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posterior segment • innovation • enlightenment

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HIGHLIGHTS possibility of cell 04 The regeneration and its impact on the treatment of retinal vascular diseases were tackled on Day 1 of virtual ASRS 2020. and AR are 05 AIalways hot topics in ophthalmology... how soon are robots going to replace retinal surgeons?


Man versus AI… and Porcine Eyes Don’t Lie!

World-renowned retinal surgeons provide maneuvers and tricks for better surgical outcomes in challenging cases.

The Latest in Innovations and Data in Retinal Imaging by Hazlin Hassan

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etinal diseases such as age related macular degeneration (AMD) and diabetic retinopathy (DR), which require repeat standardized investigations and analysis, contribute to the majority of causes of vision loss in developed and developing countries. The digital revolution in ophthalmology, with improved diagnostic abilities, could ensure a more accurate image analysis leading to earlier detection and treatment, and ultimately better outcomes for patients.

But how traditional imaging with fluorescein angiography (FA) stacks up against novel techniques such as wide-field, swept-source optical coherence tomography angiography (WF SS-OCTA) with and without ultra-widefield color fundus photography (UWF CFP) for detecting DR lesions has not been previously studied. This is where a study by Dr. John Miller et al comes in, comparing different scan protocols of WF SS-OCTA versus FA for detecting DR.

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The latest innovations and data in retinal imaging were among the many interesting topics discussed virtually during the first day of the American Society of Retina Specialists 38th Annual Scientific Meeting (ASRS 2020), as experts seek ways to transform diagnostic and treatment methods.

Detecting diabetic retinopathy: WF SS-OCTA versus FA Diabetic retinopathy (DR) is a common cause of irreversible vision loss worldwide, and early and accurate detection is critical to ensure appropriate treatment and management of the disease.

A prospective, observational study at Massachusetts Eye and Ear (Boston, USA), involving diabetic patients with proliferative, non-proliferative, and no DR, comprising 176 eyes in 119 participants, was carried out from December 2018 to July 2019. The conclusion? “WF SS-OCTA imaging is clinically useful in detecting microaneurysms (MA), intraretinal microvascular abnormalities (IRMA), and neovascularization of the disc (NVD)/neovascularization elsewhere (NVE) and nonperfusion areas (NPAs),” said Dr. Miller, adding that WF SS-OCTA is comparable to UFA for DR lesion detection. When combined with UWF CFP, SS-OCTA showed identical detection rates to UWF FA. WF Cont. on Page 3 >>

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25 July 2020 | Issue #2

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PIE magazine’s Daily Congress News on the Posterior Segment

>> Cont. from Page 1

SS-OCTA may offer a less invasive and more frequently testable alternative to FA for DR.

Quantifying IRMAs IRMAs can be difficult to detect clinically, as they are often obscured by other DR pathology. In a retrospective review of 200 patients with DR who had undergone SS-OCTA (ZEISS Plex Elite), it was concluded that the SS-OCTA is a useful tool to characterize and quantify IRMAs in DR, said Dr. Thomas Mendel of the Cleveland Clinic Cole Eye Institute (Ohio, USA). Different IRMAs demonstrate different degrees of leakage, he noted. IRMAs were analyzed and determined to have significantly decreased flow density compared to control areas in the same retina, with similar flow length density measurements. IRMAs tended to develop in microregions of the retina, adjacent to areas of nonperfusion, thus resulting in less density in a given area. “SS-OCTA seems to be a viable measure of overall retinal ischemia. SS-OCTA can quantifiably characterize IRMAs in diabetic retinal microvasculature,” explained Dr. Mendel. The ability to quantify and characterize IRMAs with SS-OCTA will provide the clinician with a valuable tool to identify subtle microvascular changes without the need for vascular access and traditional FA.

MIOCT: The potential for a more precise surgical maneuver The use of new generation, high speed (400 kHz), Microscope-Integrated Optical Coherence Tomography (MIOCT) system* with real time volumetric 4D visualization via heads-up stereoscopic display “allows for a more precise manipulation of delicate retinal tissue or subretinal therapy delivery,” said Associate Professor Dr. Lejla Vajzovic of the Duke Eye Center (North Carolina, USA). This was evidenced during mock surgical maneuvers in ex-vivo porcine eyes.

Although the needle was obscured by the retina on the en-face microscope view, 4D MIOCT provided clear visualization of the needle within the bleb and under the surface of the retina. “Ophthalmic surgery is performed through an en-face surgical microscope that provides limited depth information. With limited depth information comes limited precision in delicate retinal surgical maneuvers such as subretinal therapy delivery,” she pointed out.

Man versus AI In neovascular AMD, retreatment decisions are based mostly on qualitative assessments of retinal fluid presence by retinal specialists. This is highly time-consuming and accuracy may be sub-optimal. Artificial Intelligence (AI) algorithms that help identify the presence, location and quantity of fluid may aid retinal specialists in detecting retinal fluid on OCT in AMD, said Dr. Michael Elman of Elman Retina Group (Maryland, USA). This was shown in the AREDS2 10-year follow-up study in which the performance of retinal specialists in detecting retinal fluid presence in spectral domain OCT macular volume scans from eyes with AMD was compared with the performance of an AI algorithm. In a large and challenging sample of OCT scans of over 1,000 eyes, retinal specialists had imperfect accuracy in detecting retinal fluid, with low sensitivity, particularly for low fluid volumes. “AI had higher sensitivity in identifying SRF/IRF than retinal specialists (82.2% versus 46.8%), said Dr. Elman.

HYPERVIT: Stability and improved performance New data about the effectiveness of Alcon’s HYPERVIT® Dual Blade Vitrectomy Probe and the latest updates to its NGENUITY® 3D Visualization System (NGENUITY 1.4) were also showcased at the virtual ASRS 2020. An Alcon-funded study on the HYPERVIT Dual Blade Vitrectomy Probe, which enhances stability and control during microincision vitrectomy, showed how

the HYPERVIT 20,000 cpm probe may provide more continuous engagement, more effective cutting and less repulsion of both soft and hard cataracts than single cutting 7,500 cpm probes. Another study, by Dr. Dina Abulon of Alcon, showed that HYPERVIT 20,000 cpm probes may provide more optimal vitreous aspiration near the port than previous generation single-cutting probes, such as the ULTRAVIT® 10,000 cpm probe. “During retina surgery, having a controlled workspace with minimal movement helps drive efficiency,” said Dr. Martin Charles, Co-director at Centro Oftalmológico Dr. Daniel Charles S.A. in Argentina. “HYPERVIT enables me to get closer to the membrane right above the retina with a more stable movement closer to the port and more precise pulsatile motion. In the study we are presenting at the meeting, the findings confirm the advanced performance of this probe and why it’s a more efficient option for retina surgery.” In addition, the new NGENUITY 1.4 is expected to improve workflow in the operating room. The upgrade includes a color optimization and a unified CONSTELLATION® workflow, allowing retina surgeons to track key surgical parameters in real-time during surgery, enhancing the surgical cockpit, while also helping improve patient outcomes and surgeon ergonomics during surgery. These workflow improvements, along with the enhanced visualization, support surgeons in the operating room spacing and set-up when performing surgeries in the current COVID-19 environment. This latest version of the NGENUITY System will be available for the anterior segment as well later this month, according to Alcon.

* A commercially available Enfocus MIOCT scanner (Leica Microsyst; Wetzlar, Germany) was modified for 1050 nm light and hish speed, ScannerMax (Pangolin; FL, USA) galvos. The OCT engine used either a 100 or 400 khz swept-source laser (AxsunTechnologies; Billera, MA, USA) with a center wavelength of 1050 nm. A Truevision (CA, USA) 3D visualization system was used to provide heads up visualization of the surgical field and OCT data on a 3D TV.



25 July 2020 | Issue #2

Of Stem Cells and Cell Regeneration in Treatment of Retinal Vascular Diseases by Joanna Lee

“We’re looking at you looking at our retinas and trying to learn more about facilitating retinal cell regenerative therapies in humans, although, we can tell you the answers aren’t exactly black and white. Isn’t that more exciting?” the zebras mulled.

Possibilities of cell regeneration and challenges, to audacious goals and new developments in retinal vascular disease treatment, make for exciting times ahead...


ince some vertebrates like zebras, fish or salamanders can regenerate large parts of their retina after injury, the search has been on to nurture the same ability for human retinal cells. In the Retinal Cell Therapies Symposium, Dr. Steven Becker, head of the National Eye Institute’s (NEI) Office of Regenerative Medicine spoke about new imaging modalities for monitoring retinal disease, referring to NEI’s Audacious Goals Initiative (AGI) launched in 2012 with the aim to “regenerate neurons and their neural connections in the eye and visual system”. One of NEI’s three funded consortia in advancing stem cell-based therapies is to develop functional imaging technologies. There has been five NEI AGI Imaging Grant Awards given. First, Alfredo Dubra (Stanford University) is working on a suite of technologies that can enable the higher resolution monitoring of different cell types. Kris Palczewski (UC-Irvine) has been developing a two-photon ophthalmoscope for safe imaging of cells or tissues in human retina that may allow for early detection, monitoring and evaluation of treatments.

Austin Roorda (UC-Berkeley) is looking into wide-field interferometry to measure neural activity non-invasively by combining it with various imagebased eye tracking tools. Over at Washington University, Victor Song is developing diffusion functional magnetic resonance imaging (dfMRI) technologies that would allow access to optic nerve anatomy in glaucoma and optic nerve neuropathies and to identify any occurring regeneration. Lastly, David Williams (University of Rochester) is working on OCT and AOSLO (reflectance, offset aperture, and two-photon) with calcium indicators, different metabolic sensors and labelled precursor cells to see if vision restoration could be assessed as well. Dr. Becker hoped these imaging advances will give clinicians new tools for disease progression assessment as well as the further development of new functional outcome measures for clinical trials and accelerate therapies for patients. Since 2008, inducible progenitor stem cells (iPSCs) are made from individual subject’s blood or epithelial cells which create the possibility of personalized medicine, other than using embryonic stem cells. AGI program’s advisor Dr. Russell Van Gelder spoke on barriers facing cell replacement therapies.

One of the barriers is the improvement in correct cellular differentiation (some cell types currently are more easily differentiated than others). Another challenge is generating sufficient number of cells for transplantation, and establishing correct cell polarity and connectivity. Lastly, there is a need to ensure these cells don’t escape differentiation pathways to form tumors or hematomas. Other challenges include managing immune responses and regulatory hurdles (FDA, and Good Laboratory Practice [GLP]). In the Retinal Vascular Disease Symposium, Dr. J. Fernando Arevalo discussed his team’s multicenter study on intravitreal anti-VEGF injections for exudative retinal arterial macroaneuryms (RAM) for which there has never been an established therapy. The results indicated anti-VEGF injections to be effective, leading to a decrease in macular edema in RAM patients. Dr. Wael Alsakran (King Khaled Eye Specialist Hospital, Saudi Arabia) spoke about using intravitreal triamcinolone acetonide (IVTA) as an adjunctive therapy in advanced Coat’s disease with exudative retinal detachment (ERD) where 13 out of 17 eyes experienced success with IVTA and ablative therapy without requiring surgical drainage. There is improvement in VA and central macular thickness. Excitement hovers over the first ever application of deep learning to sickle cell hemoglobinopathy in terms of wide-field fundus images as Dr. Sophie Cai discussed in a presentation titled Deep Learning Detection of Sea Fan Neovascularization from Ultra-Widefield Fundus Images of Sickle Cell Hemoglobinopathy. Her team’s study contributes to currently what they esteem to be the largest existing database of ultrawidefield fundus images of sickle cell hemoglobinopathy. With further investigations and external validation, they’re expecting this system to improve automated screening for vision-threatening sickle cell retinopathy. Other exciting discussions in this session included Real-world Treatment Patterns in Patients with Macular Edema due to Retinal Vein Occlusion by Dr. Vrinda Hershberger, and how Norrin protein promotes VEGF modulation and healthy in situ retinal regeneration in retinal vascular disease.

PIE magazine’s Daily Congress News on the Posterior Segment

Optimizing Outcomes through AI and AR by Tan Sher Lynn


xperts discussed how artificial intelligence (AI) and augmented reality (AR) are being used in ophthalmology to optimize surgical procedures and outcomes in a session called Technology Symposium: Updates in Artificial Intelligence (AI), Augmented Reality (AR) and Robotics held on the first day of the (virtual) American Society of Retina Specialists 38th Annual Scientific Meeting (ASRS 2020).

AI for diabetic retinopathy screening It is estimated that 600 million people worldwide will get diabetes by 2040, with a third having diabetic retinopathy (DR).1 With the advent of deep learning, various companies have developed automated artificial intelligence diabetic retinopathy screening systems (AIDRSS) which can help reduce the incidence of preventable blindness worldwide. Dr. Aaron Lee from the University of Washington (USA), and colleagues compared the performance of seven AIDRSS in real-world setting. The five companies which participated in the study are ADCIS (Saint-Contest, France), AirDoc (Beijing, China), Eyenuk (California USA), Retina-AI Health (California, USA) and Retmarker (Coimbra, Portugal). A total of 311,604 retinal images for Seattle and Atlanta, as well as the original VA teleretinal grades, were extracted from the national VA Teleretinal Imaging Screening Program. The dataset were run through seven AI algorithms (labeled A-F) from the five companies and their performances were compared to the original VA grades. “The VA grader has 100% sensitivity for moderate non-proliferative diabetic retinopathy (NPDR), severe NPDR and PDR and results from the arbitrated dataset showed that algorithms E, F, G was statistically similar to VA grader for moderate NPDR or higher,” Dr. Lee said.

“We concluded that algorithms varied in performance despite having regulatory approval and/or being clinically deployed,” he added. It is therefore important, highlighted Dr. Lee, to understand AI models in the context of the underlying prevalence of disease. “We believe that external, independent validation with real-world imaging is critical prior to deployment even after algorithms reach regulatory approval,” he shared.

AR for macular degeneration Age related macular degeneration (AMD) is the most common cause of vision loss in older adults in the United States. There were 13M people with AMD in the US and 30M worldwide in 2019 and this number is predicted to increase up to 22M in the US and 288M worldwide.2-3 The novel augmented reality (AR) headset Oculenz (Ocutrx Vision Technologies, CA, USA) is set to change the lives of these patients. “AR enhances the real world and digital elements overlay real world surroundings. It is ideal for complete user freedom,

high or low light surroundings and applications in low vision, medicine and education,” said Dr Dr. Linda Lam, associate professor of ophthalmology of the USC Keck School of Medicine, USA. Especially designed for patients with advanced macular degeneration with central scotama(s), the Oculenz headset provides a perceived de-emphasis of the scotoma, enhanced reading of letters in a word and improved recognition of familiar faces. “Its simultaneous localization and mapping software offers instant location mapping and object identification with 7 million objects identified,” added Dr. Lam. The device is anticipated to be available in early 2021.

Deep learning applications in retinopathy of prematurity Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide, but screening is labor intensive and clinical diagnosis is subjective and qualitative. Dr. J. Peter Campbell from the Oregon Health & Science University (USA) talked about translational applications of deep learning in ROP.



25 July 2020 | Issue #2

“In terms of image analysis, AI can now automate the classification of all ROP components, including zone, stage and disease for multiple groups. AI can provide real-time segmentation of images to aid in acquisition and interpretation of images,” he said.

appropriate primary, secondary and tertiary prevention. To maximize the potential of AI’s value, we need to develop systems of care,” he said.

Deidentified images (RetCam; Natus Medical Incorporated) captured after clinical examinations between July 2011 and December 2016 were assessed as part of the Imaging and Informatics in ROP (i-ROP) cohort study. A deep learning system was used to classify the probability of an image having a reference standard diagnosis of plus disease, and converted to an automated 1 (most benign) to 9 (most severe) scale using published methods. Quantitative scale values were analyzed for 5255 clinical examinations in 871 infants and reported using descriptive statistics. Inter- and intra-examiner variability in diagnosis, and differences between hospitals were assessed using the quantitative scale.

Today, robots are revolutionizing the various fields of medicine. Speaking about how robotics helps to optimize surgical steps in ophthalmology, Dr. Richard Rosen from the New York Eye Infirmary of Mount Sinai (USA) said: “Robotics provides high positional stability as well as micrometer precision and accuracy in XYZ. This removes any time constraint on drug delivery within the retinal space, whether intracannular or subretinal. It also allows for a detailed analysis of each phase of a surgical procedure and its optimization.”

Dr. Campbell concluded that deep learning may facilitate quantitative diagnosis of retinal diseases like ROP. The ROP vascular severity scale corresponds with current clinical classifications of disease severity and may enable quantitative disease monitoring in the future. “Blindness from ROP is largely preventable with

Robotics in ophthalmology

Three main robotic approaches currently developing in ophthalmology are the assistive handheld device by the Johns Hopkins Group, co-manipulation by the UCLA Group and telemanipulation by the Einthoven Group, reported Dr. Rosen. Further, Dr. Rosen demonstrated the advantages of high precision robotics in retinal delivery over manual technique through a study of the PRECEYES Surgical Robot (PRECEYES BV, Eindhoven, The Netherlands) in conjunction with the PRECEYES

Microscope with Integrated OCT. “The surgical robot features tremor filtering and motion scaling, which enhances human performance by an order of magnitude to the precision of less than 10 microns. The arm allows for intuitive motion with positional stability and memory. Comparing between the accuracy and precision between human and robotic performance on a dynamic test, we found that the robot is able to perform for at least an order of magnitude better than the human,” he said. In short, noted Dr. Rosen, robotic assistance removes time constraints of delivery, allowing high precision positioning for controlled subretinal drug delivery. Robotic assistance also controls tremor, reducing fatigue and helps avoid inadvertent injury in tight spaces. “Robotic-assisted ocular surgery shows promise for advancing the surgeon’s ability to perform more complex maneuvers necessary for the next generation of retinal interventions,” added Dr. Rosen.

References: 1

Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35:556–564.


National Federation of the Blind. 2018 Annual Report.


Bright Focus Foundation (2016)

PIE magazine’s Daily Congress News on the Posterior Segment

Surgical Retina Techniques and Maneuvers for Better Outcomes by Tan Sher Lynn

Various novel surgical techniques and maneuvers were discussed in a live stream during the American Society of Retina Specialists 38th Annual Scientific Meeting (ASRS 2020) on July 24, 2020. Here are some of the highlights…

Sutureless intrascleral fixation The two-part Surgical Techniques and Maneuvers Symposium started with Dr. Ashkan Abbey from the Texas Retina Associates (USA) , who presented the clinical outcomes of 488 eyes which received sutureless intrascleral (SIS) fixation of intraocular lenses (IOL) as well as the comparative effectiveness of haptic flanging in the series. “Postoperative IOL dislocation in eyes undergoing SIS fixation is most likely to occur after repositioning of a previously dislocated IOL,” he shared. The risk of postoperative IOL dislocation, emphasized Dr. Abbey, may

be reduced by having a low threshold for exchanging a warped or damaged 3-piece IOL. “Flanging of the haptic tips significantly reduces the risk of IOL dislocation. Intraoperative peripheral iridotomies significantly reduce the risk of postoperative reverse pupillary block,” he added.

Using microsurgical vacuum pick Then, Dr. Carl Awh from Tennessee Retina (USA) described the use of the microsurgical vacuum pick (MVP) for membrane peeling without forceps during vitreoretinal surgery. The MVP is a new device that can perform all membrane peeling steps, including creating a membrane edge, securing the membrane, and peeling the membrane from the retina. The most novel feature of the MVP is the micropicks, which is used to create an edge or flap in the ILM or ERM, with minimal risk of damage to the underlying retina.

“The MVP seems more stable and less fatiguing – there’s no need to activate the forceps. It reduces or eliminates instrument exchange. The teasing action used to peel membranes may transmit less stress to macula than peeling with forceps. However, there are occasions when I still prefer the forceps, such as in cases of extremely thick or rigid membranes,” said Dr. Awh.

Dealing with large macular holes Despite a high success rate for macular hole repair (>90%), there are challenging cases that involves large holes (>400 microns), chronic holes (>6 months), macular holes in high myopia and recurrent holes. Dr. Jessica Lee from New York Eye and Ear Infirmary of Mount Sinai (USA) talked about the use of human amniotic graft in the repair of persistent large MH. The study involves 10 patients who had persistently open large macular holes from 3/2019 to 5/2020. All patients underwent pars



25 July 2020 | Issue #2

plana vitrectomy (PPV) with a circular patch of subretinal amniotic membrane.

Microinjector (Clearside Biomedical, GA, USA).

“Pre-op, the mean best corrected visual acuity (BCVA) was 1.6LogMar or 20/800, while the mean postoperative BCVA was 1.26LogMar or 20/320 (6 months post-op). In all 10 cases, the macular hole appeared closed at the 1-week post-operative visit. All holes remained closed at the last follow-up with a BCVA of 20/400 and no adverse events occurred,� she reported.

Seventy-four per cent (74%) of 133 total baseline injections were completed with the 900¾m needle; the remaining with the 1100¾m needle. Univariate analysis revealed no relationship between needle length and gender, lens status, uveitis location, disease course or onset. Disease duration was statistically correlated with needle length: 91% of injections were completed with the 900¾m needle for Limited (≤ 3 months) and 70% for Persistent (> 3 months).

“An important thing to note during amniotic membrane transplantation is to make sure that the sticky side of the membrane is the side that you place onto the macular hole, which will prevent it from dislodging,� explained Dr. Lee. In the second part of the symposium, Dr. Shree Kurup from the University Hospitals Cleveland (Ohio, USA) presented an interesting post hoc analysis of the new clinical suprachoroidal injection experience for non-infectious uveitis with the SCS

“Age was moderately inversely correlated with needle length. Injection quadrant was statistically related: 82% of injections administered temporally were completed with the 900 Âľm needle compared to 45% of injections administered nasally. In the user experience survey, over 80% of the physicians responded that SC injections presented no new challenges compared to other types of injections,â€? said. Dr. Kurup.


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The link to Alzheimer’s Meanwhile, Dr. Manju Subramanian from the Boston University School of Medicine (USA) talked about her investigation regarding the presence of neurofilament-light chain (NfL) in the vitreous humor and its associations with levels of Alzheimer’s Disease (AD) biomarkers such as amyloid beta (AĂ&#x;) and total and phosphorylated Tau (t-Tau and p-Tau) proteins and inflammatory proteins in eyes. “NfL is identified in all 77 samples of undiluted vitreous and 78% of our sample have levels of 20 pg/mL or more,â€? reported Dr. Subramanian. NfL level was significantly associated with increased vitreous levels of AĂ&#x;40, AĂ&#x;42 and t-Tau, specific inflammatory/ vascular protein with known systemic AD association, she noted. “NfL was not correlated with eye disease, APOE genotypes, or cognition. Cumulatively, results indicate that NfL in the vitreous appears to be a marker for systemic neurodegeneration,â€? she said.


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