical trials: the VIVID trial, the VISTA trial and the DRCR Protocol T. “Early intensive treatment in diabetic macular edema results in rapid and increasing visual acuity gains that can be maintained over time” said Dr. Sobha Sivaprasad, professor and consultant ophthalmologist, Moorfields Eye Hospital, London, United Kingdom. According to Dr. Sivaprasad, the VIVID and VISTA trials assessed the efficacy of aflibercept in patients with visual impairment due to DME. The study showed rapid clinically significant vision gains that increased with each of 5 initial monthly doses. This vision gain was achieved from the first dose and patients across both studies gained > 9 letters on average (about 2 lines of vision) after 5 monthly loading doses. Timing is important. The vision changes in the VIVID and VISTA studies were clinically significant and seen with each of 5 initial monthly doses. At week 52, the primary endpoint, patients across both studies gained > 10 letters on average from baseline. “Patients

continued to show improvements in visual and anatomic outcomes after the 4th and 5th monthly doses. The vision gains achieved were sustained over the course of 148 weeks,” said Dr. Sivaprasad. Early treatment initiation with aflibercept was vital towards treatment success as delayed treatment was associated with suboptimal vision gains in patients with DME. In the Protocol T study, early intensive treatment with anti-VEGF emerged as an important factor. Early intensive dosing resulted in rapid and increasing visual acuity gains with aflibercept that were superior to ranibizumab at the 12-month primary endpoint. “These unsurpassed gains associated with early intensive treatment were sustained over 2 years, with decreasing dosing,” noted Dr. Sivaprasad. Overall in the Protocol T study, aflibercept achieved superior VA gains at year 1 and over 2 years compared with ranibizumab or bevacizumab in patients with baseline vision < 69 letters (< 20/40). In addition, staying the course with aflibercept provides robust VA gains even in eyes with a limited early response. “Sustained VA gains with aflibercept translate into meaningful improvements in vision related quality of life,” Dr. Sivaprasad emphasized.

Aflibercept in the real world There is a need for real-world experience to complement data from randomized clinical trials (RCTs) and support treatment decisions. Emerging real-world experience is demonstrating the actual effectiveness of aflibercept in treating visual impairment due to DME. The results of ongoing studies evaluating this experience with aflibercept were presented by Dr. Jean Francois Korobelnik, professor of ophthalmology in vitreoretinal surgery and head of the Ophthalmology Department, University Hospital of Bordeaux, France. The APOLLON study was designed to describe outcomes, monitoring and treatment patterns in treatment naïve or previously treatment patients with DME in routine clinical practice. The

Timing is critical to an effective anti-VEGF treatment regimen


POSTERIOR SEGMENT RETINAL DISEASE MANAGEMENT study enrolled adult patients with type 1 or type 2 diabetes and DME, who had never received aflibercept. In summarizing the key learnings from his session, Dr. Korobelnik stressed that “the early intensive aflibercept treatment achieved rapid, clinically significant VA gains from the first dose which increases with each of 5 initial monthly doses in patients with DME”. The unsurpassed VA gains in DME sustained over time required decreasing dosing in

patients with VA < 69 letters (< 20-40) as demonstrated by the Protocol T trial and supported international guidelines. A Cochrane systematic metaanalysis of RCTs at Level 1, evidencebased review of anti-VEGF agents concluded that at 1 year, all efficacy outcomes significantly favored aflibercept over ranibizumab and bevacizumab. Aflibercept appears well accepted by ophthalmologists judging by data from the ASRT survey, in which majority of them chose aflibercept as their

treatment of choice, when costs and payouts are not an issue. “In real-world clinical practice, aflibercept has been shown to achieve outcomes similar to those observed in clinical trials when used as indicated with 5 initial monthly doses,” shared Dr. Korobelnik. Editor’s Note: The 19th EURETINA Congress (EURETINA 2019) was held from September 5 to 8 in Paris, France. Reporting for this story also took place at EURETINA 2019 Paris.

INDUSTRY UPDATE New Data on Abicipar Shows Promise for Reducing Injection Frequencies


nti-VEGF remains a mainstay to control posterior segment conditions like neovascular (or wet) age-related macular degeneration (nAMD). And while various molecules have shown efficacy in maintaining vision and preventing disease progression, there is still much debate on the ideal treatment regimen – as well as which molecules remain the most efficacious at different intervals. Frequent injections often come at a high cost, both to the patient and physician. Thus, reducing the treatment burden – while maintaining vision – has been a primary area of focus recently. During the Retina Subspecialty Day at the Annual Meeting of the American Academy of Ophthalmology (AAO) in San Francisco, delegates heard year 2 results from two global, identical Phase 3 clinical studies: CEDAR and SEQUOIA, which compared ranibizumab with Abicipar in three treatment regimens. Abicipar is in a new class of drugs called DARPin® molecules, developed by Allergan (Dublin, Ireland), a leading global pharmaceutical company and Molecular Partners (Zurich, Switzerland), a clinical stage biopharmaceutical company. “Current anti-VEGF treatments for neovascular age-related macular degeneration require frequent intravitreal injections,” said Rahul N. Khurana, MD, Northern California Retina Vitreous Associates Medical Group. “Based on


the results of CEDAR and SEQUOIA, which reinforce the efficacy of Abicipar while decreasing the number of injections, Abicipar could transform antiVEGF treatment regimens.” CEDAR and SEQUOIA were designed to assess the efficacy and safety of Abicipar 8-week and 12-week treatment regimens compared with monthly ranibizumab in treatmentnaïve patients with nAMD. Previously, Abicipar demonstrated non-inferiority to ranibizumab at week 52 in both the 8-week and 12-week regimens compared to monthly ranibizumab. Through week 104, patients received Abicipar 2mg every 8-weeks or every 12-weeks, or ranibizumab 0.5mg every 4 weeks. At week 104, the proportion of patients with stable vision was 93%, 90% and 94% in the 8-week Abicipar, 12-week Abicipar and 4-week ranibizumab treatment regimens, respectively. According to the authors, “this continuation of stable vision in year 2 further reinforces the ability of Abicipar to deliver consistent quarterly dosing for the majority of patients”. In addition, mean changes in best-corrected visual acuity (BCVA) were similar between years 1 and 2 across all treatment arms, while central retinal thickness (CRT) continued to decrease similarly between groups through week 104. Further, treatment-emergent adverse events at the end of year 2 were comparable between groups,

as well as the rate of new cases of intraocular inflammation at 1.9% and 1% in the Abicipar and ranibizumab groups, respectively. In a press release following the annual meeting, Allergan’s Chief Research and Development Officer David Nicholson said: “These latebreaking data further demonstrate the potential of Abicipar to provide consistent quarterly dosing that sustains vision gains in the majority of patients with neovascular age-related macular degeneration.” “On the heels of regulatory filings for Abicipar in the United States and European Union, these data give us confidence in our ability to meet a serious unmet need for patients and eye doctors,” he continued. The U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) are currently reviewing regulatory applications for Abicipar in patients with nAMD. The FDA is expected to take action on the BLA in mid-2020, while a decision from the European Commission is expected in the second half of 2020. “We are very excited at the continued success of Abicipar, our most advanced DARPin® molecule, in the treatment of patients with neovascular age-related macular degeneration,” added Patrick Amstutz, PhD, CEO of Molecular Partners. “We are pleased to see a sustained response at two-years with less frequent dosing of Abicipar compared to standard of care therapy.”


Rare and Interesting Cases Abound in Posters from APVRS 2019 by Brooke Herron


etween sessions, symposiums, free papers and posters, the 13th Asia-Pacific Vitreo-retina Society (APVRS) 2019 annual meeting features a plethora of brand-new scientific content. For delegates short on time, or for those unable to join the meeting in Shanghai, PIE magazine has collected a highlight reel of some of the most interesting e-Posters taking center stage at APVRS.

Can excessive smartphone use damage the retina? Light, especially blue light, has been known to cause damage to the retina – and the spectral peaks for smartphones are very similar to short-wavelength blue visible light. While the connection seems clear, there is no knowledge of ‘when’ or ‘if’ a damage threshold is reached. In an e-Poster titled “Suspected Macular Light Damage Caused by the Excessive Use of Smartphone”, Lei Gao and co-authors present an observational case report of one patient with suspected macular light damage caused by excessive smartphone use.

The patient, a young man, presented with blurred binocular vision for 3 days – and the subnormal vision couldn’t be explained by currently known macular diseases. Doctors provided various ocular examinations, including slit lamp biomicroscopy, autofluorescence, fluorescein angiography, ICG angiography, multifocal ERG, visual evoked potentials, central visual field and OCT angioplex – all of which were unremarkable at initial presentation and at 6 months follow-up. Dr. Gao and co-authors found that “OCT revealed subtle defects in the outer segment of fovea, which is in line with the pathological changes of chronic light injury”. In fact, the patient had been using his smartphone for 6 to 8 hours nightly, in the dark, for the past 3 years. This extensive, longtime viewing was considered to be the likely factor for his visual complaints. Following a 6-month behavioral intervention, the patient’s visual acuity (VA) was restored from 20/50 to 20/20, which was confirmed with revised OCT images.

This led the authors to conclude that “if similar reports are confirmed, it will surely have a profound impact on both the manufacturers and the consumers of the smartphone . . . especially when we are one step into the era of VR”.

Peculiar Manifestations: Looking at Dome-shaped Maculopathy As a rare manifestation of pathological myopia, dome-shaped maculopathy or DSM, is believed to occur because of compressional forces during growth of the eyeball, along with differential thickening of the sclera. Subretinal fluid (SRF) in DSM patients has been seen as resistant to a variety of treatments – however, these patients often have stable VA despite persistent SRF. To further report on this condition, Obuli N. and co-authors presented an e-Poster titled “Dome-shaped Maculopathy: A Retrospective Analysis”. During the analysis, the authors retrospectively reviewed 25 eyes of 14 patients with DSM (including 3 patients with unilateral DSM).

Don't get caught with your head in the sand! Learn about these rare cases and more at APVRS . . .


POSTERIOR SEGMENT APVRS 2019 POSTERS They found the mean spherical equivalent (SE) in these eyes was -3.25 + - 1.06D, with 11/25 eyes showing myopia < -3D. On SD-OCT, 11 of 25 eyes showed dome-shaped elevation in both the horizontal and vertical axis; 5 of 25 eyes had only vertical and 9 of 25 had only horizontal. The mean logMAR visual acuity of the eyes was 0.327 + 0.305, while central macular thickness (CMT) and central choroidal thickness (CCT) were respectively 267.47 + 117.87µm and 274.65 + - 94.86µm. This did not seem to differ significantly from the healthy population. Further, the mean logMAR VA of eyes with IS-OS disruption was 0.432 + - 0.245, which was poorer than eyes without the same, but not significantly so. The mean dome height (DH) measured between RPE and choroidoscleral complex below fovea was 520.24 + - 33.016µm. In the end, the authors concluded that “SRF associated with DSM is quite intractable to treatment, and although visual acuity may improve or stay stable over time, the macula may not become dry”.

It’s Complicated: Visual Loss after Photodynamic Therapy While treatments like photodynamic therapy (PDT) often help maintain vision in polypoidal choroidal vasculopathy (PCV), in rare instances it can result in sudden visual loss. Dr. Chih-Chin Chuang presented a case report of this rare complication in an e-Poster called “Acute Visual Loss After Photodynamic Therapy for Polypoidal Choroidal Vasculopathy”. The patient, a 72-year-old man with a history of cardiovascular disease, complained of the sudden onset of blurred vision in the left eye five days after receiving PDT for PCV. The patient was treated with an immediate intravitreal injection of ranibizumab and oral aspirin (100mg) once daily. After two months, the vision in the left eye improved from 20/400 to 20/25; and the reperfusion of macular choroidal vessels was noted in indocyanine green angiography (ICGA).


Dr. Chuang reported that “choroidal ischemic change, exudative maculopathy and patient’s underlying cardiovascular disease would result in subsequent visual loss after photodynamic therapy”. Therefore, to prevent complications, it’s advised to modify the settings or reduce the dose of PDT, provide aspirin to patients with cardiovascular disease, and use a combination of PDT and anti-VEGF for best outcomes in these patients.

It is Uveitis . . . or an IOFB? Intraocular foreign bodies (IOFBs) can masquerade as uveitis for years – one such case was presented in an e-Poster titled “Intraocular Foreign Body (IOFB) Masquerading as Uveitis” by Ruchi Shrestha. The patient was a 24-year-old male who complained of blurred vision in the left eye for 1.5 years, with flashes and floaters for 1 week. The patient had been treated for intermediate uveitis with oral and topical steroids for 1.5 years. Following clinical findings of a corneal scar and defect in his iris, the patient was finally diagnosed with an IOFB after referral to a retina clinic. The IOFB was confirmed on indirect ophthalmoscopy, brightness scan and computed tomography scan. His best corrected visual acuity (BCVA) at presentation was 6/6 in right eye and 6/24 in left eye.

Beware the masquerade! IOFBs can masquerade as uveitis . . . and can be hard to detect, unlike this pup masquerading as a pirate.

The patient underwent pars plana vitrectomy, IOFB removal, endolaser and silicone oil insertion in left eye. After the silicone oil was removed, the BCVA in the left eye was 6/12. Dr. Shrestha concluded that “IOFB may masquerade as intermediate uveitis . . . and the most sensitive tool to diagnose an IOFB is computed tomography scan”. It was also noted that IOFBs should be removed as early as possible to prevent complications of endophthalmitis, retinal detachment, proliferative vitreoretinopathies and siderosis bulbi.

The ‘Lost Art’ of Scleral Buckling With the rise and popularity of vitrectomy, scleral buckling rhegmatogenous retinal detachment (RRD) repair has taken a backseat in recent years – making it a bit of a ‘lost art’. However, the procedure does have its advantages, mainly a preserved vitreous and clear lens, when the external approach is used. Therefore, Drs. Chi Lik Au and Kenneth Kai Wang Li presented a poster titled “Outcomes of Rhegmatogenous Retinal Detachment Repair by Scleral Buckling: 10- year Experience of a Local Eye Hospital in Hong Kong”, which reviewed cases of scleral buckling for RRD repair from 2009 to 2018 (excluding vitrectomy). Drs. Au and Li included 135 patients, ranging in age from 8 to 78, with a mean age of 44.3. They found 48.5% eyes had multiple breaks, with the superotemporal quadrant was the most common quadrant to localize the break (55.8%). Of the reviewed records, 71.6% of eyes underwent DACE (DrainageAir-Cryotherapy-Explant) and 28.4% had non-drainage surgery, with a primary success rate of 89.7% and 81.5%, respectively. Myopic shift after encircling buckle was 0 to 3.5 diopters (D), with a mean of 1.7D. They found that epithelial defects were the most common (21.0%) transient postoperative complications, followed



by subretinal hemorrhage over the drainage site (14.5%). Additionally, epiretinal membrane developed in 14.7% of eyes over 10 years of followup, with gas injection in DACE as the identifiable risk factor. Overall, Drs. Au and Li reported that scleral buckling for RRD achieves a high anatomical and visual success. “This surgical option is useful for preservation of vitreous and clear lens, especially meaningful in young patients,” they concluded.

What time is the ‘right time’ for vitrectomy? Although endophthalmitis is a rare complication, it can still occur – and today, there’s still much debate on the timing of treatment. To investigate, Dr. Rodger Paul and co-authors presented a poster titled “Early Vitrectomy in Endophthalmitis”, which compared visual outcomes following early versus late (or no) vitrectomy, in patients who developed endophthalmitis following intravitreal ant-VEGF injections or cataract surgery from 2014 to 2019. The study included 316 cases of endophthalmitis; 32% received early vitrectomy, while 68% had a late or no vitrectomy. Although patients who received early vitrectomy had significantly worse presenting visual acuity (VA) (2.34 vs 1.89 logMAR, P < 0.0001) and better improvement in VA compared to those who received late or no vitrectomy (1.46 vs 1.04 logMAR, P = 0.008), there was no statistically significant difference in final VA was found between groups (0.869 vs 0.814 logMAR, P = 0.584). The authors found that patients with worse presenting vision were selected for early vitrectomy – however, there was no difference in final VA, as compared to those who had no vitrectomy or late vitrectomy. Meanwhile, a greater improvement in VA was achieved with early vitrectomy was observed.

This led Dr. Paul and team, to conclude that “while further research is required, this data appears to be suggestive of a benefit of early vitrectomy in endophthalmitis”.

New animal model shows promise for photoreceptor regeneration in RP Exciting new research on the possibility of protecting and regenerating photoreceptors is explored in a poster by Dr. Baoyi Liu and co-authors, titled “Non-invasive Electrical Stimulation Promotes Photoreceptor Survival and Regeneration in Mice with Inherited Photoreceptor Degeneration”. In this study, the authors tested if electrostimulation (ES) protects photoreceptors from degeneration – and induces photoreceptor regeneration by mobilizing retinal endogenous stem cells in retinal degenerated mice. The investigators applied transpalpebral ES or sham stimulation to mice carrying inherited retinal degeneration for 7 consecutive days at 5 minutes per day. An electroretinogram was used to test the ES effect the retinal function. They found that a “significant increase of ERG b wave amplitude was observed at the end of the first week post-ES, and this was maintained for 4 weeks compared with the shamstimulated eyes”. After ED, they also observed significant preservation of photoreceptors and an increase in proliferating cells in the retina. This led the authors to conclude that “transpalpebral ES promotes neuroprotective, regenerative, and repairing potentials of the retinal cells, suggesting the exciting possibility of using non-invasive ES as a versatile tool for preventing photoreceptor degeneration, potentially reversing vision loss in patients with RP”. Editor’s Note: Media MICE Pte Ltd, parent company and publisher of PIE magazine, is the Official Media Partner of APVRS 2019 Shanghai.

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‘Stand-up’ to Complications in

Posterior Segment Surgeries by Brooke Herron

Did you hear the one about the eye doctor who went into standup comedy? He made a real ‘spectacle’ of himself . . .


hile ophthalmology jokes may elicit a giggle or two, complications in posterior segment surgery are no laughing matter . . . in fact, they can permanently affect vision if not managed efficiently. Therefore, to mitigate these adverse events, surgeons must improvise and act quickly to deliver the optimal patient outcomes. Funnily enough, this is one area where eyeballs and comedy intersect: Improvisation. In delivering a standup routine, or in repairing a detached retina, there are times when unplanned instances occur, requiring off-the-cuff thinking for success (be it applause or visual). In this issue’s Cover Story, we delve deeper into improvisation in vitreoretinal surgery – including tales from complicated cases, pre-planning for adverse events, technology that helps reduce improv in the OT . . . and finally, tips for younger surgeons.

Stand-up cases in improvisation Case #1. Our first act is Dr. Andrew Chang, a vitreoretinal ophthalmologist and surgeon in Sydney, Australia. He comes to the stage with a case of extensive retinal detachment, using vitrectomy for the repair. In this instance, the surgery was progressing until they noticed the retinal detachment was worsening, rather than flattening – the BSS infusion line tip was underneath the retina, and therefore, infusing fluid underneath it.


Dr. Chang immediately stopped the infusion . . . and the improvisation began. He removed the infusion line from the cannula and placed it into another cannula, then inserted heavy liquid to stabilize the posterior retina. The subretinal fluid was then pushed back out through the original infusion line. He replaced the cannula with a longer 6mm cannula to ensure the tip was in the vitreous and proceeded with the surgery as planned.

This improvisation by Dr. Chang not only led to a reattached retina, but the patient’s vision was recovered, too. Case #2. The next headliner is Dr. Diva Kant Misra, a vitreo-retina, ocular oncology and ROP consultant, at Eye Q Super Speciality Eye Hospital in Lucknow, India. His case in improvisation begins with a 55-year-old male patient with a vitrectomized eye, who received phaco for cataract in that same eye.

Dr. Misra recalled that the surgery was very challenging: “When the trypan blue dye was injected, it seeped through the zonules (or through some area of zonular weakness) into the vitreous cavity and immediately comprised the red glow.” This complicated the surgery . . . and the improv began. Dr. Misra says that during this surgery, his mentor Dr. Ronel Soibam, senior consultant at Sri Sankaradeva Nethralaya, Guwahati, India, improvised by suggesting the use of 25-gauge chandelier-assisted retroillumination to proceed with phacoemulsification. “This technique has been previously described for combined cases of phacoemulsification and posterior segment surgeries, when there is a poor glow because of posterior segment pathologies,” explained Dr. Misra, noting a 2018 study published in the Indian Journal of Ophthalmology.* In this prospective observational study, Dr. Manish P. Nagpal and coauthors found that while cases with a poor red reflex pose a challenge, “chandelier-assisted retroillumination proves to be a safe and effective tool in combined phacovitrectomy surgeries”. The authors explained that during surgery, the “sclerotomy port for chandelier tip was made in the inferotemporal or superonasal quadrant, based on the incision site for phacoemulsification. Later, it was replaced with infusion cannula or endoilluminator”. This method markedly enhanced the red reflex in all cases during phacoemulsification. The investigators reported that visual acuity (VA) in all patients improved, and the median best-corrected visual acuity (BCVA) was 20/60 at 6 months. In addition, there were no intraoperative or postoperative complications. Continuing the case from Dr. Misra, he explained that a single sclerotomy was required in the inferotemporal quadrant, 3.5mm from the limbus – then, using a valved cannula, the chandelier tip was introduced. He says that important

steps (like capsulorhexis, cortex removal, capsular bag polishing and IOL implantation) were done under chandelier retroillumination, with the operating microscope and room lights turned off. “Xenon light source, which comes with the Constellation Vision System (Alcon, Geneva, Switzerland) was used for chandelier illumination [during this procedure],” said Dr. Misra. “We were able to achieve a red reflex during the crucial steps of phacoemulsification – which resulted in an uneventful phacoemulsification and an excellent outcome.”

Anticipating complications: keep calm and carry on Sometimes, things just go wrong during surgery. In some instances, recognizing risk factors can help surgeons anticipate potential complications, ensuring preparation rather than improvisation. In the case of a worsening retinal detachment, Dr. Chang says the complication can be anticipated if the retina detachment is extensive and the eye has low intraocular pressure (IOP). “These cases may be associated with choroidal thickening due to choroidal effusions, which poses a risk that a standard 4mm-long cannula for infusion may be too short to ensure that the tip is in the correct position within the vitreous cavity,” said Dr. Chang, adding that surgeons should check the tip of the infusion line carefully. In addition, he says clinical examination for choroidal effusions or using B-scan ultrasounds of the globe (to image choroidal effusions) can also help anticipate this complication

It's important to keep calm when complications arise.

preoperatively. Intraoperatively, if the retina detachment increases during the vitrectomy, then doctors should suspect a subretinal position of the infusion line. Moreover, Dr. Chang says that in anticipation of this complication, he advises surgeons to have longer 6mm cannulas available in the OT, while heavy liquid can be used to stabilize the retina posteriorly during the subretinal infusion. Dr. Misra says that a surgeon should always be ready for complications: “There is no surgical step that cannot lead to a possible complication . . . and the success of each and every step guarantees the ultimate success of the surgery,” he explained. Like comedians performing onstage, surgeons should conduct a mental ‘dress rehearsal’ prior to hitting the OT, which should include preparedness for possible complications. “Before a surgery, I mentally go through all the steps of the surgery,” said Dr. Misra. “This helps me to be mentally prepared for all possible complications and reminds me to keep the instruments ready for these possible complications.”

There is no surgical step that cannot lead to a possible complication . . . and the success of each and every step guarantees the ultimate success of the surgery. – Dr. Diva Kant Misra


COVER STORY Thankfully, there are ophthalmic ‘props’ that can help prevent and mitigate complications when they arise. According to Dr. Misra, there have been various advances that have helped reduce complications in retina practice. Innovations like 25- and 27-gauge vitrectomy systems, newer designs in forceps and cutters, as well as intraoperative OCT (iOCT), have allowed surgeons to lower the rate of iatrogenic breaks, while improving the ability to identify and peel membranes. “All surgical advances in ophthalmology are targeted towards making it less invasive and reducing the overall complication rate,” said Dr. Misra.

Keep learning: tips for beginners When complications occur, surgeons often rely on previous experience to overcome any challenges. However, newer surgeons might not have that backlog of prior cases to draw from. “Even a beginner can perform all the steps of the surgery easily – but what sets apart an experienced surgeon [from a beginner], is his ability to gauge impending complications and swiftly take measures to mitigate the problem,” said Dr. Misra. He added that beginners should keep in mind that complications are part of the learning process – and they can occur in the hands of the most experienced surgeons, too. “One should accept their complications and use them as steppingstones to greater surgical conquests in the future. Though unfortunate, a complication will teach more than many uneventful surgeries,” continued Dr. Misra. “The single most important factor in managing complications is to keep calm once a complication occurs, pause for a moment, rethink your strategy and go ahead.” In addition, he suggests that younger surgeons should always be in ‘learning mode’. “As they say, ‘life is too short to learn from your own mistakes’,” said Dr. Misra. To optimize the learning of surgical procedures, he suggests using the REPEAT strategy: Read, Observe and Assist, Perform, Audit and Teach.


The single most important factor in managing complications is to keep calm once a complication occurs, pause for a moment, rethink your strategy and go ahead. – Dr. Diva Kant Misra

Final curtain call Following a stand-up comedy routine, success is measured in laughter and applause – and while vitreo-retinal surgeons often deserve a standing ovation following complicated procedures, visual outcomes are simply not measured by clapping. Like comedians interacting with an audience, surgeons can find themselves in situations where quickthinking is required to deliver the punch line (or successfully complete the

surgery). And sometimes improvisation during complications, like in the cases described by Drs. Chang and Misra, is vital to patient satisfaction and outcomes. Of course, improvisation in comedy is unplanned . . . but in surgery, every element must be carefully considered. Therefore, through preparation, planning and continued learning, there can be less improv in the OT and more efficient management of complications.

*Nagpal MP, Mahuvakar SA, Chaudhary PP, et al. Chandelier-assisted retroillumination for phacoemulsification in phacovitrectomy. Indian J Ophthalmol. 2018;66:1094-1097.

About the Contributing Doctors Associate Professor Andrew Chang (PhD FRANZCO), is an ophthalmologist and retinal specialist. He is head of ophthalmology and head of the Retinal Unit at the Sydney Eye Hospital, clinical associate professor at the University of Sydney and medical director of Sydney Retina Clinic. In international ophthalmology, he serves as the secretary general of the Asia-Pacific Vitreoretinal Society (APVRS) and council member of the Asia Pacific Academy of Ophthalmology (APAO). Other professional roles include clinician advisor to the Department of Health Australia, board director of Royal Australian and New Zealand College of Ophthalmologists (RANZCO) and the Sydney Eye Hospital Foundation. He is the recipient of the Achievement Award and Distinguished Service Award of the APAO and the RANZCO Teaching Award. [Email: achang@sydneyretina.com.au] Dr. Diva Kant Misra (MBBS, DO, DNB, MNAMS, FVRS) is a vitreoretina, ocular oncology & ROP consultant at Eye Q Super Apecilaity Eye Hospital in Lucknow, India. He completed his retina training from reputed institutes like Sri Sankaradeva Nethralaya, Guwahati and Byers Eye Institute, Stanford, California, USA. He holds the post of general secretary, Young Ophthalmologists Society of India & Chief Editor, Young Ophthalmologists Times. He is the recipient of various International ophthalmic awards like the Achievement Award by Asia Pacific Academy of Ophthalmology (APAO) 2019, Ophthalmic Hero of India 2019 & 2018, The Yasuo Tano Award from APAO 2017 and the APVRS Award 2018, and IJO Best of Best Award 201718. He has published extensively and has been invited faculty at various international conferences like American Academy of Ophthalmology (AAO), APAO and EURETINA, and has presented in conferences held at various international locales (WOC Mexico, APAO Singapore, APAO Hong Kong, APVRS Malaysia, EURETINA Vienna) and national forums. [Email: divakant@gmail.com]

jokes have been sourced from the finest eyeball comedians from around the interwebs...

Sol had lived a long life, which was drawing to its end. As his family surrounded him on his deathbed, he asked to see his optometrist. “Optometrist?” they asked. “Why in the world do you want to see your optometrist?”

“Just get him for me.” So they go get Dr. Kaplan, who, on seeing Sol about to depart this life, asked, “Sol, it pains me to see you like this. What can I possibly do for you?” Sol opened his eyes slightly and said,

Q: a:

What happens when the retina cries?

“Doc, before I go, there’s one thing I have to know. Which one was clearer – A or B?”

You get retinal tears!

What do you call a blind stag?

Elderly patient: Doctor, are you sure I will be able to read after my cataract surgery? Ophthalmologist: Yes, you will be able to read after your cataract surgery. Elderly patient: That’s so wonderful! I have never been to school. Submitted by Dr. Au Eong Kah Guan

Dr. Au Eong Kah Guan, medical director and senior consultant ophthalmologist at International Eye Cataract Retina Centre, Mount Elizabeth Medical Centre and Farrer Park Medical Centre, Singapore

Q: a: No Eye-Deer AhHaAhHaA!! hHa An ophthalmic surgeon is doing an operation. He’s about to finish when, surprisingly, the patient wakes, sits up, and demands to know what’s going on. “I’m about to close,” says the surgeon.

The patient grabs the surgeon’s hand and says, “I’m not going to let you do that. I’ll close my own incision.” The surgeon hands him the needle and thread and says, “Suture self.”


INNOVATION DIGITALIZATION IN EYE CARE The Digital Revolution is not Coming to Ophthalmology . . . by Matt Young


he rise of smartphones – and the fact that nearly everybody owns one – has paved the way for innovations in remote diagnostics and in-home monitoring. And while we can argue that too much screen time is detrimental, these new technologies can help patients improve or maintain their vision. At PIE magazine, we’re forecasting that these – plus the other vision-improving devices presented during the recently held Digital Showcase at OIS@AAO 2019 – will flood the ophthalmic market in no time. According to Linda Lam, the chief scientific and strategy officer for Ocutrx Vision Technologies (Irvine, CA, USA), ophthalmology has already been transformed by the digital revolution in imaging and AI, and it has the potential to augment telemedicine, personalized healthcare data, home healthcare, disease monitoring, screening, diagnosis and treatment. “The future generation includes systems for in-home monitoring of visual acuity, visual field, and intraocular pressure; mobile fundus cameras have the potential to reach ophthalmic telemedicine so we can provide telemedicine in rural areas; and AI systems for diabetic retinopathy and visual field interpretation are really improving the efficiency of screening,” said Ms. Lam. She says current technology includes smartphone vision screening (with a clip-on adapter for retinal imaging) and virtual reality headsets to help magnify or help improve facial recognition. She said this digitalization will be of particular importance to meet the challenges of rising costs and the changing demographics of an aging population: “This digital-health revolution provides compelling healthvalue propositions to all stakeholders, including the patients, physicians, payers and pharma.” “Technology advancement could lead to controlling these healthcare


it has Arrived!

Doctors and technology can be stronger together.

This digital-health revolution provides compelling health-value propositions to all stakeholders, including the patients, physicians, payers and pharma. – Ms. Linda Lam, chief scientific and strategy officer, Ocutrx Vision Technologies costs, particularly in our field of ophthalmology,” continued Ms. Lam, adding that providers are using digital healthcare services in an effort to reduce inefficiencies, improve access, reduce cost and increase quality. With an annual growth rate of 29% annually for digital healthcare, this is one innovation that is certainly a ‘haute’ priority in the future of ophthalmic screening, diagnostics and treatments – all designed to tackle the rising challenges faced by both patients and healthcare providers. Digitalization isn’t a future trend – it’s here now – and it’s certain to impact the way both patients and physicians operate. To address its opportunities and impacts, several healthcare leaders offered their insight during the Healthcare Leaders’ Perspectives: Opportunities and Challenges discussion, moderated

by James Mazzo, the global president of ophthalmic devices for Carl Zeiss Meditec (Jena, Germany). Mr. Mazzo asked the panel to discuss not what’s happening now – but what’s happening in the next three to five years . . . “I think the digital revolution is already here – and yes, it will change the way doctors practice,” said Michael Kaschke, PhD, president and CEO, ZEISS Group, adding that the fundamental job of a doctor interfacing with a patient will not change, rather how this interface is going to happen will change. “First, digitalization will make the healthcare industry more efficient – there’s no way around it. And the second, essentially by higher patient education, the ability of every person to interface with a health professional and to get a better understanding of his or

her health – these are basically the two effects that will change.” Regarding digitalization, Peter McDonnell, MD, William Holland Wilmer Professor and director, John Hopkins School of Medicine, Wilmer Eye Institute said that “our belief is that if it’s the right thing for the patient, if it’s a good thing for the patient, then it’s a good thing. Definitely, it’s a learning process, trying to do the right thing with encryption and protecting patient data to help ensure it won’t get misused. But we’ve got to develop these protocols rapidly – particularly for the younger patients who have an expectation when it comes to responsiveness”. He elaborated further on one key demographic: “Younger patients are connected, they expect to be able to send us an email, they want to schedule without talking to a person, and they don’t want to hear that the doctor doesn’t have an opening for the next six months. They want to be part of the process with the doctor, they don’t

just want to hear the doctor talk. So hopefully, it’s a great opportunity for the young doctors to embrace this new way of doing business,” he said. According to Ashley McEvoy, EVP, worldwide chairman, medical devices at Johnson & Johnson (New Brunswick, NJ, USA), when there’s high consumer engagement, there seems to be really good disruption of innovation – with lower engagement it’s slower. “Technology can be our friend to say ‘get more engaged in the lifetime value of your eyes’,” she explained. “Technology can enable more of that connective experience, and we’re in the early days and I think that technology can enable a transformation in ophthalmology... things like enabling better telemedicine, that’s a really good thing for patients... it’s not a replacement but rather complementary.” Meanwhile, David Pyott, the former chairman and CEO, Allergan (Dublin, Ireland), provided some examples of how digitalization can improve the

current healthcare system. “The big idea is what I call stratification of care,” he said. “Imagine a scenario of someone who’s been in the ICU and they get discharged and sent home. That patient at home with those monitors can be monitored by a machine and filter out what needs to be looked at by a healthcare professional.” Certainly, this saves valuable time, money and effort for both patient and doctor. Indeed, the innovations seen at OIS@AAO will help style the future of treatment and patient outcomes in ophthalmology . . . and we’re looking forward to seeing more of these trending technologies in the near future. Editor’s Note: A version of this article was first published in PIE Today, PIE Magazine’s electronic daily congress news, Media MICE’s daily at the Ophthalmology Innovation Summit (OIS) held alongside AAO 2019 in San Francisco, California.


Welcome You All

To the largest Scientific feast in the world of Ophthalmology

Prof. S. Natarajan President

Prof. Namrata Sharma Hony. General Secretary


Regaining Vision with

Optic Nerve Cell Regeneration

We can rebuild it . . . we can make it stronger . . .

by Gerardo Sison


ewly published research has elaborated on the various pathways and factors that may contribute to optic nerve regeneration. Through developing treatments with a focus on these factors, the future of vision loss treatment looks brighter. Dr. Larry Benowitz, professor of neurosurgery and ophthalmology at Harvard Medical School, Boston, USA, and his colleagues compiled research on optic nerve regeneration in their latest review published last month.*

Regenerative limitations of the optic nerve The regenerative ability of the human nervous system is greatly limited, compared to that of other animal systems. This limitation is apparent during injury and conditions that can


affect the retina and ultimately cause vision loss. Patients may experience vision loss from traumatic, degenerative and ischemic causes that often cause damage to the retinal ganglion cells (RGCs). “We summarize[d] efforts by our group and others to regenerate the optic nerve, including the discovery of multiple cell-intrinsic and cell-extrinsic factors that promote or suppress RGC survival and axon regeneration,” said the authors of the study. Retinal ganglion cells are the vital neurons of the retina that relay visual information to the brain via axons. These projection neurons have been the focus of research over the last two decades in determining their role in retinal nerve injury. Researchers have made considerable progress in identifying specific inflammation-

derived growth factors and inter-cellular pathways that could contribute to the restoration of damaged retinal neurons. Recent studies have found functional value in using the mouse model to understand the regenerative capabilities of retinal axons after damage. Studies have also shown that cold-blooded vertebrates, like zebrafish and frogs, experience only modest RGC damage after optic nerve injury. “Cold-blooded vertebrates can even regenerate the retina following partial injury, as Müller cells, the radial glia of the retina, and de-differentiate to produce progenitor cells that replace lost tissue,” said Dr. Benowitz and his colleagues. “After ablation of the inner retina, Müller cells can give rise to new RGCs that extend axons down the optic nerve.”

Optic nerve regeneration from intraocular inflammation Dr. Benowitz and his colleagues had initially found that inducing intraocular inflammation produced some axon regeneration. Using zymosan, a pro-inflammatory agent, to induce inflammation, they found that regeneration was related to changes in RGC growth-associated proteins (GAPs). Their subsequent studies sought to identify these different inflammatory factors that may contribute to optic nerve regeneration. Two major growth-promoting factors closely tied with inflammation include Oncomodulin (Ocm) and SDF1. Using column chromatography, mass spectrometry and bioassays, researchers were able to pinpoint a significant growth factor called Oncomodulin that collects in the neural retina up to a day after inducing inflammation in the retina. An elevation of cAMP is necessary with Oncomodulin and shows pro-regenerative effects mirroring those of zymosan. SDF1 is another growth factor linked with intraocular inflammation and resulting regeneration. This growth factor is expressed in different cells such as neurons and inflammatory cells which have a broad range of effects. “SDF1 is highly expressed in infiltrative macrophages and acts synergistically with Ocm to induce optic nerve regeneration,” stated the principal investigators of the study. “Deletion of SDF1 in myeloid cells diminishes inflammation-induced optic nerve regeneration by one-third and completely eliminates the benefits of inflammation on RGC survival.”

CNTF, PTEN, and other regenerative factors Ciliary neurotrophic factor (CNTF) has also been linked as a mediator of intraocular inflammation. Although CNTF does not efficiently promote axon regeneration by itself, it is believed to have effects on macrophages and other inflammatory cells. This inability

to enhance regeneration alone is due in part to the SOCS3 gene that is increased after optic nerve injury. The effects of CNTF are improved after deletion of this gene. PTEN, or phosphatase and tensin homolog, is a key suppressor of axon regeneration. It works as a negative regulator of intracellular signaling pathways. “Conditional deletion of PTEN substantially improves RGC survival, albeit transiently, and enables RGCs to regenerate axons into the optic nerve,” according to the research team. “Combining PTEN deletion with other pro-regenerative treatments strongly augments optic nerve regeneration.” Other factors include fibroblast growth factor-2 (FGF2) which has been shown to trigger axon regeneration and BDNF which can increase RGC survival following optic nerve injury. Overexpression of the TrkB gene also leads to improved RGC survival. Insulinlike growth factor (IGF-1) can stimulate axon regeneration in selective RGCs when combined with osteopontin, a glycoprotein that acts as a mediator for inflammation. Intrinsic interneurons called amacrine cells also play a critical role in mediating axon growth and development. Gene expression in amacrine cells contributes to these effects. Overexpression of Lin28, for example, has shown improved tissue repair and optic nerve regeneration. “Virally-mediated overexpression of Lin28 in the retina induces sustained optic nerve regeneration without affecting RGC survival,” said the investigators of the review.

Combination treatment for optic nerve regeneration According to this review, treatments have been developed combining elements to regenerate the RGC and their axons. For example, inducing intraocular inflammation, elevating cAMP and performing a PTEN deletion works synergistically to regenerate axons by 10-fold compared to individual treatments. By 6 weeks, some axons

reach the optic chiasm with this combination and afterwards, results in some recovery of the optomotor response. Deletion of the PTEN and SOCS3 genes has also shown substantial regeneration when combined with CNTF overexpression. This combination has resulted in axons regenerating and reaching the chiasm within one month. In situations where the optic nerve is damaged near the optic chiasm, this combination showed reinnervation in the suprachiasmatic nucleus within one month. Overexpression of other proteins such as cRheb1, a regulator of the mTOR signaling pathway, and Bcl-2, an anti-apoptotic protein, has shown improved axon regeneration within weeks after injury. When overexpression of Bcl-2 was complemented with expression of CNTF, there was enhanced survival of RGCs, allowing further regeneration.

Conclusion Findings from this research review can likely be useful in developing new treatment modalities for treating optic nerve damage. By reversing degeneration, maintaining the RGCs after injury, and even regenerating these cells, treatment may be able to reverse vision loss. Insight from animal models can help lay the groundwork for potential drug treatments or gene therapies targeting these specific factors and pathways. RGC regeneration is therefore a critical area for vision loss treatment and may one day help restore vision in those with optic nerve injury.

An expert opinion Considering optic nerve regeneration, especially as a retina specialist, is not always an easy task, noted Dr. Hudson de Carvalho Nakamura, retinal specialist from The Eye Bank Foundation of Goiás, Brazil. “We deal with many diseases involving the optic nerve, ranging from glaucoma to complicated retinal


INNOVATION OPHTHALMIC RESEARCH detachments that involve the optic nerve and the neural pathways too,” said Dr. Nakamura. “Trauma, other mechanical influences or inflammation, growth, neurotrophic and other factors, are far advanced options to think about aiming at visual restoration through nerve regeneration,” he added. Recent studies, according to Dr. Nakamura, have shown that for the successful restoration of vision, retinal ganglion cells would have to be present and healthy. “Also, their axons should grow to specific sites at the damaged areas and at the brain, as well, so as to enable the function of specific targets in the brain and making functional synaptic circuits available. Combination therapy involving cAMP also plays a role,” he added. “More often we get trapped and end up asking for visually evoked responses in order to track the visual pathway. But that is usually just a palliative measure to find out whether there’s any response from the patient to predict a usually poor outcome,” said Dr. Nakamura. “So that when we think of other retina capabilities in animals, such that of in zebrafish and frogs, we come to a better understanding of the pathways we could possibly involve in the human retina with that knowledge,” he explained. Currently however, in terms of vitreoretinal surgery, retinal specialists, according to Dr. Nakamura, still end up manipulating the retinal layers. For example, in the ILM (internal limiting membrane) folding technique for large macular holes: “The ILM autologous graft is transported towards the macular hole to actually fill in the hole defect and allow the ILM to grow over a new scaffold tissue to proliferate filling in the missing retina defect. This may grow a normal retina with its neural ganglion cell layers,” shared Dr. Nakamura. “Considering a normal eye anatomy and the different appearance of the ILM, the ILM forms the innermost boundary of the retina,” emphasized Dr. Nakamura. The outer retinal surface of this membrane is uneven and is


Trauma, other mechanical influences or inflammation, growth, neurotrophic and other factors, are far advanced options to think about aiming at visual restoration through nerve regeneration.

– Dr. Hudson de Carvalho Nakamura composed of extensive, expanded terminations of Müller cells (often called footplates) covered by a basement membrane. Anteriorly, the internal limiting membrane of the retina is continuous with the internal limiting membrane of the ciliary body. “It is present over the macula but undergoes modification at the optic disc, where processes from astrocytes replace those of the Müller cells. Type Ib astrocytes populate the nerve fiber layer and form the inner limiting membrane, serving as a barrier between the retina and the vitreous,” he added. “Therefore, if we think of Müller cell fragments inserted inside the hole, that could well support macular hole closure by inducing glial cell proliferation,” said Dr. Nakamura. “The process would create a scaffold for tissue proliferation in a larger manner because we are putting more substance inside the hole,” he explained.

Since a basement membrane is required for cell proliferation, that hypothesis, highlighted Dr. Nakamura, agrees with histopathologic findings, that the ILM, being a basement membrane, allows glial cell proliferation, and large macular holes will fill with tissue over time. “If we could ‘turn back the clock’, we could possibly make retinal regeneration feasible in glaucoma or trauma cases,” said Dr. Nakamura. “The fish and frog models are for sure teaching us on that subject and we need to learn more,” he advised. For the time being, according to Dr. Nakamura, while many other approaches are being tested, nothing is known for sure about definite results. “Results are coming in slowly, but despite some good results – for example in the field of retinal pigment epithelium transplant and amniotic membrane graft – we are not sure yet if we can link all these mentioned procedures to optic nerve regeneration,” he explained. “There are still questions that we don’t know the answer to, like the top of the new outer retina . . . could that be a place for retinal cell growth instead? That’s also a good question, but we don’t know as of yet,” concluded Dr. Nakamura. Editor’s Note: Dr. Nakamura was not involved in the study discussed in this article but was generous enough to share his expert opinion on the matter.

*Yin Y, De Lima S, Gilbert HY, et al. Optic nerve regeneration: A long view. Restor Neurol Neurosci. 2019 October [Epub ahead of print]

About the Contributing Doctor Hudson de Carvalho Nakamura, MD is an ophthalmologist specializing in the retina and vitreous. He completed his medical degree from School of Medicine at the Federal University of Goiás – UFG and residency from the Base Hospital of the Federal District - Brasília - DF. Presently, Dr. Nakamura is a member of the American Academy of Ophthalmology (AAO), Brazilian Council of Ophthalmology, Canadian Society of Ophthalmology and The Association for Research in Vision and Ophthalmology (ARVO). He currently works as a professor in the Department of Retina and Vitreous Course of Medical Residency in Ophthalmology at the Bank of Goias Eye Foundation and holds a vitreoretinal disease fellowship from the University of Toronto Canada and the Brazilian Center for Eye Surgery. [Email: hudson.nakamura@gmail.com]


Championing the Vitreoretinal Field

Women are shattering the glass ceiling in vitreoretina . . . and are becoming champions for sight.

by Tan Sher Lynn


or Dr. Rekha Sidramayya Bainchincholemath (or as she simply refers to herself, Dr. Rekha S.), her interest in ophthalmology was ignited when her maternal uncle experienced a retinal detachment while she was studying for her medical degree in Gulbarga, Karnataka. Wanting to know more about the subject, as well as the best treatment options available, she decided to venture into ophthalmology. She did her postgraduate studies in the J.N. Medical College, Belgaum, Karnataka, and obtained her Diplomate of National Board (DNB) and vitreoretinal fellowship at Sankara Nethralaya, Chennai. According to Dr. Rekha, when she took up ophthalmology she though that it was ‘pretty cool’, however when she delved into the vitreoretinal subspecialty, she soon found out that it was a whole different ball game.


“Vitreoretinal surgery is a complex blend of difficult high-tech microsurgery applied to a complex pathobiologic system. There are so many uncertainties and emergencies involved in the surgical field,” she said. Despite being in one of the most challenging subspecialties of ophthalmology, Dr. Rekha loves the challenge of treating difficult cases, which often require innovative problem-solving skills. She also finds

fulfilment in helping patients save their vision. Today, she works as a senior vitreoretinal surgeon at Agarwal Eye Hospital in Chennai, India. Throughout her journey in ophthalmology, her parents have been most supportive, although initially they placed some restrictions on her traveling. “Being in this industry, sometimes there’s a lot of travel to do in a single day and I will only return home after midnight. At first, my parents were

worried about me travelling at night, but I’ve proven to them that I am able to take care of myself,” she shared. As a professional, she feels that work and family should be separated. “Matters at work should not be brought home, and matters at home should not be brought to the workplace. This will ensure that you really focus on your family when you are home, while keeping your work professional.” Looking back to her college days, Dr. Rekha hopes that medical students will be given more chances to perform more work. “During my studies, I had to rely a lot on observation. When young people are given more opportunities to get their hands dirty, they will learn more and may even come out with new ways of doing things. They will also gain more experience and have more confidence in their skills.”

To those who are looking to enter the vitreoretinal field, she stressed that passion and the willingness to work hard are key to tackle the demands of this field. “If you are taking up a vitreoretinal subspecialty, be prepared to give 100 percent effort and maximum time to pursue it. You should

be hardworking and have a strong grasp of the basics in ophthalmology. When met with challenges or difficulties, do not give excuses but continue to strive towards your goals. Persistence is the way to go and at the end of the road, you will be rewarded,” she concluded.

About the Contributing Doctor Dr. Rekha S. is an ophthalmologist and eye surgeon in Himayat Nagar, Hyderabad, with 18 years of experience in medical retina, retinopathy of prematurity (ROP) screening, vitreoretina and cataract. She currently practices at Dr. Agarwal’s Eye Hospital in Himayat Nagar, Hyderabad and Dr. Agarwal’s Eye Hospital in JP Nagar 3 Phase, Bangalore. She completed her MBBS from M.R. Medical College, Gulbuarga in 2001, Diploma in Ophthalmic Medicine & Surgery (DOMS) from Jawaharlal Nehru Medical College, Belgaum, Karnatata in 2005, and Diplomate of National Board (DNB) from Sankara Nethralaya, Chennai in 2010. She is a member of the All India Ophthalmological Society (AIOS) and Tamil Nadu Ophthalmic Association (TNOA). In 2017, she received the Best in New Technique/ Device/Innovation Video Award by IIRSI. [Email: rekha.s@dragarwal.com]

INDUSTRY UPDATE U.S. FDA Approves Beovu (Brolucizumab) for nAMD


new anti-VEGF has been approved and is showing promising results for patients with wet or neovascular age-related macular degeneration (nAMD). Beovu (Brolucizumab; Novartis, Basel, Switzerland) injections were approved by the U.S. Food and Drug Administration (FDA) in October 2019. Compared with aflibercept, Beovu is the first FDA approved anti-VEGF to offer both greater fluid resolution and as well as the ability to maintain eligible nAMD patients on a threemonth dosing interval immediately after a three-month loading phase, with uncompromised efficacy. Its FDA approval was based on findings from the Phase III HAWK and HARRIER clinical trials, where Beovu demonstrated non-inferiority to aflibercept in mean change BCVA at year 1 (48 weeks) – in both clinical

trials approximately 30% of patients gained at least 15 letters at year one. Additionally, Beovu showed greater reduction in central subfield thickness (CST) as early as week 16 and at year 1, and fewer patients had intraretinal (IRF) and/or subretinal fluid (SRF) – a key marker of disease activity. In both clinical trials, at year 1, over half of patients were maintained on the threemonth dosing interval (56% in HAWK and 51% in HARRIER). “Beovu meets our goals in clinical practice for treating wet AMD: improving vision and drying retinal fluid,” said Dr. Pravin U. Dugel, principal investigator of the HAWK clinical trial. “With Beovu, greater fluid reduction was demonstrated through larger decreases in retinal thickness and a higher proportion of patients with drier retinas. Coupled with the potential to treat patients with quarterly injections, this approval may change

the way we approach the treatment of wet AMD.” The Beovu molecule is engineered to deliver the highest concentration of drug, providing more active binding agents than other anti-VEGFs. By inhibiting VEGF, Beovu suppresses the growth of abnormal blood vessels and the potential for fluid leakage into the retina. “The approval of Beovu delivers on the Novartis commitment to reimagining treatments for patients suffering from serious visual impairment,” said MarieFrance Tschudin, president, Novartis Pharmaceuticals. “The product labels of existing treatments state that they are not as effective when dosed every 12 weeks. Beovu is the first to offer less frequent dosing in the first year of therapy while maintaining its effectiveness. This gives more time for wet AMD patients to focus on what’s important in their lives.”



Media MICE goes to Lucknow for

VRSI 2019


Research Presented at AAO Shows Promise for New Therapies by Brooke Herron


or vitreoretinal specialists, the Retina Subspecialty Day at the American Academy of Ophthalmology’s annual meeting (AAO 2019) was jam-packed with new research, including first-time clinical trial results to updates on ongoing studies. Below, we’ve selected some of the posterior segment highlights from the meeting’s exciting scientific program.

In search of a better vitreous substitute While there are various vitreous substitutes currently used in vitrectomy (i.e. air and expansile gases, perfluorocarbon liquids and silicone), each has limitations which can result in the need for postoperative posturing or further surgery for removal, as well as possible toxicity to ocular tissues. Rather, the ideal vitreous substitute would be biocompatible and degradable, while maintaining structural integrity and oxygenation to the retina. Now, recent Phase 1 clinical trial results suggest a new – and potentially better – vitreous substitute might be on the way: Vitargus (American BriVision Corporation, CA, USA), an injectable, transparent hydrogel with a refractive index of 1.34. Its potential applications include retinal detachment repair, management of diabetic retinal hemorrhage with tractional retinal detachment, repair of penetrating eye trauma, including removal of intraocular foreign bodies. Dr. Andrew Chang presented the results from the trial, which studied the safety and efficacy of intravitreal Vitargus. Eleven patients with retinal detachment or vitreous hemorrhage requiring vitrectomy were enrolled in the study. Vitargus was injected in its liquid form, with subsequent gelation. Follow-up occurred on days 1, 7, 14 postoperatively, then monthly up to day 120.


The trial found that Vitargus sets as a stable, semi-solid gel adhering to the retina and maintains its position without face-down positioning. Not only that, its optical properties allow patients to see well and it was shown to be a well-tolerated vitreous substitute. No

apparent toxicity to the ocular tissues or systemic adverse events could be attributed to Vitargus. Overall, the trial concludes that “the unique properties of Vitargus hold promise for its use following vitrectomy surgery”.

Is a longer-lasting therapy on its way? While anti-VEGF is a mainstay of treating various conditions, the high number of injections is a frequent complaint. And in fact, the limited intraocular durability of current antiVEGF agents is a potential contributor to the recurrence of disease. Antibody Biopolymer Conjugates (ABCs) are a class of molecules engineered to maintain effective drug levels over longer periods of time than the current-generation anti-VEGFs. One in particular – KSI-301 – is an anti-VEGF ABC, with a possible dosing interval as infrequent as once every 12-20 weeks (following three loading doses) for patients with neovascular age-related macular degeneration (nAMD) or diabetic macular edema (DME). Dr. Charles C. Wykoff discussed results from current and ongoing studies of KSI-301 in patients with AMD, DME and retinal vein occlusion (RVO). Results from the Phase 1a single ascending dose study are in: KSI-301 was welltolerated at all three dose levels (1.25, 2.5 or 5mg), and no drug-related adverse events, inflammation or doselimiting toxicities were observed. After a single dose of KSI-301, investigators saw rapid visual and anatomic improvements as early as one-week post-treatment. This effect continued through week 4, with patients exhibiting a median BCVA improvement of +12.5 letters and a median CRT improvement of -120 microns from baseline. At week 12, following a single dose, median improvements were sustained with BCVA (+9 letters) and CRT (-121 microns). Of course, there are additional trials ongoing to test its efficacy and safety. The Phase 1b open-label study of KSI-301 is evaluating two dosing levels, 2.5 and 5mg, in patients with nAMD, RVO and DME. In this study, patients receive 3 initial monthly injections with evaluation every 4 weeks through week 36. Meanwhile, a Phase 2 study with 400 treatment naïve patients with nAMD will receive either KSI-301 (5mg) every 12 to 20 weeks or aflibercept (2mg) every 8 weeks, after 3 monthly doses.

Do changes in retinal thickness impact visual outcomes in nAMD patients? Dr. Usha Chakravarthy and investigators hypothesized that patients who experienced greater variations in retinal thickness when treated with anti-VEGF for nAMD would have worse visual outcomes than patients with less variation. They conducted a meta-analysis of the IVAN and CATT trials, extracting foveal center point thickness (CPT) measurements for a total of 1,711 patients.

Changes in retinal thickness may indicate worsening visual outcomes in nAMD.

Patients were grouped by quartiles based on S-CPT (standardized CPT) standard deviation (SD). In patients with the least S-CPT variation, mean BCVA at the final visit was 73.2 letters (SD, 14.2); while for those with the most S-CPT variation, the final mean BCVA was 59.4 letters (SD, 14.2). These results led the investigators to conclude that “fluctuation in retinal thickness, despite optimal treatment frequency, is adversely associated with visual outcome”.

Uveitis Clinical Trial Update Four clinical trials – MUST, POINT, MERIT and ADVISE – test various therapies to treat uveitis. According to a synopsis provided by Dr. Douglas Jabs, “approximately 40% of eyes with uveitic macular edema will have persistent or relapsed edema at 2 years of treatment, despite control of evident inflammation and use of adjunctive regional corticosteroid injections”. The MUST trial compared systemic therapy with oral corticosteroids and

immunosuppression versus regional (ocular) therapy with the 0.59mg fluocinolone acetonide intraocular implant (Retisert) for noninfectious intermediate, posterior, or pan-uveitides. The investigators found the risk of blindness was nearly doubled in the regional therapy group due to retinal damage from relapse, and this group also saw significantly increased rates of ocular side effects like cataract, elevated IOP and glaucoma. This led the authors to conclude that “systemic therapy may be a better initial choice”. The POINT Trial compared periocular triamcinolone, intraocular triamcinolone and intraocular dexamethasone implant (Ozurdex) for treating uveitic macular edema. Both intravitreal triamcinolone and intravitreal dexamethasone were superior to periocular triamcinolone; and dexamethasone was noninferior to intravitreal triamcinolone. This led the authors to conclude that intravitreal approaches might be preferred when treating uveitic macular edema. The MERIT trial is currently ongoing and is looking at the comparative effectiveness of intravitreal dexamethasone implant versus intravitreal ranibizumab versus intravitreal methotrexate injections for the treatment of persistent or relapsed uveitic macular edema. Another ongoing trial is ADVISE, a randomized comparative effectiveness trial of adalimumab versus conventional immunosuppression with antimetabolites of calcineurin for patients with noninfectious intermediate, posterior or panuveitis. All in all, it’s an exciting time to work in vitreoretina – with new molecules, therapies and innovation all showing promise for improved visual outcomes for patients suffering from sight threatening back-of-the-eye conditions. Editor’s Note: The American Academy of Ophthalmology’s annual meeting (AAO 2019) was held from October 12 to 15, 2019, in San Francisco, California, USA. Reporting for this story also took place at AAO 2019.


high resolution posterior image

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