THE WORLD’S FIRST FUNKY OPHTHALMOLOGY MAGAZINE THE “BACK TO THE FUTURE” ISSUE Sept/Oct 2020 piemagazine.org
nAMD DME RVO
EYLEA® is indicated for adults for the treatment of neovascular (wet) age-related macular degeneration (AMD), visual impairment due to macular edema secondary to retinal vein occlusion (branch RVO or central RVO), visual impairment due to diabetic macular edema (DME), and visual impairment due to myopic choroidal neovascularization (myopic CNV).
REFERENCES: 1 EYLEA® approved package insert Singapore March 2019, Bayer (South East Asia) Pte Ltd. 2. Wells JA, Glassman AR, Ayala AR, et al. Aﬂibercept, bevacizumab or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123:1351-1359 3 Korobelnik JF, Do DV, Schmidt-Erfurth U et al. Intravitreal aﬂibercept for diabetic macular edema. Ophthalmology 2014;121:2247-2254. 4 Eleftheriadou M, Gemenetzi M, Lukic M, et al. Three-year outcomes of aﬂibercept treatment for neovascular age-related macular degeneration: evidence from a clinical setting. Ophthalmol Ther. 2018;7:361-368. 5 Pielen A, Clark WL, Boyer DS, et al. Integrated results from the COPERNICUS and GALILEO studies. Clin Ophthalmol. 2017;11:1533-1540.
ABBREVIATED PRESCRIBING INFORMATION
EYLEA SOLUTION FOR INJECTION IN VIAL 2MG. Approved name(s) of the active ingredient(s) One ml solution for injection contains 40 mg aﬂibercept. Each vial provides a usable amount to deliver a single dose of 50 µl containing 2 mg aﬂibercept. Indication EYLEA is indicated for the treatment of neovascular (wet) age-related macular degeneration (AMD), macular edema secondary to retinal vein occlusion (branch RVO or central RVO), diabetic macular edema (DME) and myopic choroidal neovascularization (myopic CNV). Dosage Regimen wAMD: The recommended dose for EYLEA is 2 mg aﬂibercept, equivalent to 50 µl. EYLEA treatment is initiated with one injection per month for three consecutive doses, followed by one injection every two months. Based on the physician’s judgement of visual and/or anatomic outcomes, the treatment interval may be maintained at two months or further extended, such as with a treat-and-extend dosing regimen, where treatment intervals are increased in 2- or 4- weekly increments to maintain stable visual and/or anatomic outcomes. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly to a minimum of two months during the ﬁrst 12 months of treatment. There is no requirement for monitoring between injections. Based on the physician’s judgement the schedule of monitoring visits may be more frequent than the injection visits. Treatment interval greater than 4 months between injections have not been studied. Branch RVO or central RVO: The recommended dose for EYLEA is 2 mg aﬂibercept, equivalent to 50 microliters. After the initial injection, treatment is given monthly until visual and/or anatomic outcomes are stable. Three or more consecutive, monthly injections may be needed. The interval between two doses should not be shorter than one month. If there is no improvement in visual and anatomic outcomes over the course of the ﬁrst three injections, continued treatment is not recommended. If necessary, treatment may be continued and the interval may be extended based on visual and/or anatomic outcomes (treat and extend regimen). Usually, monitoring should be done at the injection visits. During treatment interval extension through to completion of therapy, the monitoring schedule should be determined by the treating physician based on the individual patient’s response and may be more frequent than the schedule of injections. DME: The recommended dose for EYLEA is 2 mg aﬂibercept, equivalent to 50 microliters. EYLEA treatment is initiated with one injection per month for ﬁve consecutive doses followed by one injection every two months. There is no requirement for monitoring between injections. After the ﬁrst 12 months of treatment with EYLEA, and based on visual and/or anatomic outcomes, the treatment interval may be extended, such as with a treat-and-extend dosing regimen, where the treatment intervals are gradually increased to maintain stable visual and/or anatomic outcomes; however there are insufﬁcient data to conclude on the length of these intervals. If visual and/or anatomic outcomes deteriorate, the treatment interval should be shortened accordingly. The schedule for monitoring should therefore be determined by the treating physician and may be more frequent than the schedule of injections. If visual and anatomic outcomes indicate that the patient is not beneﬁting from continued treatment, EYLEA should be discontinued. Myopic CNV: The recommended dose for EYLEA is a single intravitreal injection of 2 mg aﬂibercept, equivalent to 50 microliters. Additional doses should be administered only if visual and anatomic outcomes indicate that the disease persists. Recurrences are treated like a new manifestation of the disease. The monitoring schedule should be determined by the treating physician based on the individual patient’s response. The interval between two doses should not be shorter than one month. Method of administration Intravitreal injections must be carried out according to medical standards and applicable guidelines by a qualiﬁed physician experienced in administering intravitreal injections. Following intravitreal injection patients should be instructed to report any symptoms suggestive of endophthalmitis (e.g., eye pain, redness of the eye, photophobia, blurring of vision) without delay. Each vial should only be used for the treatment of a single eye. Contraindications Hypersensitivity to the active substance aﬂibercept or to any of the excipients, active or suspected ocular or periocular infection, active severe intraocular inﬂammation. Special warnings and special precautions for use Endophthalmitis, increase in intraocular pressure, immunogenicity, systemic adverse events including non-ocular haemorrhages and arterial thromboembolic events. As with other intravitreal anti-VEGF treatments for AMD, the safety and efﬁcacy of Eylea therapy administered to both eyes concurrently have not been systematically studied. When initiating Eylea therapy, caution should be used in patients with risk factors for retinal pigment epithelial tears. The dose should be withheld and treatment should not be resumed earlier than the next scheduled treatment in the event of: a decrease in best-corrected visual acuity (BCVA) of ≥30 letters compared with the last assessment of visual acuity; a subretinal haemorrhage involving the centre of the fovea, or, if the size of the haemorrhage is ≥50%, of the total lesion area. The dose should be withheld within the previous or next 28 days in the event of a performed or planned intraocular surgery. EYLEA should not be used in pregnancy unless the potential beneﬁt outweighs the potential risk to the foetus. Women of childbearing potential have to use effective contraception during treatment and for at least 3 months after the last injection of aﬂibercept. Undesirable effects Very Common: Conjunctival hemorrhage, eye pain. Common: Retinal pigment epithelial tear, detachment of the retinal pigment epithelium, retinal degeneration, vitreous haemorrhage, cataract (cortical, nuclear, subcapsular), corneal erosion, corneal abrasion, intraocular pressure increased, vision blurred, vitreous ﬂoaters or detachment, injection site pain, foreign body sensation in eyes, lacrimation increased, eyelid edema, injection site hemorrhage, punctate keratitis, conjunctival hyperemia, ocular hyperemia. For a full listing of precautions and undesirable effects, please refer to the full product insert. For further prescribing information, please contact: Bayer (South East Asia)Pte Ltd. 2 Tanjong Katong Road #07-01 Paya Lebar Quarter 3 Singapore 437161. Date of revision of text March 2019.
Bayer (South East Asia) Pte Ltd
2, Tanjong Katong Road #07-01, Paya Lebar Quarter 3, Singapore 437161. Tel: +65 496 1888 Fax: +65 6496 1491 Website: www.bayer.com
TRE A T W I T H Achieve uns
24 34 36 Matt Young CEO & Publisher Robert Anderson Media Director Hannah Nguyen Production & Circulation Manager Gloria D. Gamat Chief Editor Brooke Herron Editor International Business Development Ruchi Mahajan Ranga Brandon Winkeler Writers Andrew Sweeney April Ingram Chow Ee-Tan Joanna Lee Hazlin Hassan Konstantin Yakimchuk Khor Hui-Min Olawale Salami Sam McCommon Tan Sher Lynn Maricel Salvador Graphic Designer Media MICE Pte. Ltd. 6001 Beach Road, #19-06 Golden Mile Tower, Singapore 199589 Tel: +65 8186 7677 / +1 302 261 5379 Email: email@example.com www.mediaMICE.com Published by
Asia-Pacific Vitreo-retina Society Vitreo-Retinal Society - India IN THIS ISSUE... We are looking for eye docs who can contribute articles to PIE magazine. Interested? Let's talk! Send us an email at firstname.lastname@example.org. To place an advertisement, advertorial, symposium highlight, video, email blast, or other promotion in PIE magazine contact CEO Matt Young at email@example.com. Retinopathy of Prematurity: Fine-Tuning Current Treatments to Optimize Patient Outcomes COVID-19 and its Impact on Retina Practice The Balancing Acts of Dr. Mae-Lynn Catherine Bastion Ophthalmology Leaders Beyond Borders Posterior Segment Enlightenment 30 32 34 World’s Apart? Outcomes of AntiVEGF for Diabetic Macular Edema in Routine Clinical Practice Safe and Effective Laser Therapies: Targeting Retinal Diseases Amidst COVID-19 Evidence Mounts in Support of Supplements for Ocular Health Taking Timely Action in DME with a Multimodal Approach Exciting Developments in Retinopathy Treatment on the Horizon Real World Results: Findings from the Protocol T Extension Study Challenging Retinal Cases in Vitreoretinal Surgery Improving Diabetic Retinopathy Treatment Innovation Conference Highlights 16 12 10 08 24 28 36 38 40 18 Cover Story m a g a z i n e poster or segmen nnova on en gh enmen Ophthalmology Innovation Summit All India Ophthalmological Society
Time is a funny thing . . . especially right now. Over in Da Nang, Vietnam, (where a few of the PIE folks are based), we’re in our second COVID-19 lockdown. As this issue goes to print, we’re in week six, and anxiously awaiting updates from the government.
During these times of social and self isolation, many of us have wished (at some point) to be anywhere else . . . or in many cases, at any “time” else. Some of us would go back to the same time last year, when we were attending EURETINA in Paris . . . exploring the
sights and generally being blissfully unaware of what’s to come.
Others would travel to the future. Maybe one year from now . . . or to any point in the future when the world has come right and our normal way of life is restored. Gosh, wouldn’t it be great to just press fast forward and be done with 2020?
However, time travel hasn’t been invented yet — although, the 1980s Back to the Future (BTTF) movie trilogy made it seem right around the corner (also still waiting on my hoverboard). Growing up, these were some of my favorite movies: Who doesn’t want to travel through time, be it past or future? As a young girl, I was ready to jump into that DeLorean and hit 88 miles-perhour (the speed needed for time travel in BTTF). Unfortunately, we don’t have a DeLorean, so our journey through time will remain figurative . . .
The first BTTF film came out 25 years ago in 1985. It doesn’t seem that long ago . . . until it’s compared with advances in ophthalmology — specifically retina.
For example, back in 1985, a patient with neovascular age-related macular degeneration (nAMD) had a pretty bleak outlook. Anti-VEGF was nothing but a speck in the distance — rather laser was the go-to option. [Although, we admit laser sounds pretty futuristic ...]
We finally got the first anti-VEGF approval for pegaptanib in 2004, just a short 16 years ago. However, once ophthalmologists and patients got a taste of the benefits of medical retina, it became unstoppable. Encouraged by outcomes using pegaptanib, ophthalmologists began injecting another anti-VEGF — bevacizumab, which was approved for colon cancer. Today, bevacizumab remains unapproved for ophthalmic use and is still widely used off-label as an affordable anti-VEGF solution.
Of course, more innovation followed rapidly — it was as if someone pushed a “fast forward” button. Another popular anti-VEGF, ranibizumab, was FDA-approved in 2006. Aflibercept followed five years later, obtaining approval in 2011 — a mere nine years ago.
Now, in 2020, we are on the cusp of some very exciting developments in medical retina. From longer-lasting and more durable anti-VEGF agents (as well as other molecules) to advances in gene therapy and drug delivery devices.
If so much has changed in just the last decade . . . imagine where the practice of ophthalmology will be in 2030. Completely bionic eyes? Fully assisted robotic surgery? Mass use of artificial intelligence for disease screening? Pharmaceuticals that cure vision threatening conditions, rather than treat symptoms? It’s all possible. See
LETTER TO READERS Editor, PIE & CAKE magazines Brooke Herron
| Sept/Oct 2020 4
in the future,
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Dr. Cheung currently serves as deputy head and senior consultant of the medial retina service for Singapore National Eye Centre (SNEC), as well as senior clinician investigator for the Singapore Eye Research Institute (SERI). Her research interests include the study of risk factors and clinical features of macular diseases that may be unique in Asian populations.
Dr. Cheung has published more than 150 articles, mostly regarding age-related macular degeneration, including polypoidal choroidal vasculopathy, and conducted several clinical trials in anti-vascular endothelial growth factor therapies. Dr. Cheung has also been actively involved in training and education, and has served as an instructor on Asia-Pacific Academy
of Ophthalmology (APAO) and American Academy of Ophthalmology (AAO) courses and many other educational programmes. In addition, she is also a volunteer faculty member for the ORBIS Flying Eye Hospital Programme.
Dr. Cheung has received a number of prestigious awards, including the Macula Society Young Investigator Award (2017), APAO achievement award (2017), APAO Nakajima Award (2014), APAO Outstanding Service in Prevention of Blindness Award (2013), the Bayer Global Ophthalmology Research Award (2012), the Roper-Hall Medal (2005) and the Elizabeth Hunt Medal (Royal College of Ophthalmologists, UK).
Prof. 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.
Prof. 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. Prof. Gillies has also appeared in national media on numerous occasions, including the evening news of all major networks, on ABC radio as a local expert, as well as in print media.
His dedication and research has resulted in multiple awards. Most recently, he received Gerard Crock trophies for the best papers at the Royal Australian and New Zealand College of Ophthalmologists (RANZCO) Annual Scientific Meeting (2013 and 2015), an achievement award from the Asia-Pacific Academy of Ophthalmology (APAO) in 2014, and an achievement award from the American Academy of Ophthalmology (AAO) in 2015.
Dr. 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).
| Sept/Oct 2020 6
Dr. Gemmy Cheung
Prof. Mark Gillies
Dr. Vishali Gupta
firstname.lastname@example.org ADVISORY BOARD MEMBERS
POSTERIOR SEGMENT OPHTHALMIC TOOL
APVRS 2021 Taipei December 10 -12, 2021
62 Annual Meeting of TOS
Evidence Mounts in Support of Supplements for Ocular Health
by Brooke Herron
For elderly patients, losing vision due to chronic disease like age-related macular degeneration (AMD) and diabetic retinopathy (DR) is a serious cause for concern. As there is no cure, these progressive diseases require consistent monitoring and are often treated using repeated anti-vascular endothelial growth factor (VEGF) injections to reduce vascularization in the eye.
However, as we further our understanding of these conditions’ underlying mechanisms, the role of micronutrients has been evaluated for their potential benefits in reducing the risk or progression of these debilitating conditions. For example, groundbreaking studies AREDS/ AREDS 2 demonstrated that oral supplementation with antioxidant vitamins and minerals showed beneficial effects on the development of advanced AMD. Further, the investigators shared that nutritional supplements could further reduce risk of AMD progression.1
Switzerland-based Aprofol AG is one company that’s taken notice of these potentially sight saving results with the creation of Ocufolin® forte. A FMSP (or food for special medical purposes), Ocufolin® provides the needed nutrients that are insufficiently absorbed in diseases like AMD and DR. And recently, numerous studies have been published exploring the benefits of Ocufolin® in these patients.
How does it work?
To understand how these supplements work, we must first understand the disease mechanism causing the nutritional deficit. The main player here is homocysteine (Hcy) — and when it is not metabolized correctly, it can lead to a host of health problems, including vascular, neurodegenerative and ocular diseases. To metabolize Hcy, enzymes with vitamins including Vitamin B9 (folate) and vitamins B6 and B12 are required, and therefore,
studies have recommended treatment with folate and B12 to reduce Hcy levels.2
In search of further evidence, investigators from the Medical University of Vienna recently completed a pilot study to look into the effects of supplements on Hcy plasma concentrations and ocular blood flow in 24 diabetic patients who received Ocufolin. They found that after three months, plasma Hcy concentration significantly decreased from 14.2 ± 9.3 to 9.6 ± 6.6 µmol/L (p < 0.001). The authors also saw a tendency toward an increased total retinal blood flow from 36.8 ± 12.9 to 39.2 ± 10.8 µl/ min, but noted that this didn’t reach the level of significance (p = 0.11, n = 13). In addition, a small but significant decrease in intraocular pressure (IOP) was observed.3
This data led the authors to conclude that consuming dietary supplements like Ocufolin®, which contains L-methylfolate, can
OCULAR HEALTH POSTERIOR SEGMENT
| Sept/Oct 2020 8
significantly reduce blood Hcy levels in patients with diabetes.
These results were further confirmed by Wang, et al, in a retrospective case review on retinopathy reversal in patients on Ocufolin®, and a similar nonprescription multivitamin, Eyefolate.4 Results showed that all microaneurysms (MAs) were resolved, and exudates were decreased in 8/8 cases after taking the FMSP. Retinal edema was found in 2/8 cases and improved or resolved in both cases. Dr. Wang concluded that “it appears that the use of nutritional supplements and medical foods containing L-methylfolate and vitamin D may be effective in facilitating the improvement of diabetic and hypertensive retinopathy.”
Further delving into the function of nutritional supplements and eye health was Shi, et al.5 “Patients with DR have high incidences of deficiencies of crucial vitamins, minerals and related compounds, which also lead to elevation of Hcy and oxidative stress,” the authors explained. In addition, they explain that “common genetic polymorphisms such as those of methylenetetrahydrofolate reductase (MTHFR), increase Hcy and DR risk and severity.”
Therefore, addressing the effects of the MTHFR polymorphism and comorbid deficiencies as well as insufficiencies could reduce the impact and severity of the disease. After a comprehensive review, they reported that combinations of vitamins B1, B2, B6, L-methylfolate, methylcobalamin (B12), C, D, natural vitamin E complex, lutein, zeaxanthin, alpha-lipoic acid and N-acetylcysteine are identified for protecting the retina and choroid.5
Additionally, further studies are underway to assess the impact of Ocufolin® on intraocular pressure (IOP), particularly the effect of L-methylfolate on patients with elevated retinal venous pressure.
Further applications of nutritional supplements
Benefits of supplements like Ocufolin® could extend beyond the eye, and indeed, help boost the immune system to fight off other infectious pathogens.
To help substantiate the claims of nutrients on the immune system, the European Food Safety Authority (EFSA) has asked the Panel on Dietetic Products, Nutrition and Allergies (NDA) to support the scientific substantiation of claims on the maintenance of (unspecified) functions of the immune system based on the essentiality of nutrients (e.g. vitamins C, D, A, B12, B6, zinc, copper, folate, iron, selenium), were evaluated with a favorable opinion.6
And off course, boosting immune systems is of high importance — especially now, in the midst of the COVID-19 pandemic. In fact, one Italian study suggests routine determination of plasma Hcy as a potential marker for severe disease in SARS-CoV-2 patients.7
A study by Bayer et al., notes that folate is critical to proper cell function and metabolism.8 They hypothesized “that defects in the folate pathway in genetically susceptible individuals could lead to immune dysfunction, permissive environments for chronic cyclical latent/lytic viral infection and, ultimately, the development of unchecked autoimmune responses to infected tissue.”
Much research, in the context of diabetes, has neglected the role of natural killer (NK) cells, the authors shared. “Dampened NK responses to infections result in improper signaling, improper antigen presentation, and amplified CD8+ lymphocyte proliferation and cytotoxicity . . . this would suggest a critical role for NK cells in (type 1) diabetes development linked to viral infection and the importance of the folate pathway in maintaining
proper NK response,” the authors concluded.
Another study from Angstwurm et al.9, found that “d-dimer plasma levels strongly correlated with the severity of the disease and organ dysfunction in patients with circulatory impairment or infections.” Importantly, this suggests that elevated d-dimer levels may reflect the extent of microcirculatory failure.
Thus, the mounting evidence shows that lowering Hcy, through supplements like Ocufolin®, might not only reduce the risk of progression of chronic eye disease — they might also support the immune system in the fight against viral infections, like COVD-19.
1 AREDS2 Research Group; Chew EY, Clemons T, SanGiovanni JP, et al. The AgeRelated Eye Disease Study 2 (AREDS2): study design and baseline characteristics (AREDS2 report number 1). Ophthalmology. 2012;119(11):2282-2289.
2 Ajith TA, Ranimenon. Homocysteine in ocular diseases. Clin Chim Acta. 2015;23 (450):316-321.
3 Schmidl D, Howorka K,Szegedi S, et al. A pilot study to assess the effect of a threemonth vitamin supplementation containing L-methylfolate on systemic homocysteine plasma concentrations and retinal blood flow in patients with diabetes. Mol Vis. 2020;26:326-333. eCollection 2020.
4 Wang J, Brown C, Shi C, et al. Improving diabetic and hypertensive retinopathy with a medical food containing L-methylfolate: a preliminary report. Eye Vis. 2019; 6:21
5 Shi C, Wang P, Airen S, et al. Nutritional and medical food therapies for diabetic retinopathy. Eye Vis. 2020; 7:33.
6 Guidance on the scientific requirements for health claims related to the immune system, the gastrointestinal tract and defence against pathogenic microorganisms. EFSA Journal. 2016;14 (1): 4369
7 Ponti G, Ruini C, Tomasia A. Homocysteine as a potential predictor of cardiovascular risk in patients with COVID-19. Med Hypotheses. 2020;143:109859.
8 Bayer AL, Fraker CA. The Folate Cycle As a Cause of Natural Killer Cell Dysfunction and Viral Etiology in Type 1 Diabetes. Front Endocrinol (Lausanne). 2017;8:315.
9 Angstwurm MWA, Reininger AJ, Spannagl M.D-dimer as marker for microcirculatory failure: correlation with LOD and APACHE II scores. Thromb Res. 2004;113(6):353-359.
| Sept/Oct 2020 9
Safe and Effective Laser Therapies Targeting Retinal Diseases Amidst COVID-19
In this time of uncertainty, one thing is certain (at least in ophthalmology): Retinal pathologies are not going anywhere.
In fact, chronic conditions like agerelated macular degeneration (AMD) and diabetic retinopathy (DR) are thought to be causing more concerns during this period of worldwide lockdown and social distancing. Either out of safety concerns, or because their doctor’s practice is closed, some patients are not visiting clinics for screening, diagnosis, monitoring or treatment — all of which can lead to sight-threatening vision loss.
As a result, laser is stepping up as a popular (yet, perhaps underutilized) treatment modality for retinal pathologies. Indeed, doctors and patients alike are turning toward laser to reduce repeated in-person office visits — which are required for effective anti-vascular endothelial growth factor (VEGF) treatment.
To learn more, Quantel Medical, an ophthalmic laser manufacturer based in Cournon-d’Auvergne, France, sponsored a recent webinar called Modern Laser Therapy for the Treatment of Retinal Diseases, which addressed the benefits of laser from two retinal specialists, Drs. Kenneth Fong and Victor Chong.
Peripheral treatments: Best cases for laser
Now that patients are making fewer visits to eye clinics, Dr. Fong, from OasisEye Specialists in Kuala Lumpur, Malaysia, suggests that retinal laser should be considered to reduce further risk in patients with diabetic retinopathy (DR) and associated conditions.
While Dr. Fong notes that the older versions of PRP (panretinal photocoagulation) could cause severe anatomical damage to the peripheral retina, he says the newer PRP has several benefits. “It’s really considered a cure,” said Dr. Fong. “Thanks to multi-spot laser technology, we can complete the entire PRP treatment in one session, without the need for further anti-VEGF injections.”
“Given the chronic nature of proliferative diabetic retinopathy (PDR) and the intravitreal half-life of antiVEGF drugs currently in use, the main disadvantage of anti-VEGF monotherapy for PDR is that these drugs need to be administered periodically,” said Dr. Fong. “Interruption of treatment can be catastrophic and may lead to irreversible blindness.”
Macular laser: Comparing apples and oranges
Not all lasers are created equal — and as the technology has advanced so has the understanding in regard to safety and efficacy. And indeed, finding the balance between delivering more energy, but with less anatomical damage, is crucial to positive outcomes.
by Brooke Herron
From conventional laser, the evolution to Endpoint Management (PASCAL; Topcon, California, USA) decreased the power and duration, said Dr. Chong, from London Medical and the Royal Free Hospital in London.
“However, this modality offers a very small therapeutic window, so you have to be very precise: Too much energy and there is damage, too little and you cannot see the benefits.”
Additionally, this modality shows scarring on optical coherence tomography (OCT), fundus fluorescein angiography (FFA) and autofluorescence (AF).
“This is why, for many years, we have been working on a system that can deliver more energy with less damage thanks to a pulsed laser delivery mode,” he said. “The good thing about SubLiminal is that you don’t kill any cells — or at least you aim not to.”
Meanwhile, the SubLiminal laser from Quantel Medical has the energy to target the RPE and is effective without scarring on OCT, FFA and AF. Thus, according to Dr. Chong, SubLiminal threshold laser may hold the key. “We have previously published that using
| Sept/Oct 2020 10 LASER THERAPY POSTERIOR SEGMENT
SubLiminal Laser Technology
this type of methodology improves retinal sensitivity and reading speed,” he shared, adding that there are multiple papers on the safety and efficacy of SubLiminal laser.
“SubLiminal laser has a long track record, and over the years we have improved the protocol and we can show the clinical benefit,” shared Dr. Chong.
He also briefly discussed the selective retinal therapy laser (2RT; Nova Eye, California, USA), which he noted has a very short duration of 3 nanoseconds. However, it can also produce some scarring, which can be seen on OCT, FFA and AF.
Digging deeper into SubLiminal laser therapy
Dr. Fong helpfully summed up the SubLiminal laser treatment guidelines as follows: 577 nm wavelength; 160 µm spot size; 5% duty cycle; 0.2 second exposure time. Since there is no intended thermal injury using SubLiminal laser, “the key is doing a dense treatment, using a large spot size of 160 µm,” explained Dr. Fong, adding that the most important step is power titration, as every patient is different. “Once the thermal threshold is achieved, the power should be reduced by 50%, and then the laser should be performed,” he said.
As far as efficacy, SubLiminal laser is ideal for patients with non-center
involving macular edema because those areas can be treated easily. “For those with fovea-involving, I would usually give anti-VEGF first to reduce the thickness, and then I would supplement it with laser. At one month after anti-VEGF, we are ready to treat the remaining thickened areas, avoiding the fovea at all times.”
SubLiminal laser treatment can also be used in chronic CSC (central serous chorioretinopathy) and is an alternative to mid-fluence PDT (photo dynamic therapy) in first-line treatment.
“For DME patients, I just use an OCT thickness map,” he continued. “For patients with CSC, you need indocyanine green angiography (ICGA) for complex cases or FA-guided (for simple cases) because it’s important to be precise of where you are treating.”
So, how long does it take to see improvement following treatment? For DME patients, it takes a minimum of about 3 months; for CSC, the result is much faster, at about 6 weeks.
Expanding clinical applications
According to Dr. Chong, SubLiminal laser therapy may be trending toward increased uptake. The therapy is already established as effective and safe for treating DME and CSC. It can also be used in branch retinal vein occlusion (BRVO) — although in some
cases of BRVO it doesn’t always work, so it can be a supplement to anti-VEGF, noted Dr. Chong.
It has also been effective with macroaneurysms, but it is not applicable in cases of PDR for which multispot laser is the treatment of choice, he explained. It could also possibly be an option for nAMD patients who are nonresponsive to antiVEGF. “SubLiminal technology might be able to revitalize RPE cells and make them more responsive to antiVEGF treatment,” shared Dr. Chong.
There is some evidence that SubLiminal laser could work in PCV (polypoidal choroidal vasculopathy), but it would likely need anti-VEGF in combination. “But if you catch some of the earlier polyps with laser, then that certainly seems to work,” he continued.
Regarding applicability to drusen, Dr. Chong said that they are working on a study — but it’s currently on hold due to COVID-19, with plans to resume in the fall. However, he did point to some other smaller studies, one of which found that out of 30 cases, drusen load was reduced in 20 using SubLiminal laser.
“In summary, I think it’s very clear that in DME and CSC patients, it works. In BRVO and macroaneurysm, it seems to work — and it could possibly work in PCV and drusen. But, I don’t think it works in PDR,” concluded Dr. Chong.
The webinar, Modern Laser Therapy for the Treatment of Retinal Diseases, sponsored by Quantel Medical, was held on 22 nd June 2020. Reporting for this story also took place during the said event.
| Sept/Oct 2020 11
Images courtesy of Victor Chong
Outcomes of Anti-VEGF for Diabetic Macular Edema in Routine Clinical Practice
by Rod McNeil
Treatment outcomes observed in routine clinical practice are often inferior to those of clinical trials using the same intervention. Variable treatment patterns, more diverse patient presentations and missed or cancelled appointments may all contribute to poorer results in real life.
Randomized, controlled trials demonstrate that treatment with intravitreal anti-vascular endothelial growth factor (VEGF) therapy can reduce edema, improve vision and prevent further visual loss in eyes with diabetic macular edema (DME). Through one year, continued treatment with anti-VEGF agents generally yielded substantial improvement in mean visual acuity (VA) with one third or more of patients gaining at least 15 letters in vision (3 lines) from baseline.
Let’s take a closer look at recentlypublished evidence from well-designed observational studies of real-world outcomes in patients treated with antiVEGF for DME.
The United States
Real-world DME patients in the United States receive fewer injections and achieve worse vision outcomes compared with patients in clinical trial settings.1 Among 28,658 treatmentnaïve eyes treated with anti-VEGF for DME from 2013 to 2018, mean VA improved by 4.2 letters with a mean of 6.4 injections over one year. Outcomes improved with increasing injection frequency, reaching a plateau at 9 or more injections.
The global LUMINOUS observational study of treatment-naïve patients with DME revealed a one-year mean vision gain of 3.5 letters (n=502) from a mean baseline VA of 57.7 letters, with a mean of 4.5 ranibizumab 0.5mg injections.2 Significantly larger VA gains were recorded in patients who received 5 or more injections compared with those receiving ≤4 injections, particularly in those receiving a monthly loading schedule (Figure 1). The mean change in VA was highest in patients from the UK (+6.9) who received a mean of 6.0
injections. Variable access to funded care, with many paying for their own treatment, and delays in follow-up presentations, all impacted injection frequency, noted investigators.
The United Kingdom
A recent retrospective cohort study from Moorfields Eye Hospital in London evaluated aflibercept therapy for DME (99 eyes of 89 patients).3 A majority (86%) received the recommended
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56.6 59 58.1 57.7 6.9 9.7 3.5 0 20 40 60 80 ≤4 injections (n=264) ≤5 injections (n=238) 5-7 injections, with loading phase (n=118) Global 4.5 injection (n=502) Mean VA (ETDRS) letters Baseline VA Mean VA M12 0.5 ≤
Figure 1. LUMINOUS study of effectiveness of ranibizumab in DME over 12 months: greater vision gains achieved in patients who received ≥5 injections, particularly with a loading phase.
DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study; M12, month 12; VA, visual acuity. Adapted from Mitchell P, et al. PLoS ONE. 2020.
treatment initiation of 5 consecutive monthly injections, reflecting good compliance with the product label regimen. The total cohort received a mean of 6.9 injections through 12 months, with a mean of 7.4 and 6.6 injections, respectively, in subgroups with baseline best-corrected visual acuity (BCVA) <69 letters and ≥69 letters.
Mean (standard deviation [SD]) BCVA at presentation was 59.7 (16.1) ETDRS letters and the mean improvement in vision at month 12 were 9.9 letters. Even better outcomes were seen in the subgroup with baseline BCVA <69 letters (66% of the total study population), where mean BCVA improvement at month 12 was 13.8 letters. A gain of 2.6 letters was observed in the subgroup having baseline BCVA ≥69 letters (34%), reflecting a ceiling effect related to starting vision, but this group overall secured better final VA. Overall, 34% of eyes gained ≥15 letters through month 12 and 97% maintained vision (i.e., losing <15 letters from baseline).
A previous study at Moorfields Eye Hospital assessed 12-month outcomes with ranibizumab for DME involving 200 eyes of 164 consecutive patients, demonstrating outcomes comparable to those from clinical trials.4 Treatment was initiated with three monthly injections, followed by as needed retreatment based on OCT and visionrelated criteria. From a mean (SD) VA at baseline was 54.4 (±15.26) letters, there was a mean letter improvement of 6.6 (±13.35), and 25.1% gained at least 15 letters, with an average of 7.2 (±2.3) injections, over 12 months.
Improvements in functional and anatomic outcomes over 12 months were also observed in both treatmentnaïve and previously treated patients with DME treated with aflibercept in French clinical practice, according to an interim analysis of the APOLLON study.5 At month 12, the mean (SD) change in BCVA was +7.8 (12.3) letters from baseline BCVA (SD) of 62.7 (14.3) for treatment-naïve patients, and +5.0 (11.3) letters from baseline BCVA of 60.0 (13.7) letters in previously treated
patients. Mean CRT decreased in both patient cohorts, with a total mean reduction of 133.2µm for the overall population.
While patients in APOLLON received a mean of 7.6 injections over the year, which is close to the label regimen for aflibercept, less than half of the cohort completed the full 5 initial doses within the first 5 months. Among the treatment-naïve cohort, greater VA gains were achieved in those who received initial treatment with 5 monthly loading doses (51.9%, n=40) compared with those who did not (48.1%, n=37); change in mean (SD) BCVA was +8.4 (13.98) vs. +7.2 (10.4), respectively. The proportion of three-line gainers was also markedly higher in those receiving treatment initiation with 5 monthly doses (35% vs. 24.3%, respectively, for those with and without the full loading phase).
Figure 2 charts reported outcomes from Moorfields Eye Hospital and French clinical practice alongside results from the aflibercept DME registration studies and the DRCR.net Protocol T study.
Among study eyes with a baseline VA < 69 letters in the DRCR.net Protocol T study, the mean (±SD) letter score improvement at 1 year was 18.9 ± 11.5 for aflibercept and 14.2 ± 10.6 for ranibizumab, with a median of 9 and 10 injections, respectively.6
Both ranibizumab and aflibercept improved vision and decreased macular thickness in a cohort of treatment-naive eyes with DME (n=383) from the Fight Retinal Blindness! Registry [Bhandari 2020].7 In eyes with baseline VA of 20/50 or worse, mean change in VA from baseline to month 12 was +10.6 letters in the aflibercept group and +7.6 letters in the ranibizumab group (mean difference +3 letters, P <0.01). Aflibercept-treated eyes received a median of 8 injections compared with 6 injections in the ranibizumab group.
“Clinical trials give us the ideal results in terms of treatment efficacy and
DME, diabetic macular edema; DRCR.net, Diabetic Retinopathy Clinical Research Network; ETDRS, Early Treatment Diabetic Retinopathy Study; M12, month 12; MEH, Moorfields Eye Hospital; RCT, randomized clinical trial; RW, real world; VA, visual acuity.
Adapted from: Korobelnik JF, et al. Graefes Arch Clin Exp Ophthalmol. 2020; Lukic M, et al. Eur J Ophthalmol. 2020; Korobelnik JF, et al. Ophthalmology. 2014; The Diabetic Retinopathy Clinical Research Network. N Engl J Med. 2015.
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Baseline VA Final VA M12 67.2 61.4 67.9 52 65.8 75 77.6 59.7 69.6 69.5 59.4 70.1 78.4 65 58.8 64.9 60 70.5 0 10 20 30 40 50 60 70 80 Mean VA ETDRS letter score APOLLON RW Treatment naive (n=77) MEH RW <69 ETDRS letters (66%) MEH RW Overall (n=99) VIVID RCT DRCR.net Protocol RCT VISTA RCT MEH RW ≤69 ETDRS letters (34%) APOLLON RW Overall (n=147) APOLLON RW Previously treated (n=70)
Figure 2. Real-world one-year outcomes of aflibercept for DME in France and the UK compare favorably to landmark clinical trials.
safety that we might strive to achieve with practical protocols in the real world,” observed Dr. Marko Lukic, consultant ophthalmologist, Moorfields Eye Hospital, London, speaking in a telephone interview with the author.
He added: “The approach to antiVEGF dosing regimen in the first year of treatment is important in order to achieve maximum visual improvement early on. Using aflibercept for DME, we start with 5 initial monthly injections, which is our loading phase, followed by 3 bimonthly injections after loading for
most patients and then retreatment as needed beyond year one.”
A further real-life study of aflibercept for treatment-naïve DME at Moorfields showed significant improvements in VA and anatomical outcomes sustained over 36 months of follow-up (n=64 eyes).8
From a mean (SD) baseline VA of 61.45 (16.30) letters, the mean VA gain was 6.89 letters and one quarter of eyes gained ≥15 ETDRS letters through 36 months. Patients received a mean of 12.59 injections over the 3 years, with fewer than 3 injections in years 2 and 3.
Resolution of edema and VA response continue to improve in most DME cases through 6 months of consecutive monthly anti-VEGF injections.6 A review of VIVID and VISTA DME outcomes among aflibercept-treated patients (n=576) demonstrated a continuous improvement in BCVA throughout the monthly loading schedule (Figure 3).9 Moreover, patients are unlikely to lose vision if treated intensively at the start and given subsequent injections or laser treatments as needed to achieve stability.10
• Real life patients with DME differ from participants in clinical trials and are often undertreated in everyday practice
• Vision gains are greater in patients treated with the recommended initiation protocol of monthly loading
• Patients with higher baseline VA often achieve the best final vision at one year, illustrating the benefit of early intervention
• Same-day injections for patients with bilateral DME may alleviate overall attendance burden and improve adherence
• Rapid improvements in vision may be maintained longer term, with a reduced retreatment burden over time
BCVA, best-corrected visual acuity; DME, diabetic macular edema; ETDRS, Early Treatment Diabetic Retinopathy Study.
Adapted from Ziemssen F, et al. Int J Retina Vitreous. 2016.
1 Ciulla TA, Pollack JS, Williams DF. Visual acuity outcomes and anti-VEGF therapy intensity in diabetic macular edema: a real-world analysis of 28 658 patient eyes. Br J Ophthalmol. 2020. pii: bjophthalmol-2020-315933. [Epub ahead of print]
2 Mitchell P, Sheidow TG, Farah ME, et al, LUMINOUS study investigators. Effectiveness and safety of ranibizumab 0.5 mg in treatmentnaïve patients with diabetic macular edema: results from the real-world global LUMINOUS study. PLoS One. 2020;15(6):e0233595.
3 Lukic M, Williams G, Shalchi Z, et al. Intravitreal aflibercept for diabetic macular oedema: Moorfields’ real-world 12-month visual acuity and anatomical outcomes. Eur J Ophthalmol. 2020;30(3):557-562.
4 Patrao, NV, Antao, S, Egan, C, et al. Real-world outcomes of ranibizumab treatment for diabetic macular edema in a United Kingdom National Health Service setting. Am J Ophthalmol. 2016;172:51–57.
5 Korobelnik JF, Daien V, Faure C , et al. Real-world outcomes following 12 months of intravitreal aflibercept monotherapy in patients with diabetic macular edema in France: results from the APOLLON study. Graefes Arch Clin Exp Ophthalmol. 2020;258(3):521-528.
6 The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372:1193-203.
7 Bhandari S, Nguyen V, Fraser-Bell S , et al. Ranibizumab or aflibercept for diabetic macular edema: comparison of 1-year outcomes from the Fight Retinal Blindness! Registry.
Rod McNeil is an independent medical journalist.
8 Lukic M, Williams G, Shalchi Z, et al. Intravitreal aflibercept for diabetic macular oedema in real-world: 36-month visual acuity and anatomical outcomes. Eur J Ophthalmol. 2020;30(3):557-562.
9 Ziemssen F, Schlottman PG, Lim JI, et al. Initiation of intravitreal aflibercept injection treatment in patients with diabetic macular edema: a review of VIVID-DME and VISTA-DME data. Int J Retina Vitreous. 2016;2:16.
10 Bressler NM, Beaulieu WT, Glassman AR, et al, Diabetic Retinopathy Clinical Research Network. Persistent macular thickening following intravitreous aflibercept, bevacizumab, or ranibizumab for central-involved diabetic macular edema with vision impairment: a secondary analysis of a randomized clinical trial. JAMA Ophthalmol. 2018;136:257-269.
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Gain ≥5 letters Loss ≥5 letters 59.8 2.6 18.6 16.3 14.6 14.4 7.1 6.8 Proportion (%) of eyes that gained or lost ≥5 ETDRS letters 0 10 20 30 40 50 60 70 Week 4 Week 8 Week 12 Week 16 Week 20 8.5 8
Figure 3. In VIVID and VISTA, the proportion of aflibercept-treated eyes that gained or lost ≥5 letters in BCVA compared with the previous visit during the initial monthly loading phase (n=576), showing rapid, continuous vision improvement.
DME TREATMENT POSTERIOR SEGMENT
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Retinopathy of Prematurity Fine-tuning Current Treatments to Optimize Patient Outcomes
by Olawale Salami
Each year, up to 20,000 newborn infants worldwide face the grim risk of blindness due to retinopathy of prematurity (ROP). ROP poses an even greater challenge in low income countries in South Asia Sub-Saharan Africa, due to higher numbers of preterm births coupled with inadequate neonatal care. Therefore, research into understanding the limits of existing treatments in different stages of ROP and patient populations is urgently needed.
VEGFs in retinal hyperoxia: More harm than good?
Research and development into new drugs to prevent ROP-associated blindness has gained attention globally in the last decade with the increasing understanding of the vital role of growth factors, like vascular endothelial growth factor (VEGF) in normal physiologic and pathologic retinal angiogenesis. Thus, inhibition of VEGF using anti-vascular endothelial growth factors (anti-VEGF) such as bevacizumab, ranibizumab and aflibercept administered via the intravitreal route, has been shown to reduce retinal non-perfusion and consequent neovascularization, demonstrated by numerous clinical studies. In many countries, anti-VEGFs have become the primary mode of treatment for ROP over traditional laser photocoagulation to the avascular retina.
The variations in retinal oxygen levels in preterm infants and the role of retinal hyperoxia in ROP underscores the importance of studying available VEGFs in different scenarios of retinal perfusion. Dr. Swati Agarwal-Sinha, Dr. W. Clay Smith and their team of
researchers at the Department of Ophthalmology, University of Florida College of Medicine, have been studying the effects of aflibercept on retinal
blood vessels exposed to a hyperoxic state. Their findings were published recently in the peer-reviewed journal Ophthalmic Research titled Efficacy of Aflibercept Treatment and its Effect on the Retinal Perfusion in the OxygenInduced Retinopathy Mouse Model of Retinopathy of Prematurity.*
Their research was driven by existing knowledge gaps in previous work in the field which showed that although aflibercept promoted neovascular tuft regression, higher doses inhibited normal retinal revascularization, and potentially led to permanent changes in neuroretinal structures. The causes of
this seemingly paradoxical effect, according to the publication, could be related to differences in capacities of VEGF to vitreous and retinal tissues.
Furthermore, differential effects of how aflibercept blocks VEGF in physiological, compared to pathological, angiogenesis could may be important. But what if it’s related to how much aflibercept is administered? Could there be a dose relationship that is critical in determining the trajectory of aflibercept-induced retinal nonperfusion? According to Dr. AgarwalSinha: “One of the questions that needs to be addressed is the effective dosage of the anti-VEGF used and its effects on physiological angiogenesis.”
Finding the right dose
To understand the differences in retinal nonperfusion at varying doses of aflibercept, Dr. Agarwal-Sinha and her team designed experiments using a well-characterized oxygeninduced retinopathy (OIR) model in mice. The purpose of their study was to determine if a lower dose of aflibercept could lead to significant reduction in areas of nonperfused retina, while simultaneously preserving normal retinal vascular angiogenesis in the OIR mouse model. The team focused on areas of nonperfusion, as these represent the driving factor for
| Sept/Oct 2020 16 ROP TREATMENT POSTERIOR SEGMENT
VEGF production and consequent neovascularization.
In this study, Dr. Agarwal-Sinha and team assigned newborn mice to two groups: a control group in which mice were exposed to room air; and a hyperoxia group, where mice were exposed to 75% oxygen. Subsequently, 14 days after birth, (PN14) the mice in the hyperoxia group were then assigned to 3 different groups, with each group given one of three intravitreal doses of aflibercept: 0 ng, 100 ng or 1000 ng.
observed until 11 days post-treatment (PN25 group).
Dr. Agarwal-Sinha emphasized: “Screening and providing treatment for retinopathy of prematurity has gained awareness around the world in preventing blindness. Anti-VEGF injections are now used primarily for the treatment of type 1 ROP, taking precedence over the traditional laser photocoagulation.”
“Though anti-VEGFs regress the neovascularization, they also inhibit the physiological angiogenesis of the normal retinal vasculature, which is seen as persistent avascular retina post-treatment,” said Dr. AgarwalSinha.
Furthermore, she said: “The study enforces the need for precise titration of anti-VEGF dose to balance inhibition of neovascularization with retinal nonperfusion, and longer observation after anti-VEGF treatment to evaluate its effect on vascular recovery and physiological angiogenesis.”
Randomized clinical trials in patients across many countries have recently commenced to study the efficacy of aflibercept in the treatment of ROP.
Non toxic intraocular dye for ILM and ERM staining
Eyes were evaluated at PN17 and PN25 post-injection using a variety of imaging techniques. The results, according to Dr. Agarwal-Sinha and colleagues show a significant reduction of retinal nonperfusion at PN25 in mice given both the 100 ng and 1000 ng aflibercept doses. However, it was the 100 ng aflibercept treatment group at day 11 postinjection which displayed vascular recovery and preserved physiologic angiogenesis, when compared to the 100 ng and 1000 ng treated groups at day 3 post-injection. The higher dose 1000 ng aflibercept treatment group did not show a significant difference in nonperfusion. The data showed that treatment with aflibercept can reduce nonperfusion of retinas exposed to hyperoxia in the mouse model of OIR, although treatment effects may not be
Swati Agarwal-Sinha , MD, is an associate professor in the Department of Ophthalmology and the chief of Retinopathy of Prematurity (ROP) Services in the J. Hillis Miller Health Science Center, UF College of Medicine (Gainesville, Florida, USA). Her research interests include anti-angiogenesis treatments and retinal imaging (ocular coherence tomography, fluorescein angiography) in retinopathy of prematurity and pediatric retinal diseases.
(Pure benzyl-Brilliant Blue) LUTEIN based intraocular dyes
* Amin S, Gonzalez A, Guevara J, et al. Efficacy of Aflibercept Treatment and its Effect on the Retinal Perfusion in the Oxygen-Induced Retinopathy Mouse Model of Retinopathy of Prematurity. Ophthalmic Res. 2020. [Online ahead of print.]
The study enforces the need for precise titration of anti-VEGF dose to balance inhibition of neovascularization with retinal nonperfusion, and longer observation after anti-VEGF treatment to evaluate its effect on vascular recovery and physiological angiogenesis.
- Dr. Swati Agarwal-Sinha
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Now while we wouldn’t recommend using Doc Brown’s manner when communicating with patients, what is certainly true, however, is that there’s plenty being done in the retina field today. Retina is all the rage — innovative technologies are emerging and new treatments offer a tantalizing taste of future advancements. It’s an exciting time to work in the retina segment.
More exciting than a time traveling DeLorean? You better believe it, the developments taking place will
leave you spinning around like the aforementioned DeLorean’s licence plate. Indeed, if you had an actual time machine, this would be a good period to return to in the future, if someday you felt the need for buzz and excitement.
Good things often come in threes (like the Back to the Future film trilogy) and the same applies to the retina field today. The most exciting developments are mainly found in medical retina (such as gene therapy), imaging devices and new technologies. That’s not to say there aren’t innovations in other areas of course, but this tech triumvirate is what excites us the most.
Why are we so excited about these three areas of the retina field? It comes down to two factors: the huge impact these technologies and techniques will have on patient outcomes (both medically and socially), and their promise as a
launching pad for further progress. Gene therapy serves as a good example.
Gene therapy is allowing ophthalmologists to treat eye conditions in ways that wouldn’t have been thought possible 10 years ago; it can prevent hereditary blindness, improve visual acuity (VA), and is propelling the development of advanced drugs. Developments in imaging are providing patients with advanced screening methods across further distances than previously thought possible. Artificial intelligence (AI), along with its close relatives augmented reality (AR) and virtual reality (VR), are revolutionizing prosthesis production, surgery, and a variety of other areas.
All in all, it’s a veritable smorgasbord of science — a plerotha of advances that Doc Brown himself would be proud of.
“It’s your retina Marty, something’s got to be done about your retina!”
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Are you telling me you built a time machine?
Recent developments are all the more remarkable when you view them through the lens of history. If we are to head back to the future (see what we did there?), we must also remember how far we’ve already traveled. Ophthalmology is one of the oldest medical disciplines, with records of treatment going back more than 4,000 years.
Indeed, the earliest recorded mention of a medical issue comes from Hammurabi, a king of the ancient Babylonian civilization. In 2550 B.C. King Hammurabi propagated laws on ophthalmology, more specifically, on malpractice.1 For example, according to the king’s law, if a physician opens an abscess in their patient’s eye with a bronze lancet and saves the eye, they are to be rewarded with ten shekels.
However, if the physician destroyed the eye instead — by accident or negligence — then they would lose their fingers. Ouch.
As a speciality, retina is young and owes much of its existence to increased life expectancies. According to the Retina Research Foundation, at the turn of the 20th century, retinal diseases were not frequently encountered, as lifespans in the West averaged around 49 years.2 As people began to live longer, retinal diseases began to be encountered more frequently.
Ever since Jules Gonin introduced his Iginipuncture in 1919, retina treatment has improved exponentially. Robert Machemer would go on to develop vitreous surgery in 1972; retinal tacks implantation would follow a decade later — and now treatments like antivascular endothelial growth factor therapy (anti-VEGF) have become highly popular and effective.3
The development of retina has been spurred by aging populations across the globe and by diseases caused by lifestyle choices, like diabetic retinopathy. This means that a once rarely encountered mystery, retina is now one of the greatest focuses of ophthalmology.
The future of medical retina
Indeed, the explosion in the number of retinal issues is not just a medical phenomenon, it is also sociological in nature. We don’t need finger-chopping Hammurabi to make us realize that the medical impact on retina conditions is important. For Dr. Ashish Sharma, an ophthalmologist at the Lotus eye Hospital and Institute in Tamil Nadu, India, brolucizumab (Beovu; Novartis, Basel, Switzerland) is symbolic of the issue.
“We have many promising original molecules in the pipeline and gene therapy has shown signs of advancement. However, I still feel that gene therapy has a long way to go,” Dr. Sharma said.
“If brolucizumab can find a way out to control retinal vasculitis it could be a transformational change. The biggest impact the molecule can have is the reduced frequency of injections. Frequent hospital visits are not only a financial burden for the patient and healthcare system, it also takes a major portion of the chair time for retinal physicians,” he said.
With innovation comes risk, and brolucizumab has come into its own share of controversy after 14 patients using the drug in a trial were diagnosed with vasculitis. Novartis was quick to emphasize its overall safety, and Dr. Sharma’s own brolucizumab study argues in favor of its safety, with reports showing safety and efficacy in stabilizing best corrected visual acuity (BCVA) in patients.4
Dr. Hudson Nakamura, from the Brazilian Center for Eye Study, believes other medicines deserve greater attention. One such is Luxturna (voretigene neparvovec-rzyl; Spark Therapeutics, Pennsylvania, USA), a gene therapy medication used to treat inherited retinal disease. According to one study, Luxturna offers a favorable benefit-to-risk profile with similar improvement demonstrated in navigational ability and light sensitivity, however, observation will be required for four years.5
“The second is abicipar pegol — DARPin — a naturally occurring protein that can be used to treat age-
related macular degeneration (AMD) complications. Studies compared the drug with ranibizumab showed that the endpoint results were satisfactory, despite inflammation issues,” Dr. Nakamura said.
“Still, it was not enough for the drug to be approved by the U.S. FDA, citing a benefit-risk ratio for its approval. However, we cannot give it up as more studies and products are being tested,” he added.
A revolution in imaging
Optical coherence tomography (OCT) imaging is hardly new (it was first presented at a conference in 1990), but it is undergoing revolution. A number of studies are examining the use of deep learning AI in OCT to provide more accurate and detailed diagnoses than previously possible. For Dr. Sharma, this combination of OCT and AI is highly promising.
“Shortcomings such as speed, artifacts and area of imaging have now improved, thanks to better wavelengths with swept-source (SS-OCT). It will help us to better understand the pathology of diseases, such as AMD and diabetic retinopathy,” Dr. Sharma said.
“It is a revolution and retina specialists cannot afford to miss out on using it, as it might help us to make better decisions about the futility aspect, an emerging concept in AMD,” he added.
SS-OCT is a variation of OCT and includes hardware that differs in several ways, including the light source, bulk optics components and photodetection device. SS-OCT utilizes a point photodetector, whereas SD-OCT uses a spectrometer consisting of a diffraction grating, Fourier transform lens, and a detector array.6
iOCT systems are basically adaptations of OCT systems to be used specifically during surgery. iOCT images are usually displayed live and some dynamic information is also revealed including movement of tissues when force is applied.7
Dr. Sharma’s views are echoed by Dr. Cynthia X. Qian, head of the
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electrophysiology laboratory and pediatric retina service at the University of Montreal, Canada. She views OCT as a catalyst in more than just patient treatment and diagnosis. She believes that OCT-based technology will have farreaching consequences for ophthalmic education.
“Intraoperative OCT (iOCT) and 3D heads-up display [which uses a microscopic image on a panel display sent from a 3D camera during surgery] are two of the imaging modalities that I currently use in my vitreoretinal surgeries, they are very useful and I find them to be enjoyable,” said Dr. Qian.
“They provide new unparalleled imaging information which was previously unavailable, and wonderful image documentation for future review of surgical cases, allowing for in-depth analysis and learning opportunities after the actual surgery itself,” she said.
This represents a cyclical approach where data gathered via OCT is used to educate new ophthalmologists, who then go on to use the equipment and continue the cycle. Simply put, it’s a little bit like going “back to the future” . . . and it’s not the only fascinating concept to emerge from the academic sphere.
Are we going to get bionic eyes?
In June this year, a group of scientists at the Hong Kong University of Science and Technology (HKUST) announced that they had developed the world’s first 3D artificial eye. A remarkable achievement in and of itself — but the scientists also claim that the eye’s capabilities are better than existing bionic eyes — and could even exceed those of regular human eyes.8 So, can we expect to see widely available 3D eyes in the next decade?
“Let’s stick with reality, we already have very good 3D visualization with wide angle vitrectomy viewing systems, as well as 3D heads-up vitrectomy. This is already a great advance in and of itself,” said Dr. Nakamura.
A 3D eye, with an accompanying 3D retina, represents extraordinary progress, but compared with AI, it’s very much stuck back in 1985, regardless of the HKUST study. Where 3D holds tremendous future potential, AI is already having an impact in the retina field. While it’s not surprising to learn that AI is being used in operating theatres and research labs, the data aspect of the technology is also proving beneficial to ophthalmologists.
“I was very impressed by the data shown by Google AI, which showed that while studying diabetic retinopathy and large data sets of retinal fundus images, the deep learning algorithm was able to detect information such as an individual patient’s gender, age, smoking-status and 10-year risk of cardiovascular diseases,” said Dr. Qian.
“I think this is an immensely powerful tool that shows great promise in more areas than we can anticipate as of yet,” she added.
This demonstrates the broad applicability and appeal of AI as it can be utilized by ophthalmologists in a variety of circumstances. We should drop the mindset of viewing AI simply as robotics, even when it pertains to surgery. AI has far more applicability than medical haemonculi, and robotic surgery itself may be too far off, according to Dr. Nakamura.
“If we compare today’s technology to 30 or 35 years ago, we are in the best times of retina and vitreoretinal surgery. Robotic surgery is too far ahead for us to think about right now,” Dr. Nakamura said.
2020’s Favorite words
If Marty McFly was to pilot his DeLorean to this point in time and ask an ophthalmologist what the biggest developments have been in the last 12 months (beyond the aforementioned triumvirate) the answer would likely be two-fold. The first would be
telemedicine, and the second would be anti-VEGF. Indeed, these two terms have become buzzwords.
Telemedicine is the word of 2020 thanks to coronavirus, while antiVEGF treatment represents one of the most exciting developments in retina specifically, and in ophthalmology in general. Every single conference this year had seminars and symposia on the subject. Similar to some of the other issues we’ve covered, anti-VEGF holds more than just potential for physicians — according to many clinicians, it could have a beneficial impact on wider society too.
“The use of anti-VEGF to treat vascular conditions of the retina over the past decade-and-a-half has had the largest impact on our field and made a positive difference and quality-of-life in the lives of millions of patients worldwide,” Dr. Qian said.
“The advent of anti-VEGF intravitreal injections has brought a big change during the last decade. With newer molecules on the horizon and biosimilar drugs on the edge of approval, treatment cost might come down. This may lead to better compliance towards the treatment especially in the developing world,” added Dr. Sharma. While the advantages of anti-VEGF treatment are numerous, some clinicians are sounding a note of caution. For Dr. Caroline Baumal from Tufts University Medical Center in Boston, Massachusetts, USA, anti-VEGF should be recognized as a great development, but they are still something of a work in progress.
“The efficacy and safety of the traditional anti-VEGF agents will be a high bar for new therapeutics to reach. Thus far, it appears that increasing the dose of some of the current anti-VEGF agents does not increase effectiveness,” Dr. Baumal said.
“As a result, the search for combination therapies, new molecules and sustained drug delivery to increase efficacy and durability continues. The concept of gene therapy to deliver a vector, which can lead to prolonged production of VEGF binding antibody, is also appearing,” she concluded.
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Dr. Hudson Nakamura is a medical specialist in ophthalmology and specializes in retina and vitreous. He completed a fellowship in vitreoretinal diseases in Canada at the University of Toronto, and another retinal fellowship in his hometown, Goiânia, Brazil, at the Brazilian Center for Eye Surgery. He completed his medical studies at the School of Medicine at the Federal University of Goiás – UFG, and was a resident at the Base Hospital of the Federal District in Brasília. He is currently a professor at the Department of Retina and Vitreous Course of Medical Residency in Ophthalmology at the Bank of Goias Eye Foundation. He is the founder of the Retinawesome meeting, which brings together retinal specialists and vitreoretinal surgeons around the world for discussions on many subjects in retina and retinal surgery. In addition, he is also a member of the Brazilian Council of Ophthalmology.
Dr. Cynthia X. Qian is an assistant professor in the Department of Ophthalmology and the head of the electrophysiology laboratory and the pediatric retina service at the University of Montreal, Canada. Dr. Qian completed medical school at McGill University. She completed her residency at the University of Montreal, where she was voted chief resident and graduated as the school valedictorian. She completed dual fellowships in surgical retina at the Massachusetts Eye and Ear Infirmary at Harvard Medical School in Boston, and in inherited
retinal diseases at the Kellogg Eye Center, University of Michigan. She is the current vice president of the Canadian Retina Society and the provincial representative for Quebec in ophthalmology at the Royal College of Physicians and Surgeons of Canada. She is a fellow of the Royal College of Physicians and Surgeons of Canada and of the American Academy of Ophthalmology, and a member of the Canadian Ophthalmological Society, the Association for Research in Vision and Ophthalmology, the American Society of Retina Specialists, and the Pan-American Association of Ophthalmology.
Dr. Caroline R. Baumal is a professor of ophthalmology and director of retinopathy of Prematurity Service at the New England Eye Center at Tufts Medical Center in Boston, Massachusetts. She specializes in diseases and surgery of the retina and vitreous. Her research interests include novel retinal imaging and drug development. Her clinical interests include age-related maculopathy, diabetic retinopathy, complex vitreoretinal surgery and retinopathy of prematurity.
Dr. Baumal completed her medical school and ophthalmology residency at the University of Toronto after undergraduate studies at McGill University. She completed two fellowships: one at the New England Eye Center in medical retina and lasers and another in vitreoretinal diseases and surgery at Wills Eye Hospital in Philadelphia. Dr. Baumal is board certified by the American Board of Ophthalmology. She has received multiple awards from various societies including the American Academy of Ophthalmology, The American Society of Retinal Surgeons, The Retinal Hall of Fame, the
Donald J. Gass Beacon of Sight Award from the Florida Ophthalmologic Society and recently was awarded the Crystal apple award from the ASRS. She is on the editorial board for Retina Cases and Brief Reports and Ophthalmic Surgery, Lasers and Imaging (OSLI) Retina. Dr. Baumal has authored over 100 publications, 28 book chapters on retinal diseases and recently edited the book Treatment of Diabetic Retinopathy. She is actively involved in teaching vitreoretinal fellows and residents and was previously director of education and the residency program at the New England Eye Center.
Dr. Ashish Sharma is an ophthalmologist at the Lotus Eye Hospital and Institute in Coimbatore, Tamil Nadu, India. He previously held a position at the Prasad Eye Institute, Hyderabad, Andhra Pradesh, India and was a part-time faculty member at the University of California in Irvine, California. He received his MBBS degree from MGM Medical College, Indore, Madhya Pradesh, India, went on to become an intern and then a resident at Maharaja Yeshwantrao Hospital in Indore, before becoming a medical research and retinal fellow at the University of California and a research fellow at the Bascom Palmer Eye Institute, Miami, Florida. Dr. Sharma holds board certification from the Medical Council of India (MP5527) and is a member of the American Academy of Ophthalmology, the All Indian Ophthalmic Society and the Vitreo-Retina Society of India. He holds two patents, the Portable Fundus Imaging Device (MII Ret Cam) and the Smartphone-Based Imaging Device for the Diagnosis of Glaucoma.
1 Wheeler JR. History of Ophthalmology Through the Ages. Br J Ophthalmol. 1946; 30(5): 264–275.
2 Retina Research Foundation. History. Available from: https://retinaresearchfnd.org/about-rrf/history/ Accessed August 26, 2020.
3 Machemer R, Buettner H, Norton EW, Parel JM. Vitrectomy: A Pars Plana Approach. Trans Am Acad Ophthalmol Otolaryngol. 1971;75(4):813-820.
4 Sharma A, Kumar N, Parachuri N, et al. Brolucizumab — Early Real World Experience: BREW study. Eye (Lond). 2020 Jul 24. [Online ahead of print.]
5 Maguire AM, Russell S, Wellman JA, et al. Efficacy, Safety, and Durability of Voretigene Neparvovec-rzyl in RPE65 Mutation–Associated Inherited Retinal Dystrophy. Ophthalmology. 2019;126(9):1273-1285.
6 Cole ED, Duker JS. (2017, April 7). OCT Technology: Will We Be “Swept” Away? Review of Ophthalmology. Available from: www.reviewofophthalmology.com/ article/oct-technology-will-we-be-swept-away. Accessed August 27, 2020.
7 Tadayoni R. Intraoperative OCT: Would You Like Some Extra Information? Ophthalmol Retina. 2018;2(4):261-262.
8 Gu L, Poddar S, Lin Y, et al. A biomimetic eye with a hemispherical perovskite nanowire array retina. Nature, 2020; 581 (7808): 278
| Sept/Oct 2020 21
Seeing the Unseeable Innovations in Retinal Imaging
By the end of the 19th century, the first photograph of the human retina had been obtained . . . and since then, we’ve come a long way. Optical imaging has played a major role in our understanding of retinal and choroidal disease.
“We currently stand on the cusp of a revolution in retinal optical imaging with numerous recent advances, including OCT, OCTA, adaptive optics, SLO, fundus autofluorescence (FAF), photoacoustic microscopy (PAM), and molecular imaging,” noted Li et al., in a report titled Advances in Optical Imaging *
Below, we look at some of our old favorites, as well as some new standouts, in retinal imaging.
Optical coherence tomography (OCT)
has been widely adopted in ophthalmology. It allows for an unparalleled combination of high axial resolution (1–10µm) with appropriate tissue penetration depth (1–2mm in tissue)
Fluorescein angiography (FA)
is a vitally important diagnostic tool and has been the gold standard for the evaluation of patients with retinal disease — however, it is an invasive test and requires typically 10–15 min to obtain images. The author notes: “OCTA, in comparison, is a non-invasive technique and has the capability to image all layers of the vasculature.”
Swept-source OCT (SS-OCT)
is the latest development in OCT technology and enables deeper penetration, excellent axial resolution and fewer motion artifacts, to generate ultrahighdefinition B-scan images of the retinal microstructure.
| Sept/Oct 2020 22
I m a g e o f movingtissues,like fast c a rs, is hardtocapture . T h e SSOCTdoesthat(what the O C T cannot), sotospeak . I f o n ly the fluor scenceinFA is as e x t ra visible astheski o f thi ad... no more i nvasive issue
Scanning laser ophthalmoscopy (SLO) uses a single, monochromatic laser with low power and a confocal raster scanning technique to collect an image of the retina and optic nerve head. SLO images demonstrate higher contrast than standard fundus camera photos as they can reduce the effect of light scatter.
OCT angiography (OCTA) is a new, noninvasive imaging technique based on OCT imaging which allows for the visualization of the retinal and choroidal microvasculature without the injection of exogenous dyes.
“OCTA can clearly visualize and quantify nonperfusion, neovascularization, and the foveal avascular zone (FAZ) area change, which can be helpful to identify non-proliferative DR and macular ischemia in patients with DR.”
Photoacoustic microscopy (PAM) remains at an early stage in the development process. No clinically approved system exists for eyes, and all the photoacoustic imaging work in eyes has been performed in animals or in vitro,” noted the authors.
Fundus autofluorescence (FAF) imaging is a noninvasive imaging modality for in vivo mapping of naturally or pathologically occurring fluorophores of the ocular fundus.
Adaptive optics (AO) is an emerging discipline that seeks to improve the performance of an optical system by reducing the effects of wavefront distortions.
Lightandshade... and sound Capture that!
Molecular imaging (MI) is an area that combines retinal molecular biomarkers and advanced ocular imaging technologies and has the potential to visualize the earliest cellular and biochemical proces s before advanced retinal disease.
| Sept/Oct 2020 23
*Li Y, Xia X, Paulus YM. Advances in Retinal Optical Imaging. Photonics. 2018;5(2):9 [Epub 2018 Apr 27]
S t u d e n ts in t he ‘90s thoughttheelectron microsc o p e was the ‘bomb’inlookingat cell s i n
v i v o. Here comestheFAF... and the year i s 2020. “Theresomethingin your ey e ” su asadeeper m e aning... like omore dye s , ” says theO omelight- ye a rs away.
Taking Timely Action in DME with a Multimodal Approach
by Joanna Lee
Currently, the prevalence of diabetes in the United States is 30 million and that number is expected to increase dramatically over the next 10 to 20 years. Further, about 25 percent of these patients will develop diabetic retinopathy (DR) and 10 percent will develop diabetic macular edema (DME).
At the recently held Virtual American Society of Retina Specialists 38th Annual Meeting (ASRS 2020), a multimodal approach to manage DME was discussed by Dr. Nancy Holekamp, director of retina service at Pepose Vision Institute in St. Louis, Missouri, USA, and Dr. Arshad Khanani, director of clinical research at Sierra Eye Associates in Reno, Nevada, USA. Both shared their views and clinical experience using Ozurdex (dexamethasone intravitreal implant) to treat patients with DME.
Symposium Moderator Dr. Peter Kaiser from Cleveland Clinic in Ohio, USA, said DME patients are often of working-age and thus, can find it challenging to keep up with monthly or bimonthly clinical treatments.
The speakers began by detailing the usual way of treating DME patients (with persistent fluid during the first six months of diagnosis.
Dr. Holekamp said it’s important for patients to get injections for the first six months. “We don’t want to
undertreat because we don’t know if the treatment is really working or not,” she said. Apart from measuring visual acuity, she also believes in OCT as a primary biomarker for making decisions. Good foveal depression and a dry macula are factors that enhance patients’ chances of better vision, she said.
After the third or fourth month of injections, and if OCT results do not show any improvement, she would then discuss steroid treatment.
Experience with the first line of defense
Patients’ progress seems to hinge on their initial response to treatment.
The DRCR.net Protocol T study has shown that if a patient responds positively after the first three antiVEGF injections, this course of treatment would most likely be continued.
Dr. Khanani shared that he treats conservatively at first, moving from one anti-VEGF to another, only counseling patients to switch to other modes of treatment after six months.
“I think Protocol T is very helpful
| Sept/Oct 2020 24 TREATMENT REGIMEN INNOVATION DME TREATMENT
In DME tre a t m ent, timingiseverything .
in guiding treatment. If a patient has good vision, they probably have early disease, so it’s going to be a VEGF response. Protocol T tells us that patients do well with all the agents,” said Dr. Holekamp.
“But if someone has a really thick retina and extremely poor vision, you might as well start with aflibercept, as data suggests these eyes do better with it,” she continued.
The percentage of DME patients gaining three lines or more of bestcorrected visual acuity (BCVA) with monthly treatments after at least one year seems small. In Dr. Khanani’s experience, it is less than 50 percent. The challenge is in the heavy treatment burden in real world situations: DME patients, he said, are significantly undertreated with a high rate of appointment no-shows.
Furthermore, Dr. Kaiser cited studies like RISE and RIDE, and VIVID and VISTA, which showed less than 50 percent of patients gained three lines gains of BCVA.
The pandemic’s influence in patient management patterns
“Especially in the COVID-19 era, patients don’t want to come in. So, really, we need options that are more durable and more potent to control the disease,” Dr. Khanani said, echoing real world studies which show how it is difficult to get patients to come in consistently for 12 months.
The pandemic has also caused a change in how doctors see patients over the past few months. Most DME patients are diabetic and are elderly, thus, more likely to contract the disease. Due to this situation, Dr. Khanani said he’s now using more intravitreal steroids.
COVID-19 has also altered doctors’ ways for imaging DME. “I’m trying to streamline visits and socially distance patients while they’re in the office, so
I really can’t have a bottleneck at the Heidelberg, where I’m trying to do the OCT and fluorescein. I have cut back on fluorescein and in DME patients, I’m primarily using just the OCT,” shared Dr. Holekamp.
Along with this, she also stated patients’ DR scores can be lowered, noting how intravitreal corticosteroids could also have this effect. “I feel that if they’re being categorically treated, I can pull back on the invasive testing,” she said.
A new factor to consider
Diabetes is also now being recognized as systemic inflammation, affecting the entire body, rather than simply localized inflammation.
“We’re also starting to realize these inflammatory factors lead to both vascular dysfunction in the form of leakage and neuronal dysfunction,” Dr. Kaiser mentioned.
There have been recent papers1 looking at this idea — that inflammation within the retina leads to neurodegeneration. The fact of the matter is . . . diabetes is a neurodegenerative disease.
It was thought that inflammation only played a role in the initial part of the disease, which was VEGF-dependent — but now, they’ve discovered that it plays a role throughout the disease process. Higher inflammatory cytokine levels can be observed in DME patients. Dr. Kaiser said attacking inflammation earlier may prevent some of the neurodegeneration affecting patients.
Thus, incorporating steroids in the treatment plan for DME patients could address these inflammatory issues.
Dealing with biomarkers
Some inflammatory biomarkers include hyperreflective spots, DRIL, subretinal fluid, lipid exudates, peripheral ischemia, vessel leakage and staining.
Dr. Khanani said he would look at DRIL, but would still want to see patients’ response to anti-VEGF, to which Dr. Kaiser concurred that DRIL and hyperreflective foci would be consistent with poor outcome and inflammation.
For Dr. Holekamp, she said she’s changed her thinking 180-degrees over fluid in DME treatment. “In DME, the fluid is more damaging. It tends to be intraretinal as opposed to subretinal. I think it is destructive and can limit future visual acuity gain because of this functional loss of neurons. I now have zero tolerance on fluid in DME,” she said.
For comparison, Dr. Kaiser said that in the Cleveland, Ohio, trials, it had been shown that dexamethasone, a very powerful type of steroid, seems to work a little better than triamcinolone.
Combinations of treatment, frequency
For Dr. Khanani, he would treat with anti-VEGF for one month and then add a steroid the next month and observe. Dr. Holekamp thinks differently, though. She rarely mixes her drugs and would prefer to “switch” instead. They both met in the middle by agreeing that a combination of switching treatments from anti-VEGF to steroids does show durability and efficacy.
However, Dr. Holekamp cautioned that switching sooner is better than later, as there is not much randomized clinical data on combo-therapies. “The one thing I learned from Protocol-U, is that we’ve got to switch or add sooner because those eyes that ended up having combination therapy really have lost the ability to recover vision,” she said.
In answer to a question by a member of the audience on the frequency of Ozurdex injections, Dr. Holekamp said she usually gives the corticosteroid injection and then sees them after 6 to 8 weeks followed by another injection and would see them after 6 to 8 weeks again.
| Sept/Oct 2020 25
“You have to actually follow them through the first or two or three injections to get a feel for what their eye is telling you it needs,” she said, adding that in the beginning, it’s like a treat-and-extend interval, “right before they fall off the cliff.”
Based on the MEAD2 study, Ozurdex has been approved to treat DME, retinal vein occlusion and
posterior segment uveitis, with contraindications if there has been a presence of active infection at baseline, as well as with glaucoma patients with a disc at risk (greater than 0.8), or in patients with torn or ruptured posterior lens capsule or hypersensitivity.
For Dr. Kaiser, he said the MEAD study’s OCT findings seemed better than the visual acuity results. Dr. Holekamp agreed. “The one thing I learned from the MEAD study is that Ozurdex is really good at drying the retina, and we see the results after one (injection of) Ozurdex,” she said, adding this influenced her decision to employ a “switch” approach as opposed to adding on.
Navigating side effects
What about side effects? Intraocular pressure increases (IOP), as well as cataracts (in 6-8 percent of patients), are known side effects of Ozurdex. Dr. Kaiser said that although 28 percent in the patient group experienced an increase in IOP, it is episodic and could be addressed with topical medication.
Thus, both Drs. Holekamp and Khanani expressed their confidence in using Ozurdex despite IOP and cataract risks. Dr. Khanani said most of his patients are elderly and have cataracts anyhow, while younger patients would be counseled pertaining to the risks of developing cataract one or two years after the treatment (depending on their age, whether they are phakic or pseudophakic and other factors).
On IOP spikes, Dr. Khanani said: “I tell my patients that a third of patients on steroids would get them, but I don’t call it glaucoma because we can control the high pressure and not use the steroids again.”
Another factor that helped, according to Dr. Khanani is the predictability of IOP spikes during the week 6 and onward with Ozurdex.
“So we can catch it and treat it without any severe damage,” he said.
“Bazooka in your eyes”
For an acute and urgent response to control and dry the eyes, Dr. Khanani said he would prescribe the more potent steroids instead of delaying the long-term delivery system.
Dr. Khanani uses a simple analogy with his patients: Although antiVEGFs are powerful, you sometimes need something even more powerful than that.
“They’re like bazookas in your eyes,” he said, adding that steroids cover more inflammatory markers, whereas anti-VEGF agents don’t.
In conclusion, Dr. Kaiser said DME is still increasing and with newer understanding of its behavior, it is becoming clearer that inflammation plays a large role, especially in the idea of neurodegeneration, not only in the eye but the whole body. Ozurdex’s anti-inflammatory effects in DME (as well as in diabetic retinopathy) are very profound, with changes seen in OCT and BCVA.
1 Romero-Aroca P, Baget-Bernaldiz M, Pareja-Rios A, et al. Diabetic Macular Edema Pathophysiology: Vasogenic versus Inflammatory. J Diabetes Res. 2016; 2016: 2156273.
2 Boyer DS, Young HY, Belfort R Jr, et al. (Ozurdex MEAD Study Group) Threeyear, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-1914.
This satellite symposium took place at ASRS 2020 on 30 th July 2020. Reporting for this story also took place during the session.
| Sept/Oct 2020 26 TREATMENT REGIMEN INNOVATION DME TREATMENT
Like with these clothes, DME treatment isn’t one size fits all . . .
APAO COVID-19 Guidelines
The World Health Organization declared the Coronavirus Disease 2019 (COVID-19) caused by Severe Acute Respiratory Syndrome
Coronavirus 2 a “Pandemic” on March 11, 2020. As of August 28, 2020, Severe Acute Respiratory Syndrome
ocular manifestations of COVID-19 and the APAO guidelines in mitigating the risks of contracting and/or spreading COVID-19 in ophthalmic practices.
The Asia-Pacific Academy of Ophthalmology (APAO) recently published the APAO COVID-19 Prevention Guidelines for Ophthalmic Practices.*
Coronavirus 2 has infected >24.4 million people and caused >832,000 deaths, including many health care personnel. It is highly infectious and ophthalmologists are at a higher risk of the infection due to a number of reasons including the proximity between doctors and patients during ocular examinations, microaerosols generated by the noncontact tonometer, tears as a potential source of infection, and some COVID-19 cases present with conjunctivitis. This article describes the
For the continued safety of physicians, staff and patients, we encourage you to read the full article, with additional tips, data and in-depth explanations. Free access here
*Wong, R, Ting, D Lai K, et al.
COVID-19: Ocular Manifestations and the APAO Prevention Guidelines for Ophthalmic Practices. Asia-Pacific Journal of Ophthalmology: July-August 2020;(9)4:281-284.
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| Sept/Oct 2020 27
Exciting Developments in Retinopathy Treatment on the Horizon
by Andrew Sweeney
The summer’s drawing to a close (for most of us) and the last big conference of the season has passed. The American Society of Retina Specialists (ASRS) held its annual scientific meeting online last month, and it was a fascinating experience.
A number of exciting developments were discussed at ASRS 2020, with great applications in retina and other areas of ophthalmology. The season’s favorite topics of telemedicine and coronavirus were naturally discussed, but so too were gene therapy, emerging technologies and drug delivery devices. All in all, it’s an exciting time for anyone involved in retina.
Coming soon from a sci-fi screen to you
For the technology obsessed or sci-
fi fans among us (including your correspondent), one of the most exciting developments is of course, artificial intelligence (AI). How ophthalmology is harnessing this technology, (and preventing Skynet from taking over the planet), is a fascinating area of study. We are now witnessing AI deployment for screening diabetic retinopathy, visual field tests and in a variety of other fields.
AI’s sister technologies, namely augmented reality (AR) and virtual reality (VR) are now even being used to help people with low vision due to diseases like AMD. For example, California-based Ocutrx are offering headsets that are incredibly light and easy to use, like the company’s flagship product Oculenz, which is specifically designed for use by age-related macular degeneration patients.
Oculenz was discussed during the first day of the ASRS conference and it’s easy to understand why. The lens uses complex algorithms to reposition video pixels from blurred vision areas to adjacent areas with viable vision. It is completely wireless and smart-enabled, meaning it can be integrated with laptops, smartphones or tablets in the home.
Another exciting development is observable in the realm of gene therapy too, particularly in treating RPE65associated Leber Congenital Amaurosis (LCA). This condition is a severe inherited retinal degeneration (IRD) with a typical presentation between birth and 5-years-old.
As you can imagine there is strong demand for therapy that can identify the genes that cause the condition. This process often requires the guidance of
| Sept/Oct 2020 28 TREATMENT REGIMEN INNOVATION RETINOPATHY
a specialist or genetic counselor, which has generally limited patient access. There is also a considerable paucity of online resources devoted to gene therapy.
With the launch of voretigene neparvovec (Luxturna®, Spark Therapeutics, PA, USA) the first in vivo gene therapy approved by the U.S. Food and Drug Administration (FDA), a new frontier is opening. This is a welcome development as voretigene neparvovec is an exciting and novel development. It is of the utmost importance that patients are able to access as much information as possible in tandem with the drug’s launch.
One more product now cleared for use by the FDA is the EyeArt® AI Eye Screening System for diabetic retinopathy (DR). Manufactured by Eyenuk Inc, an AI and medical technology and services company based in California, this autonomous AI technology has diagnostic outputs for each eye of any given patient. It can be used to screen for all forms of DR, one of the leading causes of blindness globally.
Eyenuk claims an impressive 97% imageability rate for the device, that is, of all patients screened who already had diabaetic retinopathy 97% were correctly identified. This rate was replicated at primary care centers where the machine’s operators did not have prior ophthalmic experience. Also, 90% of participants were diagnosed without
the need for dilation.
The EyeArt system is designed for use by Canon CR-2 AF and Canon CR-2 Plus AF cameras. We’re very excited to see how this apparently easy-to-use AI technology is fully implemented. It certainly represents a welcome development for DR patients.
We’re always going to have to use needles (probably)
Anesthesia is very much a bread-andbutter aspect of the medical industry. While the basic technology behind anesthesia is relatively unchanged, ophthalmology is experiencing interesting developments, especially for patients receiving intravitreal injections (IVIs).
IVIs can cause discomfort for patients and are often considered to be a bottleneck in clinical efficiency, thus more research is being devoted to finding a more painless approach. One of these novel ideas was applying anesthesia with a cooling effect. In one study presented at ASRS, Cooling Anesthesia for Intravitreal Injection with a Novel Device: Results of the Prospective COOL-2 Study, cooling anesthesia was applied in lieu of regular anesthesia, and pain was recorded in visual analog scale at the time of injection.
All in all, 70% of the patients preferred the cooling anesthesia, though overall
pain levels were reported to be the same. Improving patient comfort is an excellent goal, and while there is more work to do in this area, cooling anesthesia holds great potential. Not only that, it will have broad applicability to many disciplines in ophthalmology.
Finally, if you’ve ever seen the Tom Cruise film Minority Report, you might be about to feel a pang of déjà vu. A group of scientists at the Hong Kong University of Science and Technology (HKUST) are currently working on the world’s first artificial eye: the Electrochemical Eye (EC-Eye) This 3D eye is feted to likely offer better vision than bionic eyes, and even a regular eye, in the future.
The EC-Eye’s most remarkable feature is a fully 3D retina. This manufactured retina is made of an array of nanowire light sensors which mimic the photoreceptors in human retinas. Nanowire has a higher density than photoreceptors in the human retina, which means that in theory, this ECEye can receive more light signals and view higher image resolutions than the regular human retina.
The technology behind the EC-Eye still needs further development and more studies on its performance and biocompatibility are required. That being said, this is seriously cool stuff. Who knows, maybe in a decade or so we’ll be swapping our boring old peepers for the EC-lEyes, especially if they come in my favorite color purple.
The American Society of Retina Specialists Annual Scientific Meeting (ASRS 2020) was held virtually on 24-26 July. Reporting for this story also took place during the meeting. A version of this article was first published online [ PIE website ] on August 19.
| Sept/Oct 2020 29
Soon you might have eyes like Pepper’s here
and its Impact on Retina Practice
by Hazlin Hassan
the outbreak when the staff had to adapt to changes, with the varying recommendations and advice on social distancing, sanitizing, sterilizing, and wearing different levels of personal protective equipment (PPE) and masks.
Health and safety measures had to be implemented, including temperature checks for all patients and staff, while intraocular pressure (IOP) screenings and refraction tests have been suspended.
Only one attendant is allowed in the consulting room, while slit lamp examinations have been reduced, and a 20D lens is used to do a quick distant examination for the retina.
Lockdowns, closed borders and quarantine orders.
Over the last few months, the coronavirus outbreak has resulted in massive changes which have also affected how eye doctors all over the world are supporting their patients during this challenging time.
We take a look at how one ophthalmologist in India is protecting patients from exposure to the risk of COVID-19, while at the same time adapting to the “new normal” during the pandemic.
“Like everyone else, the Retina Foundation has also been impacted by the COVID-19 pandemic,” said Dr. Manish Nagpal, vitreoretinal consultant of the Retina Foundation and Eye Hospital.
Located in India’s western state of Gujarat (in Ahmedabad), Dr. Nagpal’s Retina Foundation and Eye Research Center has been impacted by the country-wide lockdown that started on March 24.
Restrictions have been eased gradually in some parts of India since June 1, but have been tightened in some Indian cities and states when there has been a surge in the number of COVID-19 cases.
“At the beginning, we thought this would be a transient issue for a couple
of weeks, and then it would resolve. However, the pandemic continued unabated and the lockdowns increased. Hence, the work has been seriously impacted,” he said.
The Foundation was completely shut during the first week of lockdown, he recalled. After that, emergency patients were allowed to come in twice a week for several weeks.
In a move toward gradually resuming normal hours, the Foundation has shifted to operating daily, for a half-day in the morning.
All of this has resulted in a sharp slump in the number of visitors to the practice.
“We are seeing less patients for sure,” said Dr. Nagpal.
In the first few months, the number of patients dropped by around 90 percent, although figures have improved slowly.
The number of patients seeking treatment at the retina practice have increased to about 60 to 70 percent of normal traffic. However, the anterior segment practice, which is based on planned procedures and is also tissuedependent for cornea, is still seeing less than 20 percent, compared to precoronavirus days.
There was an initial period of adjustment during the early days of
For diagnostics, only crucial tests are done, mainly using optical coherence tomography (OCT), or optical coherence tomography angiography (OCTA) and wide field imaging, which are quicker and less invasive than using fluorescein angiography (FA) or indocyanine green angiography (ICGA).
For surgeries, not much has changed as masks and disposable gowns are normally worn.
“Our anesthetist does wear PPE, which earlier was not the norm, and now they wear full PPE for cases under general anesthetic (GA) as they are at higher risk in those cases.”
Some practices in India are already conducting rapid screening tests for COVID-19 for all surgical patients.
At Dr. Nagpal’s Foundation, patients who have to go under GA will be tested, while other surgical patients may also be tested once the kits become more accessible.
While the number of patients have decreased due to the shutdowns, teleconsultation is still not a viable way of managing retina patients, without getting a view of the fundus or using OCT.
There has, however, been an increase in cases where patients have visited a local doctor and obtained a report or an image which they then share on WhatsApp, and the Foundation
| Sept/Oct 2020 30 RETINA PRACTICE ENLIGHTENMENT
has been able to guide and make recommendations in such cases.
“This may work in some other specialties, but in ophthalmology and especially retina, it is going to be difficult as one cannot derive much by just listening to the patient’s complaints of visual issues.”
Slowly, as everyone gets used to the safety measures, it looks as if the current situation may be the norm . . . and it could remain for a long time.
Dr. Nagpal, who organizes a biannual surgery workshop showcasing the latest in surgical and medical retina, said he was fortunate in that he had failed to schedule one this year.
“I think I had a sort of sixth sense maybe sometime last year and I had not planned it for this year. Somehow, there have been just too many meetings and I was not inspired enough to organize one this year.”
The Advanced Vitreo Retinal Techniques and Technology (AVRTT) meeting is typically scheduled in March, which would have been around the time when the lockdowns began.
“Now, there are too many webcasts,” he said, adding that he does not particularly enjoy sitting for too long in front of his laptop for meetings.
Meanwhile, it is difficult to foresee when the pandemic will abate.
“Second waves keep coming in various places, and one never knows when issues worsen. For now, we are optimistic that maybe the worst is behind us and it will be a slow road to recovery. Until then, we have to be careful and follow guidelines, wear masks, sanitize and keep us, and others around us, safe.”
Once that happens though, returning to work and a more normal life may prove to be a bit of a challenge for those used to life under lockdown.
“We have been working an extended morning from 9 a.m. to 3 p.m. all these months, and now are finding it difficult to restart the second half,” he said, adding that he had recently extended working hours for the second half of the day.
“I was worried that if I go on like this a bit longer, I would forget what it is to work like before.”
Dr. Manish Nagpal , MBBS, MS (Ophthalmology), FRCS (Edinburgh, UK), is a vitreoretinal consultant at the Retina Foundation in Ahmedabad, Gujarat, India. He has been recognized for his development and presentation of surgical videos and educating the ophthalmic community of advancements in information technology within the field.
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The Balancing Acts of Dr. Mae-Lynn Catherine Bastion
by Chow Ee-Tan
Dr. Mae-Lynn Catherine Bastion was already interested in ophthalmology by the time she entered into the first year of her internship at the Universiti Kebangsaa Malaysia (UKM) Medical Centre in 2000.
Now a professor of ophthalmology at UKM, Dr. Bastion subspecializes in vitreoretinal diseases and vitreoretinal surgery.
“I have been interested in ophthalmology since medical school,” shared Dr. Bastion. “It was just a short posting of only two weeks, but I enjoyed the mix of medical and surgical approaches to treatments, as well as the chance to use various devices in assessment for ophthalmic diseases.”
Of mentors and inspirations
Professor Khalid Kadir, who was dean of the Medical School at UKM at that time, was instrumental in enabling her to pursue an academic position. At the same time, her interest in teaching stems from the strong influence of her mother, who was a well-loved teacher in Bukit Bintang Girl School in Malaysia.
Dr. Bastion modestly considers herself to be fortunate throughout her career, and is thankful to the many mentors who helped her to get to where she is today — from Prof. Kadir and the supervisors she had during her internship; to Dr. Nazri Omar, who taught Dr. Bastion her first cataract surgery; and Prof. Lim Tock Han from Singapore, who accepted her as a fellow in vitreoretinal surgery in 2007.
Her years of training in Singapore prepared her for the challenges of being the only resident vitreoretinal surgeon at UKM from 2008 to 2012.
A brilliant, high-flying student since youth, Dr. Bastion was an ASEAN scholar at Raffles Junior College, Singapore, before being awarded the John Crawford Scholarship by AUSAid to study medicine at Sydney University, Australia, where she graduated with first class honors in 1999. She was then posted to UKM Medical Centre, where she took up a trainee lecturer position after completing her internship. She has served as a lecturer in the University since 2005.
Some of Dr. Bastion’s career highlights
include her appointment to associate professor in 2010, followed by full professorship in 2015, which were no ordinary feats. Another of her accomplishments was obtaining her fellowship in vitreoretinal surgery in 2007, which opened up the doors to more opportunities and accolades in the field.
Dr. Bastion was also a proud recipient of the Fellowship of the Academy of Medicine of Malaysia, which carries the title FAMM(Mal). She was invited to speak at the Asia-Pacific Vitreo-retinal Society (APVRS) Annual Congress in Shanghai last year, together with worldrenowned speaker Dr. Neil Bressler.
A passion for the academe and private practice
Dr. Bastion is truly grateful to be able to assume roles in both the academic fraternity and private practice.
“I am aware that this choice is not available to everyone in government service,” she said. “At UKMMC, we can do up to two sessions of private practice on the provision that we do not neglect our primary duties to the government patients, and that we are able to maintain our publication outputs. It is this provision made possible by the UKM administration that has allowed me to stay in government service,” she added.
Dr. Bastion remains dedicated to the academic fraternity, with a mission to teach, instruct, and guide the next generation of ophthalmologists — not only in the finer points of ophthalmology, but also in other aspects of being a specialist doctor, like teamwork and networking.
“It also allows me to fully develop my subspecialty skills in vitreoretinal surgery, as there is ample cross-referral from other subspecialties, specialties, and other hospitals,” Dr. Bastion shared.
On the other hand, she thoroughly enjoys her private practice, which provides a more direct and regular management of patients, with whom she has fostered close working relationships.
| Sept/Oct 2020 32 WOMEN IN OPHTHALMOLOGY ENLIGHTENMENT
Her demanding portfolio often calls for a challenging balancing act.
“You need to know your priorities, but you still try to accommodate everybody,” she said. “You must work harder than others because private practice is like another job. Patients can be referred at any time or day outside your allocated session.”
Dedication to research
Currently, Dr. Bastion is involved in several research projects about the impact of the COVID-19 pandemic on patients’ vision and emotions, and to shed valuable information on the effects of the movement control order (MCO). Their research team is also investigating the effects on the eye unique to COVID-19.
“Over the years, I have spearheaded several types of research into the effects of diabetes mellitus on the front, as well as the back of the eye, and these are still on-going,” shared Dr. Bastion. “I am also writing a book on this subject.”
In the past, her research has included joint projects with researchers from Universiti Putra Malaysia and Cryocord Malaysia on stem cells, another challenging yet innovative area.
Outside of the research realm, she has had the privilege of working closely with the Malaysian Society of Ophthalmology (MSO), of which she is a committee member, in organizing major international conferences in Malaysia, such as the APVRS in 2017 and the upcoming Asia-Pacific Academy of Ophthalmology (APAO) meeting in 2021.
Kudos to more women in ophthalmology
While men still outnumber women in the profession of ophthalmology worldwide, Dr. Bastion is happy to observe that at the UKM Ophthalmology Department, women lecturers have outnumbered men since she joined in 2000.
“As for our in-house trainees, we
recently conducted a survey on a new surgical teaching method and had a 100% response rate. The number of females was 73% of the whole group (unpublished data), so it would appear that in the not so distant future, women will be taking up more decision-making positions,” she shared.
Having said that, Dr. Bastion remains to be one of the few female full professors of ophthalmology in the country.
“I foresee this will change soon, hopefully,” she added. “I would like to see more men and women able to find a balance between academic work and private practice. It would be prudent to consider perks for private practitioners to take on more public work, and the other way around. The job of the academic fraternity is heavy enough with the need to balance academics, teaching, administration and clinical service.”
She further noted: “Already we are seeing those in private practice taking on more teaching roles through industry-organized teaching sessions in which they have shared the teaching burden. This is most commendable and encouraging.”
On family gratitude and hopes for the future
Dr. Bastion pays tribute to her family for who she is today. Her husband, Dr. Wong Yiing Cheong, whom she met in Sydney University, has a successful solo ophthalmology practice in Kuala Lumpur.
“My husband has provided emotional support for me to remain in the academic fraternity,” Dr. Bastion shared. “My parents have always been supportive of me and have been helping me with my children throughout the years. I could not have done it without them.”
Her three children, aged 14, 9 and 5-years-old, are her biggest joy and blessings. “My eldest has had the privilege of travelling with me on some overseas trips. I try to bring each one in turn on outstation travels so I can spend solo time with them,” she said.
Currently, Dr. Bastion endeavors to write a book that will compile her life’s work and the battles she has fought against various diseases. She remains enthusiastic to accomplish small achievements each day.
So what does she wish for the ophthalmology fraternity in the future?
“My hope and aspiration for the ophthalmology fraternity are simply that we will be able to deliver the care and concern that doctors were meant to deliver: Excellent and up-to-date medical expertise, which not only addresses the need for sight but also the need of the individual,” she said.
She concluded: “I also hope to see that the status and profile of Malaysian ophthalmology in the international arena will increase. Through this, may the visions of our nation be fulfilled in a sustainable and equitable way.”
Dr. Mae-Lynn Catherine Bastion graduated from the University of Sydney, Australia, with MBBS (First Class Honours) in 1999. In 2004, she received the Doctor of Ophthalmology degree from the Universiti Kebangsaan Malaysia (UKM). And in 2007, she completed her clinical fellowship in vitreoretinal surgery at The Eye Institute, Singapore. Following that until today, she’s been serving as head of vitreoretinal services at UKM. In 2009 she became the head of the Department of Ophthalmology, for which she served two terms. She was appointed UKM professor of ophthalmology (vitreo-retina) in 2014 and received the Academy of Medicine (AMM) Fellowship in 2016. She teaches undergraduate and postgraduate ophthalmology while maintaining private practice at UKM Specialist Centre. She currently serves on the committees of the Malaysian Universities Conjoint Committee of Ophthalmology, College of Ophthalmologists of the AMM, and Malaysian Society of Ophthalmology. This is finely balanced with a busy family life of three kids, two dogs and a vegetable garden.
| Sept/Oct 2020 33
Ophthalmology Leaders Beyond Borders
The International Council of Ophthalmology (ICO) in collaboration with the All India Ophthalmological Society (AIOS) held a 2-day virtual meeting of the World Ophthalmology Leaders Program. This year’s edition, titled Leadership Beyond Borders in Ophthalmology witnessed numerous participants from all over the world.
Dr. Neeru Gupta, the interim president of the ICO kicked off the meeting with her opening message which stressed the importance of a virtual event, especially at a pivotal time of global uncertainty. Dr. Gupta emphasized: “The ICO cares a lot about leadership and especially around this pandemic ,which has greatly impacted our personal and professional lives . . . so the ICO is supporting colleagues around the globe with resources that are provided through our eye societies.”
“We all face risks and we salute those who continue to take risks that are needed to help our patients preserve their sight,” said Dr. Gupta. She reminded the conference attendees that “It was only about 6 weeks ago that the ICO held its first ever world congress, and today, we are gathered here today to support one another as one global family.”
The opening remarks were followed by wonderful moments of spiritual connection and meditation, led by Didi Krishna Kumari.
Anyone can be a great public speaker
Mimi Donaldson, a TED Talk speaker
by Olawale Salami
coach, shared exciting insights about how public speaking can inspire teams and urged conference attendees to develop their public speaking skills. She provided tips on good public speaking techniques that can help engage the audience, noting that “Public speaking is not about you, it’s about the people you’re talking to. So, the first thing you have to decide is the purpose. What do you want your listener to do, think or feel after you communicate? That’s your purpose and all of your speech is going to be geared to that purpose.”
Furthermore, she emphasized on content: “People want to know if you’re worth listening to in the first 30 seconds. So what I recommend is lead with the needs of the audience that you’re addressing, provide answers to those needs and highlight why you are so passionate about what you do.”
The AAO Leadership Program: The making of super leaders
In his presentation titled Excellence in Leadership, CEO of the African Ophthalmology Council (AOC) Sidney Gichuru provided a set of tips on leadership, based on his experiences and learnings from the leadership development program. “Firstly, to be a good leader, the most important thing is to provide a clear vision with goals that is shared by your team members. Vision building is key to leadership,” he said.
Furthermore, Dr. Gichuru stressed the importance of communication in leadership. “Leaders are master communicators. To reach your vision, you need to be able to communicate
effectively with your team, customers and stakeholders,” he explained.
Selecting the right team members is crucial to reaching set objectives. Dr Gichuru echoed this, noting that a true leader recruits well for their team and delegates to the right team members.
A great team needs a great atmosphere that can bring out the best in them, and creating a team-oriented atmosphere is one of the key attributes of a leader. According to Dr. Gichuru, a leader should create an atmosphere where each member is valued, and embrace the principle that every member is important and failure of one team member equals failure of the whole team.
How can leaders promote innovative thinking? Dr. Gichuru provided answers to this question: “A true leader fosters an atmosphere where thoughts, ideas and innovation are required — and invited — by encouraging team members to think outside the box.”
Leadership in a pandemic: Drawing lessons from KungFu Panda
“The COVID-19 pandemic has had a major impact on all of us, including our patients,” said Prof. S Natarajan, a board member of the International Council of Ophthalmologists and previous president of the All India Ophthalmological Society (AIOS). In his presentation, Prof. Natarajan shared important leadership lessons from his own life, adding some inspiring excerpts from the movie Kung-Fu Panda.
| Sept/Oct 2020 34 ENLIGHTENMENT OPHTHALMIC EDUCATION
“Like the turtle character in Kung-Fu panda, Master Oogway said that to be happy, you must believe because you have the power to choose how to react to your predicament.” Throughout the movie, according to Prof. Natarajan, the Panda continued in his quest for the secret recipe of success, he never gave up. “So I encourage all you young ophthalmologists to adopt this mindset, of not giving up,” he pointed out.
He encouraged ophthalmologists to push the boundaries of the field, referring to another quote from KungFu panda: “If you only do what you can do now, you will never be more than what you are now.” Prof. Natarajan encouraged colleagues to think outside the box by daring to be different.” If you do what most people do, you will get what most people get. Hence, dare to think outside the box,” he noted.
Finally, reflecting on the ongoing COVID-19 pandemic, Prof. Natarajan gave, probably his most important piece of advice: “In these times of uncertainty, one needs to focus on growing from challenges, and turning stumbling blocks into stepping stones.”
Impossible dreams: Mount Everest and eradicating world blindness
Dr. Jeoff Tabin is a professor of ophthalmology and visual sciences and the director of international ophthalmology at the John A. Moran Eye Center at the University of Utah in Salt Lake City (USA). He is regarded as one of the world’s leading figures in global ophthalmology. In addition, he is an avid mountain climber.
“Rock climbing is very similar to cataract surgery, and practice makes perfect. You need to practice and practice to perfect your art,” said Dr. Tabin. As a young mountain climber, Dr. Tabin first went to Nepal, an experience he considers life-changing. “However, while I was in Africa and Asia, the disparity in medical care and need between the developing world and the United States became obvious to me,” he recalled. “The Himalayan Cataract Project was something I never thought I would do. However, my accidental encounter with preventable blindness
was inspired by people I met and that has remained with me today,” shared Dr. Tabin. To young ophthalmologists, Dr. Tabin advised them to take advantage of opportunities and to pursue their dreams.
After completing medical school at Harvard Medical School (Boston, USA) and an internship at the University of Colorado Hospital in Denver, Dr. Tabin returned to Nepal and worked as a general doctor at a remote hospital in Eastern Nepal. “Many of the problems that I saw were public health issues due to lack of clean water, poor diet and poor living conditions,” Dr. Tabin recalled. “However, the one miracle I witnessed was cataract surgery. In the village where we worked, people accepted that as one gets old their hair turns white, their eyes turn white, and then they die,” he shared.
Dr. Tabin’s work was greatly facilitated by those he met along the way. He shared fond memories about those experiences: “I was fortunate to meet my partner, Dr. Sanduk Ruit, an ophthalmologist who was the first Nepali surgeon to implant IOLs and who later developed a fantastic delivery system for high-quality, high-volume, low-cost cataract surgery.”
“My experiences working in the Himalayas and in Sub-Saharan Africa have greatly influenced my work as an ophthalmologist in the United States,” he added.
In 1998, Dr. Tabin made it to the summit of Mount Everest. “It was a perfect day with clear skies and I could see all the peaks of Nepal. I could see four of the next six highest peaks,” Dr. Tabi shared. He has since climbed the highest mountains on all seven continents.
Furthermore, Dr. Tabin emphasized the importance of resilience: “Five years earlier, I had been with a team that made the first ascent of the East Face of Everest. I did not make the ascent and turned back 800 meters to the summit. But I never gave up.”
“I’ve been very fortunate in my life’s journey and I remain grateful to all the brilliant people I’ve met,” he concluded.
Leadership in ophthalmology: Fostering patient-doctor relationships
Feedback about patient experiences is important in ensuring that doctors understand patient needs. How does leadership in the ophthalmology practice affect patients? A key session on the second day of the conference was an open forum where patients expressed their thoughts on their experiences in eye surgery, and the impact of those experiences on their lives today.
One patient who spoke, Priyanka Sathe, noted: “The patient-doctor connection is very important. Once a doctor speaks to a patient, there is a sense of relief at that moment because of the preexisting anxiety in many patients.
“A heart-to-heart talk with a patient undergoing surgery is very important, and this made a huge difference in my experience as a patient of Prof. Natajaran,” shared Ms. Sathe. “Maintaining good patient communication, even amidst the ongoing COVID-19 outbreak, goes a long way in allaying patient fears,” she added.
Meanwhile, another patient who is a practicing solicitor, shared her lifelong experience with ophthalmologists: “I started my life with congenital cataract and I’ve had a mixed experience, both good and bad. I wish doctors would be more open to patients and tell them how or when complications may occur after surgery.”
The World Ophthalmology Leaders Program, Leadership Beyond Borders in Ophthalmology (presented by ICO in collaboration with AIOS), was held on 15-16 August 2020. Reporting for this story also took place during the event.
| Sept/Oct 2020 35
Real World Results Findings from the Protocol T Extension Study
Diabetes, and its related ocular conditions like diabetic macular edema (DME), is a chronic condition. And as such, patients must be monitored and treated over long periods of time.
However, clinical trials generally don’t have that long-term (or lifetime) followup. Eventually, patients are released from strictly regimented medical studies and thrust back into the real world, where they may or may not continue treatment. So, it’s a known fact that clinical results don’t always align with the real world.
Of course, this fact is not lost on ophthalmologists and researchers. As such, results from one recent extension study were published in March 2020: Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study) 1
During the 37th World Ophthalmology Congress (WOC2020 Virtual®), study coauthor Jennifer Sun, MD, from the Joslin Diabetes Center at Harvard Medical School (USA), shared results and insights from this study which asked, “What happened after Protocol T patients were released from the study and into traditional clinical care?”
by Brooke Herron
Protocol T Extension: Results
The original Protocol T study compared efficacy and safety of aflibercept, bevacizumab and ranibizumab, where all three groups were found to have visual improvements from baseline to two years patients with center-involved DME.2 Dr. Sun pointed out that the Protocol T Extension study’s main
objectives did not include a comparison of treatment groups after 2 years, as treatment between 2 and 5 years was managed at clinician discretion.
According to Dr. Sun, there were several main questions researchers investigated in the Protocol T Extension — below, we investigate the answers to these questions further.
36 WOC 2020 COVERAGE CONFERENCE HIGHLIGHTS
1 2 3
Did patients continue treatment with a retina specialist?
Of the original Protocol T study, 317 of 463 eligible participants or 68% completed the 5-year visit. And between years 2 and 5, 217 of 317 (68%) of study eyes received at least 1 anti-VEGF treatment.
What treatments were given and how often were they received?
Regarding treatment provided over those three years, Dr. Sun said, “Thirtyeight percent received aflibercept; 32% bevacizumab; 19% ranibizumab; 10% corticosteroids; 8% focal grid laser; and 10% PRP.
“The mean number of visits among participants was 14 between 2 and 5 years, suggesting that they were being followed fairly frequently — at least 4 times per year in many cases,” continued Dr. Sun. “We saw that 98% of these visits were conducted at the Protocol T clinical site, so these patients were experiencing good continuity of care with what seemed like reasonable follow-up.”
She explained that the distribution of anti-VEGF agents received after two years was pretty widely distributed: “So, whereas 32% had no injections after 2 years, the rest of the patients — although they had a median number of injections of 4 (which was very similar to what we saw in Protocol I) — saw a very large range of patients who were getting very few treatments to patients who were still getting monthly [treatment] over that timeframe.”
How did participant VA change from baseline and between 2 and 5 years?
“As you may remember, during the randomized trial, the overall group gained a fair amount of vision, about 12 letters or more,” shared Dr. Sun. “During the observational study, we saw that at the end of 5 years, these eyes still had a positive gain of 7.4 letters from baseline, so they were still better off from where they started.”
At 5 years, mean VA improved from baseline by 7.4 letters (95% confidence
interval [CI], 5.9-9.0) but decreased by 4.7 letters (95% CI, 3.3-6.0) between 2 and 5 years.
“This was very similar when we looked at groups broken up by treatment assignment. All three groups had declines in vision of approximately one line or so during the 2 to 5 [year] visits,” said Dr. Sun.
“When we look at those with baseline VA of 20/32 to 20/40, we see that again on average the eyes gained in vision from baseline to 2 years — and then there was a slight decline in vision, and the decline was fairly similar among the treatment groups,” she continued. When baseline VA was 20/32 to 20/40, mean 5-year VA was 3.2 letters (95% CI, 1.4-5.0) better than baseline, but 4.6 letters (95% CI, 3.1-6.1) worse than 2 years.
“We also had a consistent change in the baseline groups that started with vision of 20/50 or worse, all of these three groups have a decline in vision from the 2 year visit, but at 5 years they’re all still better off than they were at the beginning of the study,” shared Dr. Sun. When baseline VA was 20/50 to 20/320, mean 5-year VA was 11.9 letters (95% CI, 9.3-14.5) better than baseline, but 4.8 letters (95% CI, 2.57.0) worse than 2 years.
treatment cannot be compared during that time. It’s also important to note that this data was retrospective.
“However, we can conclude that after Protocol T ended and patients were released to standard care, 95% of our patients continued to receive retinal care and at least 68% received at least one intravitreal anti-VEGF injection,” said Dr. Sun.
She explained that on average, patients had visual gains from baseline but their mean VA worsened between years 2 and 5. Meanwhile, there weren’t significant CST changes in the long-term follow-up.
“These results are different from prior clinical trials in DME that have demonstrated better maintenance of visual gains,” she said, explaining that Protocol I clearly demonstrated much better maintenance than what was observed in this extension study.
“This suggests that studies to improve long-term visual outcomes in clinical care among eyes with DME are still needed,” concluded Dr. Sun.
How did participant central subfield thickness (CST) change from baseline and between 2 and 5 years?
Mean CST decreased from baseline to 5 years by 154µm (95% CI, 142-166) and was stable between 2 and 5 years (-1µm; 95% CI, -12 to 9).
“Indeed, we saw basically a one micron difference between the 2 and 5 year visits,” said Dr. Sun, adding that this again, was very consistent among the three treatment groups.
Limitations and conclusions
As with any study, there can be limitations. In this instance, the researchers said that only two-thirds of eligible participants completed year 5 of the study. Plus, treatment from years 2 to 5 was at clinician discretion, so
1 Glassman AR, Wells JA, Josic K, et al. Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study). Ophthalmology. 2020;S0161-6420(20)303043.
2 Wells, JA, Glassman AR, Ayala AR, et al. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016;123(6):1351-1359.
The 37th World Ophthalmology Congress (WOC2020 Virtual®) was held on 26-29 June 2020. Reporting for this story also took place during the congress. A version of this article was first published online [ PIE website ] on August 3.
| Sept/Oct 2020 37
Challenging Retinal Cases in Vitreoretinal Surgery
by Tan Sher Lynn
To provide optimal outcomes for patients, sharing knowledge and experience from challenging cases is of utmost importance for surgeons — especially when it comes to difficult vitreoretinal procedures. Therefore, during the RETINAWESOME III virtual meeting on June 20, retinal specialists congregated (albeit online) to share their valuable insight on treating conditions including macular holes, ocular trauma, retinal detachment, diabetic retinopathy (DR) and more..
Tricky retinal detachments
The first case study presented by Keynote Speaker Dr. Yusuke Oshima (Japan) involved a junior high school student with Coat’s disease and retinal detachment. He explained the procedure, noting that the fibrosis and epiretinal membrane were removed from the retinal surface and an internal limiting membrane peel was performed. Then, using a wide-angle vitrectomy viewing system, Dr. Oshima found an angioma in the posterior pole at the retinal periphery; he inserted a buckle (240 band) around the eye for indentation and to support the retinal periphery. Following, laser and cryotherapy was used to treat the hemangioma. Dr. Oshima added that although perfluorocarbon and intraocular gas were used, silicone oil was not needed during this procedure.
Next, Dr. Marcelo Murillo Sasamoto (Bolivia) presented a case on pediatric retinal detachment which was treated
by combining large radial retinotomy and circumferential retinectomy. “Nowadays, I call the technique ‘Tetris Retinectomy’ because it follows the form of the video game,” explained Dr. Sasamoto. “We start the surgery with keratotomy to see what’s going on with the retina. The edge of the retinal detachment is then treated to remain flat and ready to laser.”
The ‘Tetris’ technique is used to change tangential traction after post inflammatory retinectomy — this multi-distribution of force vectors helps avoid a retinal redetachment.
Dr. Sasamoto said that although this was a really tough case, it ended very well: Postoperatively, the patient received three intravitreal injections of methotrexate (1200µm) every 15 days, followed by 400µm every month for 4 months, to avoid proliferative vitreoretinopathy (PVR).
That slippery dislocated lens
Dr. Oshima’s second case involved a patient with a dislocated lens and used some newer, fancier techniques. One was called “Barbeque Technique”, where he inserted forceps inside the crystalline lens and then removed the lens with the cutter. (He noted he used a 25-gauge sclerotome at 10,000 cuts per minute during this procedure.)
Once the lens was removed, Dr. Oshima used the Yamane technique for the intrascleral fixation of the intraocular lens — a sight that participants agreed was spectacular to see.
Continuing the topic of dislocated IOLs, Dr. Gustavo Huning (Brazil) discussed the scleral pocket technique, which he learned from Dr.Theodoros Potamitis (Cyprus). He explained that in this technique, “trocars are inserted through these pockets and then I did an anterior vitrectomy. The haptics are released under the pockets because they are safe — and doing so made the haptics more stable. We then suture the pockets to close them.”
To determine the distance between the limbus and IOL he shared: “I decided that the conjunctiva is the region where I will do the pocket. The inserting plane is 4mm from the limbus and I enter the pars plana 2mm from the limbus. The total length of the pocket is 2mm.”
On persistent fetal vasculature
Zeroing in on pediatric eyes was Dr. Yoshihiro Yonekawa (USA). His case detailed a 23-gauge plaque dissection of anterior persistent fetal vasculature in a 2-week old boy (who was referred for leukocoria). When he looked into the eye, there was a massive membrane and fibrotic tissue over the pupillary plane. To cut through the thick membrane, an MBR blade was used to create the initial plane; scissors were later employed when the cutter was not able to penetrate the solid mass. Dr. Yonekawa finished off the case with air and sutures. The patient was fitted with a fake contact lens and did well postoperatively, he reported.
| Sept/Oct 2020 38 WEBINAR COVERAGE CONFERENCE HIGHLIGHTS
You have to get everything just right with the Tetris technique.
“In children, the most important thing is to rule out retinoblastoma by taking a good B-scan, looking at the family history, and also the other eye,” said Dr. Yonekawa.
The future is now: Bionic eyes
The artificial retinal implant, Argus II, was then discussed by Dr. Robert Devenyi (Canada) for its merits in treating patients who are blind due to retinitis pigmentosa (RP). To date, he has performed nearly 20 of these procedures, which helps restore functional vision in patients with degenerative eye disease.
He shared that surgeons need to use care when implanting the device: “There are 600 electrodes on the retinal prosthesis, so one has to be very careful not to use regular instruments as they will damage the electronics — only instruments with silicone tips can be used to handle the electronic components,” he explained, adding that the most stressful part of the surgery is that there is only one chance to affix the titanium tack to the central macula.
And although this procedure has the potential to advance and provide further visual enhancement for patients (including facial and color recognition), he said that the company was unable to do so at the present time as it was an expensive endeavor, with each implant costing $190,000.
Diving into macular holes
Treating macular holes is often complicated. Indian ophthalmologist Dr. Vaibhav Sethi shared details from one case where he performed a macular ILM peel using triamcinolone to better visualize the posterior pole at the macula. To delineate the vitreomacular traction (VMT), he used diluted triamcinolone to stain the broad VMT. Cortical vitreous was trimmed around the VMT, thus avoiding anteriorposterior traction. Then, a cleavage plane was made around the temporal part of the optic disc to release the VMT, which was stained with brilliant blue under fluid, and the ILM flap was created.
The next case from Dr. Saad Waheeb (Saudi Arabia) concerned a patient with focal exposure to a handheld laser, which caused a lesion at the macula. During his presentation, he showed how he was able to detach the tough and adherent hyaloid. One month postoperatively, the patient’s vision was 20/40.
Ouch: Scleral ruptures
Brazilian ophthalmologist Dr. André Jucá then relayed his insights from a case of scleral perforation (with chronic severe pain) in an eye with previous scleral buckle surgery. To identify these late and unusual complications of buckle surgery, he said, “This patient had buckle surgery done 10 years ago and was now complaining of pain, so we decided to remove the buckle,” he explained.
“We didn’t see any sign of infection, but when we removed the buckle, we discovered a big hole at the sclera. We decided to cut it out and suture it. Going through the images, we realized that there was a dark area in the center which I missed. In this area, there’s no sclera, just tendon and conjunctiva blocking everything. This is a sign to take note of that scleral rupture or necrosis may be present,” he concluded.
You don’t belong here, IOFBs
Intraocular foriegn bodies (IOFBs) can cause all sorts of sight threatening complications.
One such case presented by Dr. Vasco Bravo (Brazil) involved a patient with eye trauma (iron in his eye), as well as associated cataract. This called for team work.
“Performing UBM (ultrasound biomicroscopy), we could see that the intraocular foreign body was very, very close to the wall and pars plana ... and anteriorly placed,” he said. Together with a cataract specialist colleague, they removed the cataract and IOFB using phacoemulsification, plus perfluorocarbon-assisted IOFB removal with backflush help.
Dislocated IOLs can become their own worst nightmare (hello, IOFB). Thankfully, Prof. Dr. Wai Ching Lam (Hong Kong) has been there before. He described one such case where he performed a simple scleral technique to elegantly secure the IOL into the sulcus in a stable manner, using 10-0 prolene sutures.
“This is possible as the whole capsule is very intact and it holds up against the capsular retention ring. This is just one option of securing a dislocated intraocular lens implant — in this case, it happened to have a full capsule with some residual material, and a capsular retention ring,” he said. Dr. Lam added that to keep the IOL in place for suturing, his assistant used a cutter to hold the lens against the iris.
Finally, Dr. Hudson Nakamura (Brazil) showed a case of severe intraocular injury with IOFB from a gunshot wound. He used CT images, B-scans and postoperative retinography to show the foreign bodies and to provide the roadmap for surgery. Special forceps were used to remove the IOFBs, and when a retinal detachment was found, he used PFO to reattach it. Dr. Nakamura then used endolaser at the far periphery (under silicone oil) and noted that the patient had a good postoperative outcome.
As virtual meetings go, this was of course, a fruitful one. These challenging cases inspired discussion and learning, while showcasing the evolution of best practices and techniques … all to help improve and restore sight in these devastating vitreoretinal cases.
RETINAWESOME III, Challenging Retinal Cases in Vitreoretinal Surgery, was held on 20th June 2020 and was spearheaded by Dr. Hudson Nakamura of Brazil. Reporting for this story took place during RETINAWESOME III. Visit the R ETINAWESOME YouTube Channel for more information and videos. A version of this article was first published in PIE POST @ASRS 2020 Issue #1 (p. 8-9).
| Sept/Oct 2020 39
Improving Diabetic Retinopathy Treatment
by Tan Sher Lynn
Caused by microvascular damage to the retina, diabetic retinopathy (DR) is a common manifestation of diabetes mellitus. Thankfully, its course can be altered with anti-vascular endothelial growth factor (anti-VEGF) therapy. In a series of Satellite Symposia at the virtual American Society of Retina Specialists 38th Annual Scientific Meeting (ASRS 2020), a panel of three retinal experts discussed the efficacy of anti-VEGF therapies in reducing the severity of DR and their potential to reverse disease progression in a session titled, Exercising Trial and Error to Improve the Treatment of Diabetic Retinopathy.
Treating DR: What to look for
Dr. Dilsher Dhoot, vitreoretinal surgeon at California Retina Consultants in California, USA, noted that DR is now the most common cause of severe vision loss in the United States, affecting 9.4% of the population (or 30.3 million people), while diabetes is also the seventh leading cause of death in the country, as is reported by the Centers for Disease Control and Prevention (CDC).
“Until now, the current algorithm for proliferative diabetic retinopathy (PDR) is to wait for DR severity to progress until frank neovascularization is observed. DR progresses in discrete
levels, as described by the ETDRS severity scale,” he noted.
Current modalities of treatment for DR include: panretinal photocoagulation (PRP), anti-VEGF therapy, and combined PRP and anti-VEGF therapy.
Dr. Charles Wykoff, medical and surgical retinal specialist at the Retina Consultants of Houston, Texas, USA, said he would “try to get the best of both worlds” when it comes to treating eyes with PDR. “There is a really important role for lasers in my clinic. PRP has a durable effect which I find invaluable. While I am still doing PRP on most eyes with DR, I tend to put anti-VEGF to “quiet down” the eye before proceeding with an anteriorly directed laser pathway,” he said.
Dr. W. Lloyd Clark from the Palmetto Retina Center in South Carolina, USA, agreed with Dr. Wykoff, noting that applying anti-VEGF medication before laser therapy tends to make the treatment smoother.
Subsequently, Dr. Dhoot presented data which showed that the risk of progression to PDR increases with non-proliferative diabetic retinopathy (NPDR) severity. He said: “We can see that 51% of patients with severe NPDR progresses to PDR in one year. Diabetic macular edema (DME) can occur at any
stage but it is more common as DR severity increases.”
Showcasing data from the RIDE/RISE clinical trials (which studied intravitreal ranibizumab injections in subjects with clinically significant centerinvolved macular edema secondary to diabetes mellitus), Dr. Dhoot said that at month 24, over a third of the patients had a 2-step improvement from baseline, with 9% of patients (RISE) and 17% patients (RIDE) having a 3-step improvement from baseline. “These are significant improvements compared with patients in the sham group,” he said, noting that the improvement was noticeable very early on, as between 15-19% of patients had a 2-step improvement at 3 months.
“Based on the large body of data, we can establish that patients at level 47 and 53 are really the ones that benefit the most with VEGF suppression,” Dr. Dhoot concluded.
Data from the studies showed that at 2 years, sham-treated patients with moderately severe/severe NPDR at baseline were 6 times more likely to worsen to PDR. In patients with baseline DR levels of 47/53, the proportion of sham-treated patients who progressed to PDR as assessed by the ETDRS DRSS (DRSS level >60) increased over time from 2.3% at month 3 to 18.6% at month 24. In contrast, 0% and 2.7% of patients treated with ranibizumab (0.3 mg and 0.5 mg, respectively) progressed to PDR at month 24.
“The study shows that ranibizumab (RBZ) treatment delayed the time to a new proliferative event and reduced the probability of a patient experiencing a new proliferative event by 3 times compared with sham treatment. It also shows that 12.4% patients who received RBZ 0.3 mg and 11.9% of patients who received RBZ 0.5 mg encountered a new proliferative event at 36 months,” said Dr. Dhoot.
Adding to that, Dr. Wykoff said that anti-VEGF treatment is not a cure
| Sept/Oct 2020 40 ASRS 2020 COVERAGE CONFERENCE HIGHLIGHTS
As it turns out, food coloring does not improve eyesight . . . but it might cause rubber ducks to change color.
for DR, even if it works really well in suppressing its progression, improving DME and stopping the leakage. “Some eyes will progress and we need to be careful of that. To give an injection every few months indefinitely is a huge burden. In an ideal world, I would treat all eyes with moderate and severe DR to slow their progression, but it is an invasive procedure with risks and costs. So it is an individual choice,” he explained.
Dr. Wykoff added that the biggest challenge in treating DR is to be able to catch it during the stage when it is asymptomatic. “So many patients and practitioners thought that if there aren’t any noticeable symptoms and blurriness, things must be fine. We got to break away from that false perception. This is a disease which does not necessarily lead to blindness. We can slow it down. This is a disease which we are really good at treating (as a field) as long as we can get the patients in early and treat them appropriately,” he emphasized.
Meanwhile, Dr. Lloyd stressed the importance of treating the “right” patient. “From this data, we know that patients with level 53 retinopathy are excellent candidates for treatment. But when the DR severity is reduced, the ROI in terms of treatment is very, very low. So, the key is to know who you are treating and to pick the right patients,” he explained.
Optimizing DR treatment: The future is now
The panel then discussed optimizing DR treatment, as Dr. Charles Wykoff presented data from the PANORAMA trial, a phase 3, double-masked, randomized study of the efficacy and safety of intravitreal aflibercept in 402 eyes with moderate to severe NPDR (DRSS level 47 and 53). The objective of the trial was to demonstrate 2-step improvement for the use of aflibercept in DR, and to achieve regulatory approval. It involved 2 different dosing [levels], with the primary endpoint at 6 months and 1 year.
Results show that the proportion of patients with ≥2-step DRSS improvement was significantly greater
with aflibercept compared to sham. “In the 2q16 fixed-dose group, there’s stability of 2-step improvement in about two-thirds of eyes, while in the 2q8>PRN population, there’s up to 80% of eyes that achieved 2-step improvement up to 1 year. Moving to the second year, we see stability for the 2q16 group, which is an important clinical take-home point — fixed quarterly dosing maintains that level of improvement,” he said.
“In year 2, none of the patients in the 2q8>PRN group who received 3 to 6 injections developed proliferative disease or central-involved DME. This suggested that consistent, long-term dosing probably slows the disease progression. Meanwhile, 57.7% of eyes in the sham population developed vision threatening complication (VTC) or central-involved DME. There is a 75% reduction of risk in the aflibercepttreated population. Unfortunately, even with aflibercept treatment, we are still seeing disease progression in approximately 1 in 5 patients.”
The doctors agreed that the PANORAMA datasets are excellent for facilitating discussion with patients, and are helpful in convincing them that antiVEGF treatment is a reasonable choice for the treatment of DR.
Factors that increase the need for anti-VEGF treatment
DRCR.net Protocol V is the only trial in the modern era studying well-sighted eyes with central-involved DME in three different treatment paradigms: aflibercept; FLT plus deferred aflibercept; and observation plus deferred aflibercept. Primary outcomes at 2 years show that there were no significant differences between the three treatment modalities.
“The baseline factors associated with receiving aflibercept dosing, which is central subfield thickness, DRSS and fellow eye treatment. These factors were put into multivariable modelling and all three maintain significance. Looking at the dose-response at each category, we can see that thicker retinas correlated with an increased rate of needing aflibercept dosing.
“In summary, among eyes with centerinvolved DME and good central VA, clinical factors associated with an increased probability of needing treatment are: more advanced DR severity, greater amount of DME and fellow eye treatment of DME,” said Dr. Wykoff.
VEGF is not the sole cause of DR
In the final discussion, Dr. Wykoff talked about 5-year outcomes after initial aflibercept, bevacizumab or ranibizumab treatment for DME (Protocol T Extension Study).
“Following the 2-year core trial where patients are treated as SOC, single visits are made at 5 years after Protocol T enrollment, 4 visits were made annually in years 3 to 5, with 32% of patients receiving no anti-VEGF injections and 68% receiving at least 1 injection. The average is 4 anti-VEGF injections over 3 years,” he said.
“On average, there was a 5-letter loss from years 2 to 5. This VA loss was observed in both patients with better vision at baseline, as well as worse vision at baseline. Nevertheless, the anatomy was relatively stable from year 2 to 5, suggesting that DME was not the reason for vision loss. We also saw that the DRSS was relatively stable, with worsening of the more severe levels of DR,” explained Dr. Wykoff.
Thanks to the large dataset, the doctors came to the conclusion that VEGF is not the sole cause of DR and DME. Other factors, like the neurodegenerative pathway of DR, can play a part in the worsening of VA.
This satellite symposium at ASRS 2020 was held on 3 rd August 2020. Reporting for this story also took place during the session.
| Sept/Oct 2020 41
AI-based OCT Analysis Shows Superiority Over Retina Specialists
Big news for machine learning: Data analysis from AREDS 2 shows that the Notal OCT Analyzer (NOA; Notal Vision, Manassas, Virginia, USA), demonstrates superior performance to identify, quantify and map intra- and subretinal fluid in nAMD, as well as a higher level of accuracy compared to retinal specialists (who had imperfect accuracy and low sensitivity in detecting retinal fluid).
“The study results show how challenging it is to identify fluid especially when it is not very obvious,” said Michael Elman, MD, a co-author of the article. “In many
cases, the fluid that was missed was clinically meaningful. The analysis points at the potential benefit of an AI-assisted image review in routine clinical care when the time is limited.”
NOA had significantly higher sensitivity than retinal specialists (82.2% vs. 46.8%, respectively), with only moderately lower specificity (86.5% vs. 97.0%, respectively). This showed that retina specialists correctly identified retinal fluid in fewer than half of the cases. The substantially higher sensitivity of NOA is an important advantage, since the NOA-generated fluid thickness
DOG Celebrates “Father of Modern Ophthalmology” Albrecht von Graefe
The 150-year anniversary of the death of famous Berlin ophthalmologist Albrecht von Graefe was recently commemorated in a wreath-laying ceremony by the society he founded in 1857: the Deutsche Ophthalmologische Gesellschaft (DOG; German Society of Ophthalmologists). Considered to be the “father of modern ophthalmology,” Dr. von Graefe died at the young age of 42 from tuberculosis in 1870.
Among his contributions to ophthalmology, he was the first to describe numerous eye diseases and make considerable progress in ophthalmic surgery, by developing iridectomy to reduce intraocular pressure (IOP) in glaucoma patients. He also developed a cataract surgery technique using the
Graefe knife, which was used until the second half of the 20th century.
Today, he continues to receive praise as a “role model in medical and moral terms,” according to DOG President Prof. Dr. Hans Hoerauf.
“We should remember von Graefe´s principles, which emphasized empathic medical work for the benefit of the patient and the transfer of knowledge and skills to his many students,” said Prof. Dr. Hoerauf. “He teaches us not to be discouraged by difficult conditions, but to gain motivation from the joy of ophthalmological work and research, to maintain our own independence, and to consistently pursue our own ideals.”
heatmaps drew the physician’s attention to areas of fluid that otherwise might have been missed during volume scan review.
“AI-based software could assist physicians in detecting retinal fluid and informing patient management and treatment decisions once confronted with large amounts of images from patients regularly self-imaging on a future homebased OCT device,” said Gidi Benyamini, Notal Vision’s chief technology officer and director of the Notal Vision Innovation Center.
Throughout his lifetime, Dr. von Graefe was committed to serving the socially or economically disadvantaged. From 18511852, he set up a private eye clinic in Berlin, which soon became world famous.
“It was always important for von Graefe to balance between socially underprivileged and wealthier patients,” said Prof. Dr. Hoerauf. “The income from the private clinic served also for the free treatment of destitute patients.”
Berlin commemorates Albrecht von Graefe with several memorial sites, most important the von Graefe memorial at the Charité Clinic. Further, the DOG has proclaimed 2020 as “von Graefe Year.”
| Sept/Oct 2020 42 INDUSTRY UPDATE
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