September 21 | Vol 26 Issue 8
CATARACT & REFRACTIVE | CORNEA | RETINA | GLAUCOMA PAEDIATRIC OPHTHALMOLOGY
OZURDEX® (dexamethasone intravitreal implant) acts fast1,2 and lasts3–5 with less treatment visits compared with anti-VEGFs.5 Effective DME treatment doesn’t have to be a burden.6
The most commonly reported adverse events reported following treatment with OZURDEX® are those frequently observed with ophthalmic steroid treatment or intravitreal injections (elevated IOP, cataract formation and conjunctival or vitreal haemorrhage respectively). Less frequently reported, but more serious, adverse reactions include endophthalmitis, necrotizing retinitis, retinal detachment and retinal tear. This advert is consistent with the UK marketing authorisation. Licences may vary by country, please refer to your local country SmPC. DME, diabetic macular edema; IOP, intraocular pressure; VEGF, vascular endothelial growth factor. 1. Lo Giudice G et al. Eur J Ophthalmol 2018;28(1):74–79. 2. Veritti D et al. Ophthalmologica 2017;238(1–2): 100–105. 3. Escobar-Barranco JJ et al. Ophthalmologica 2015;233(3–4):176–185. 4. Allergan. OZURDEX® Summary of Product Characteristics. 5. Kodjikian L et al. Biomed Res Int 2018:8289253. 6. Boyer DS et al. Ophthalmology 2014;121:(10):1904–1914.
OZURDEX® (Dexamethasone 700 micrograms intravitreal implant in applicator) Abbreviated Prescribing Information Presentation: Intravitreal implant in applicator. One implant contains 700 micrograms of dexamethasone. Disposable injection device, containing a rod-shaped implant which is not visible. The implant is approximately 0.46 mm in diameter and 6 mm in length. Indications: Treatment of adult patients: with macular oedema following either Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO), inflammation of the posterior segment of the eye presenting as non-infectious uveitis and visual impairment due to diabetic macular oedema (DME) who are pseudophakic or who are considered insufficiently responsive to, or unsuitable for non-corticosteroid therapy. Dosage and Administration: Please refer to the Summary of Product Characteristics before prescribing for full information. OZURDEX must be administered by a qualified ophthalmologist experienced in intravitreal injections. The recommended dose is one OZURDEX implant to be administered intra-vitreally to the affected eye. Administration to both eyes concurrently is not recommended. Repeat doses should be considered when a patient experiences a response to treatment followed subsequently by a loss in visual acuity and in the physician’s opinion may benefit from retreatment without being exposed to significant risk. Patients who experience and retain improved vision should not be retreated. Patients who experience a deterioration in vision, which is not slowed by OZURDEX, should not be retreated. In RVO and uveitis there is only very limited information on repeat dosing intervals less than 6 months. There is currently no experience of repeat administrations in posterior segment non-infectious uveitis or beyond 2 implants in Retinal Vein Occlusion. In DME there is no experience of repeat administration beyond 7 implants. Patients should be monitored following the injection to permit early treatment if an infection or increased intraocular pressure occurs. Singleuse intravitreal implant in applicator for intravitreal use only. The intravitreal injection procedure should be carried out under controlled aseptic conditions as described in the Summary of Product Characteristics. The patient should be instructed to selfadminister broad spectrum antimicrobial drops daily for 3 days before and after each injection. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active or suspected ocular or periocular infection including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. Advanced glaucoma which cannot be adequately controlled by medicinal products alone. Aphakic eyes with ruptured posterior lens capsule. Eyes with Anterior Chamber Intraocular Lens (ACIOL), iris or transscleral fixated intraocular lens and ruptured posterior lens capsule. Warnings/Precautions: Intravitreous injections, including OZURDEX can be associated with endophthalmitis, intraocular inflammation,
increased intraocular pressure and retinal detachment. Proper aseptic injection techniques must always be used. Patients should be monitored following the injection to permit early treatment if an infection or increased intraocular pressure occurs. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy between two and seven days following the injection. Patients must be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay. All patients with posterior capsule tear, such as those with a posterior lens (e.g. due to cataract surgery), and/or those who have an iris opening to the vitreous cavity (e.g. due to iridectomy) with or without a history of vitrectomy, are at risk of implant migration into the anterior chamber. Implant migration to the anterior chamber may lead to corneal oedema. Persistent severe corneal oedema could progress to the need for corneal transplantation. Other than those patients contraindicated where OZURDEX should not be used, OZURDEX should be used with caution and only following a careful risk benefit assessment. These patients should be closely monitored to allow for early diagnosis and management of device migration. Use of corticosteroids, including OZURDEX, may induce cataracts (including posterior subcapsular cataracts), increased IOP, steroid induced glaucoma and may result in secondary ocular infections. The rise in IOP is normally manageable with IOP lowering medication. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex and not be used in active ocular herpes simplex. OZURDEX is not recommended in patients with macular oedema secondary to RVO with significant retinal ischemia. OZURDEX should be used with caution in patients taking anticoagulant or anti-platelet medicinal products. OZURDEX administration to both eyes concurrently is not recommended. Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, consider evaluating for possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Interactions: No interaction studies have been performed. Systemic absorption is minimal and no interactions are anticipated. Pregnancy: There are no adequate data from the use of intravitreally administered dexamethasone in pregnant women. OZURDEX is not recommended during pregnancy unless the potential benefit justifies the potential risk to the foetus. Lactation: Dexamethasone is excreted in breast milk. No effects on the child are anticipated due to the route of administration and the resulting systemic levels. However OZURDEX is not recommended during breast-feeding unless clearly necessary. Driving/Use of Machines: Patients may experience temporarily reduced vision after receiving OZURDEX by intravitreal injection. They should not drive or use machines until this has resolved. Adverse Effects: In clinical trials the
most frequently reported adverse events were increased intraocular pressure (IOP), cataract and conjunctival haemorrhage*. Increased IOP with OZURDEX peaked at day 60 and returned to baseline levels by day 180. The majority of elevations of IOP either did not require treatment or were managed with the temporary use of topical IOP-lowering medicinal products. 1% of patients (4/347 in DME and 3/421 in RVO) had surgical procedures in the study eye for the treatment of IOP elevation. The following adverse events were reported: Very Common (≥ 1/10): IOP increased, cataract, conjunctival haemorrhage*. Common (≥1/100 to <1/10): headache, ocular hypertension, cataract subcapsular, vitreous haemorrhage*, visual acuity reduced*, visual impairment/ disturbance, vitreous detachment*, vitreous floaters*, vitreous opacities*, blepharitis, eye pain*, photopsia*, conjunctival oedema*, conjunctival hyperaemia. Uncommon (≥1/1,000 to <1/100): migraine, necrotizing retinitis, endophthalmitis*, glaucoma, retinal detachment*, retinal tear*, hypotony of the eye*, anterior chamber inflammation*, anterior chamber cells/flares*, abnormal sensation in eye*, eyelids pruritus, scleral hyperaemia*, device dislocation* (migration of implant) with or without corneal oedema , complication of device insertion resulting in ocular tissue injury* (implant misplacement). (*Adverse reactions considered to be related to the intravitreous injection procedure rather than the dexamethasone implant). Please refer to Summary of Product Characteristics for full information on side effects. Basic NHS Price: £870 (ex VAT) per pack containing 1 implant. Marketing Authorisation Number: EU/1/10/638/001. Marketing Authorisation Holder: Allergan Pharmaceuticals Ireland, Castlebar Road, Westport, Co. Mayo, Ireland. Legal Category: POM. Date of Preparation: May 2019. UK/0288/2019
Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk/ Adverse events should also be reported to Allergan Ltd. UK_Medinfo@allergan.com or 01628 494026 JOB CODE: INT-OZU-2050217 DATE OF PREPARATION: DECEMBER 2020
Publishers Therese Dolan, Operations Director ESCRS Barbara Calderwood, Divisional Director Engagement Associations and Communities MCI UK Mark Wheeler, Finance Director MCI UK Editor-in-Chief Sean Henahan Senior Content Editor Kelsey Ingram Design Director Kelsy McCarthy Designer Jen Basel Circulation Manager Vanessa McCourt Contributing Editors Cheryl Guttman Krader Howard Larkin Dermot McGrath Roibeard Ó hÉineacháin Contributors Leigh Spielberg Gearóid Tuohy Priscilla Lynch Soosan Jacob Colour and Print W&G Baird Printers Advertising Sales Matthew Clapham MCI UK Tel: +44 7342887969 email: email@example.com
Published by the European Society of Cataract and Refractive Surgeons, Temple House, Temple Road, Blackrock, Co Dublin, Ireland. No part of this publication may be reproduced without the permission of the managing editor. Letters to the editor and other unsolicited contributions are assumed and subject to editorial review and acceptance. ESCRS EuroTimes is not responsible for statements made by any contributor. These contributions are presented for review and comment and not as a statement on the standard of care. Although all advertising material is expected to conform to ethical medical standards, acceptance does not imply endorsement by ESCRS EuroTimes. ISSN 1391-8983
A EUROPEAN OUTLOOK ON THE WORLD OF OPHTHALMOLOGY
04 Challenges and
CATARACT & REFRACTIVE 06 Attaining Excellence in IOL Power Calculations
08 New IOL Materials Offer Clear Opportunity
09 France Catches Up With 250,000-Case Backlog
10 Repeat Biometry Measurements
11 French Study Sheds Light on YAG Complications
12 Sporting Few Limits for Refractive Surgery
13 When to Choose LASIK or SMILE?
14 Re-Evaluate Your Refractive Surgery Screening
15 Three Cheers for Three CCC Simulators
16 Sensing Improved Phaco Safety
CORNEA 18 Treating Ocular Surface Disease Easy as MSC?
19 Keeping an Eye on COVID-19
As certified by ABC, the EuroTimes average net circulation for the 10 issues distributed between February and December 2019 was 47,863
RETINA 22 Envisioning Better
Neovascular Eye Disease Treatment
24 Retinal Prosthesis 26 Did COVID-19 Put a
Lockdown on Intravitreal Injection Adherence?
27 How Beneficial is Remote DR Care?
28 Calling All Virtual Eye Clinics
29 Scanning AI and
30 Portable Retina Imaging
PAEDIATRIC OPHTHALMOLOGY 31 Rapid Diagnosis in the Palm of the Hand
33 Ocular Update 34 Battling Toxic Adverse Events
35 Spotting Oppurtinity with Inclusive Vision Science
36 Everything You Need to Know About...
38 Resident Diary 39 Industry News 40 Calendar of Events
GLAUCOMA 20 Beyond Vision 2020 21 Pathways to Ocular Lymphatic Outflow
EUROTIMES | SEPTEMBER 2021
EDITORIAL A WORD FROM NINO HIRNSCHALL MD, PHD, MHBA, FEBO
I’m delighted to have the opportunity to write this editorial for EuroTimes.
Emanuel Rosen Chief Medical Editor
INTERNATIONAL EDITORIAL BOARD Noel Alpins (Australia), Bekir Aslan (Turkey), Roberto Bellucci (Italy), Hiroko Bissen-Miyajima (Japan), John Chang (China), Béatrice Cochener-Lamard (France), Oliver Findl (Austria), Nino Hirnschall (Austria), Soosan Jacob (India), Vikentia Katsanevaki (Greece), Daniel Kook (Germany), Boris Malyugin (Russia), Marguerite McDonald (USA), Cyres Mehta (India), Sorcha Ní Dhubhghaill (Ireland) Rudy Nuijts (The Netherlands), Leigh Spielberg (The Netherlands), Sathish Srinivasan (UK), Robert Stegmann (South Africa), Ulf Stenevi (Sweden), Marie-José Tassignon (Belgium), Manfred Tetz (Germany), Carlo Enrico Traverso (Italy)
EUROTIMES | SEPTEMBER 2021
What a Long Strange Trip It’s Been! – J. Garcia
hese are confusing times providing bewildering choices for all ophthalmologists, particularly those just beginning their careers. One moment you were preparing to do your first phaco, the next minute you were pressed into service in the COVID ward. Exams were postponed, studies delayed or virtualised, foreign fellowships cancelled, as we all faced the grim reality of shutdown. Now, thankfully, we are beginning to recover. The content of this month’s issue reflects many of the changes underway in our field of ophthalmology. The cover article by Dr Clare Quigley details the many challenges facing those young doctors just beginning their careers in these troubled times. Dermot McGrath reports from the annual meeting of French Society of Ophthalmology on the efforts underway among our French colleagues working to catch up on the huge backlog of cataract cases seen in association with the worst days of the pandemic. COVID-19’s impact on intravitreal injection adherence was a primary concern during the shutdown. Cheryl Guttman Krader describes a study looking at the effects of delayed anti-VEGF injections on patients’ vision. Telemedicine proved its worth during the dark days and will likely become a more important part of our clinical work. In another article, Moorfields researchers describe how the pandemic became a catalyst for improving the efficiency, effectiveness, and patient experience of clinical practice. Imagine your entire healthcare software system were to crash on a national level. Clare Quigley describes working through just such a crisis when Ireland’s entire hospital record system was hit with a ransomware attack. Of course, the pandemic also led to cessation of in-person medical conferences around the world, introducing us to the idea of the virtual conference. The situation is still fluid when it comes to conference attendance. The recent ARVO conference was entirely virtual as was the last ESCRS, while the annual ASCRS conference in Las Vegas was entirely in person, with no streaming option. This year, the 39th Congress of the ESCRS will take place in Amsterdam, October 8 through 11. The Congress programme has been designed to allow delegates to participate fully, either in person or virtually. For those who are unable or unwilling to travel, virtual seating will be available. Please check our website at escrs.org for the latest guidance on the conference. As we crawl from the wreckage of the past 16 months, let’s hope we can finally get back to doing what we’ve trained for—caring for the vision needs of our patients.
Assoc. Professor Nino Hirnschall MD, PhD, MhBA, FEBO VIROS – Vienna Institute for Research in Ocular Surgery, Hanusch Hospital, Vienna, Austria.
ESCRS Education Portal An ESCRS Education Resource Centre Continue your education year-round wth ESCRS
EUROTIMES | SEPTEMBER 2021
SPECIAL FOCUS: LOOKING FORWARD
Challenges and Looking Forward Dr Clare Quigley, herself a young ophthalmologist, surveys the world now faced by those who have been obliged to enter the vision care profession in the midst of a global pandemic and who must now continue their careers as the world begins to heal.
tarting out, the learning curve was steep. Picking up a 90D and attempting to puzzle out whether a retina was attached or not, I remember vividly. Staring at an anterior chamber, willing myself to spot cells that I knew I should see floating there, and failing to spot any. Facing a crying uncooperative toddler who had burst a liquid-detergent tab in their eyes and their tired, worried parents; making an effort to appear professional and competent but feeling intimidated. I was learning on the job—watching the seniors to see how they did things and reading what was presented to me on call or in clinic. It was challenging. There was just so much to take in. In surgery too. Wet labs and Eyesi sessions certainly did help,
EUROTIMES | SEPTEMBER 2021
but operating on a living eye attached to a human head was a world apart. At that point, at the start of training, the gaps in my knowledge and experience felt huge, though I was working hard at building a scaffold to bridge them. Of course, I was never alone. With the other junior trainees, we learned together from our seniors. We especially learned from the Registrars, who were only a few years more experienced than us and yet seemed omnipotent, through our first-year ophthalmology trainee eyes. Registrars like Elizabeth McElnea, who methodically took me through the steps of phaco, and Emily Hughes, at my shoulder with encouraging whispers when I did my first full cataract surgery.
SPECIAL FOCUS: LOOKING FORWARD
I would include in this too: developing skills in research and teaching. There is a lot to learn, and we can do this when we have our downtime from surgery, when elective lists are cancelled. Reading, listening to podcasts, watching videos. Working on research and audit. Many of us have learned how virtual clinics work, as well as their limitations. There is a substantial amount we can still do to develop as ophthalmologists and improve our performance when we can’t get into the operating room.
SMELL THE ROSES
CHALLENGES—PREDICTABLE AND NOT SO PREDICTABLE Following that first year of training, the learning curve tapered to a more comfortable slope. Ophthalmology got more enjoyable the more familiar we got with the eye. But challenges were not over, as training continued. There are predictable challenges for us all. Licensing exams that include the whole range of topics in ophthalmology; exams that require reading dense tomes alongside recent publications to be sure to cover everything. We progress to tackling trickier surgical problems as our skills develop. Then, for many of us, there can be challenges taken on voluntarily, like starting a family while training, taking on a higher degree or a substantial research project, or moving abroad for fellowship training. Those things add another element to what already is a packed clinical schedule—requiring skills in organisation and time management in order to juggle commitments and deadlines alongside training requirements. Free time whittles away mercilessly. Then there are the challenges that come out of nowhere. If you talked about a global pandemic two years ago, you would be laughed off as having an overactive imagination. The notion would have seemed more science fiction than a real-life risk. How everything has changed. Even now, we are seeing a fourth wave starting here in Ireland. The suffering induced by the virus and all the knock-on effects on the health service are immense. For long months, very little elective surgery was happening. Some patients did go blind, waiting for cataract surgery. For young ophthalmologists, our training aims, our target surgical numbers, became impossible to achieve. How to deal with that? For many of us who missed out on vital hands-on experience, training will take longer. Other unannounced challenges arise for all of us during our training. I hope other health services do not experience a cyberattack such as the one we had in Ireland, that we are only now recovering from. On a personal side, too, we experience loss, or sickness, affecting our loved ones.
At the same time, we should not deny these times are a major source of stress. That slightly twee-sounding proverb, ‘Physician, Heal Thyself’, expresses an important idea: To be in any form to look after others, we must first ensure we are well. Taking time to get outside and spending time with family and friends (as much as the latest iterations of lockdown restrictions allow), is important. Those absolute basics, eating and sleeping well, are also vital. Lately at the weekend, we get outside for a stroll. A short walk from our house takes us to the entrance of the National War Memorial Gardens. A tree-lined path winds downhill through the gardens towards the Liffey. Centrally, the park opens in a wide terrace, with pergolas overlooking sunken rose gardens. Roses of every colour are tended to there, their scent filling the air now, in summertime. Michael invariably tries to climb into the central fountain, and we move on as he protests. Rowers do their lengths in front of the gardens, traversing the Liffey up towards Chapelizod. We hit the local coffee shop and then go home. It’s the simple things that recharge depleted batteries at the weekend. At this point, I am among the more senior trainees, nearing the end of training. I am the one who is helping the junior learn phaco. It makes me better appreciate the patience and judgement of the Registrars who taught me, when it is now me who is inviting the junior to sit in the operating chair. Teaching has its own learning curve, I am discovering. A Consultant is always close by, supervising, but I am now the one at the junior trainee’s shoulder. We are all learning, moving forward on the road to becoming Consultant Ophthalmologists. Even if that road is sometimes bumpy, we are on the way there. Recalling the carnival atmosphere of the ESCRS meeting I first experienced in the Athens, the 2016 winter meeting, brings back warm memories. Running into friends at Dublin airport. Staying in an Airbnb far from the conference venue, figuring out how we could navigate the city. Discovering the breadth of sessions and the huge exhibition floor. Lunches and dinners, coffees and walks together around a beautiful city. We have all missed that. But we will do it again! Not everyone who wants to will be able to travel this year, if the international travel restrictions remain tight, but we will meet again.
WHAT’S NEXT? How do we continue to learn and develop as young ophthalmologists in the current turbulent training conditions? The bottom line remains the same—our patients. We should use this time as best we can to maximise the benefit we can bring to them through our care—by developing fully as clinicians.
Clare Quigley is a resident at the Royal Victoria Eye and Ear Hospital, Dublin, Ireland.
EUROTIMES | SEPTEMBER 2021
CATARACT & REFRACTIVE
Attaining Excellence in IOL Power Calculations
Dermot McGrath reports
lthough perfection is not a realistic goal, excellence in refractive outcomes is certainly achievable for the majority of patients undergoing cataract surgery today, according to Adi Abulafia MD. “Perfection is not attainable, but if we chase perfection, we can catch excellence,” Dr Abulafia said in his keynote address at the online annual meeting of the French Implant and Refractive Surgery Association (SAFIR). In a wide-ranging lecture, Dr Abulafia—Director of Cataract Services, Ophthalmology Department, Shaare Zedek Medical Centre, Jerusalem, Israel—focused on the remaining challenges towards attaining optimal refractive outcomes for cataract patients. “Even with all the advances in technology and calculation formulas over the past decade, we are still hovering at a figure of about 80% of patients achieving within 0.50D of their target refraction. That means one out of every five patients will be off target by more than 0.50D, so there is clearly plenty of scope for improvement,” he said. Dr Abulafia noted five key areas worth highlighting in the quest for better outcomes: accurate preoperative measurements, optimised IOL power calculations, reduced postoperative refractive astigmatism, personalised refraction according to patient needs, and systematic tracking of refractive outcomes.
“Perfection is not attainable, but if we chase perfection, we can catch excellence.” Adi Abulafia MD
AXIAL LENGTH In terms of preoperative biometry, Dr Abulafia said axial length measurements are no longer a major source of inaccuracy, thanks to advanced technology such as swept-source OCT. “With swept-source OCT, we can maintain a high level of accuracy even in posterior subcapsular and dense cataracts. It makes the use of ultrasound measurements redundant—except perhaps for very dense and mature cataracts,” he said. It also remains challenging to achieve consistently accurate and reliable measurements for total corneal power, he added. “Many of our biometry devices measure the anterior corneal curvature in limited zones and extrapolate posterior corneal curvature based on population average-fixed ratios to calculate the estimated total cornea power. While extrapolating the posterior corneal power by a fixed ratio can induce
variability in normal corneas, the effect is even more pronounced in atypical corneas such as post-refractive surgery or keratoconus. This will also lead to errors in toric IOL calculations since we are ignoring the posterior corneal astigmatism,” he explained. Although technologies such as Scheimpflug devices and swept-source OCT are capable of directly measuring the posterior cornea, Dr Abulafia said the accuracy is still far from optimal. “The small difference in refractive indices between posterior cornea and aqueous makes it a tough surface to identify and quantify,” he said. “There is also no gold standard to validate our measurements. However, a clear advantage of most of the new measuring devices is we can look at raw data to evaluate the actual quality of our measurements to decide whether they are good enough or not.” Eyes with ocular surface disorders such as dry eye, corneal dystrophies, and pterygia, he added, need to be treated first, then remeasured.
MACULAR OCT Dr Abulafia also suggested introducing macular OCT scans as a routine part of the preoperative work-up. “In a recent study, we found routine macular OCT scans in cataract patients can help identify macular disease that might be missed or underestimated by standard preoperative examination and can significantly improve patients’ management,” he said. To optimise IOL power calculations, Dr Abulafia advised surgeons to use more recent formulas, drawing on newer EUROTIMES | SEPTEMBER 2021
CATARACT & REFRACTIVE
technologies such as paraxial ray tracing, internal sophisticated algorithms, and artificial intelligence (AI) for higher prediction accuracy across a wide range of IOL powers. “And remember, no formula is perfect, so it is always advisable to compare several formulas before choosing the desired IOL power,” he said. Nailing spherical equivalent (SE) refraction is just one step in the process. Another important challenge is reducing post-op refractive astigmatism. “It is better to use predicted postoperative residual astigmatism as a reference and use several measuring devices where possible. We also need to account for posterior corneal astigmatism and other factors, such as IOL tilt, in our calculations. For this, we can use regression formulas, such as the Abulafia-Koch formula, to compensate for the differences between anterior corneal-based measurements and post-op refraction and improve our outcomes with toric IOLs,” he said. Establishing individual values for surgically induced astigmatism (SIA) can also improve outcomes, he explained. “This can be a tedious process, and it is not always feasible in
some clinical settings. A reasonable compromise would be to use consistent corneal incisions with a low corneal SIA value somewhere between 0.0D and 0.20D,” he said. The importance of chair time and understanding the patient’s refractive needs in terms of their profession and lifestyle should also not be underestimated. “We need to tailor the target refraction to our patients’ needs. Hitting the surgeon’s desired refraction can be a complete failure if it is not aligned with their requirements,” he said. Finally, Dr Abulafia underscored the need to track refractive outcomes. “This is perhaps the most tedious task of all, but never tracking patients is like a chef who never tastes his own cooking. We need this information to constantly improve our outcomes,” he concluded.
Adi Abulafa: firstname.lastname@example.org EUROTIMES | SEPTEMBER 2021
CATARACT & REFRACTIVE
New IOL Materials Offer Clear Opportunity Research opens clear path to improved IOL materials. Roibeard Ó hÉineacháin reports
fter decades of dominating the intraocular lens (IOL) material market, hydrophobic and hydrophilic acrylates may soon face competition from non-acrylate materials, said Gerd Auffarth MD, PhD, FEBO, Ruprecht Karl University of Heidelberg, Heidelberg, Germany. Today’s non-acrylate materials offer superior optical properties and better biocompatibility without risk of latent opacification. Rigid PMMA lenses, foldable silicone lenses, and early acrylic foldable lenses came onto the market in the ’80s and ’90s. However, by 2017, hydrophilic and hydrophobic acrylates accounted for 85% of global IOL market share for IOL materials while PMMA accounted for 12%, and silicone for a mere 3% of market share, Dr Auffarth told the Association for Research in Vision and Ophthalmology (ARVO) 2021 Annual Meeting. The advantages of hydrophobic acrylate IOLs include a higher refractive index, which allows for thinner IOLs, and adhesive properties that give good rotational stability and a low rate of posterior opacification (PCO). Alternatively, hydrophilic IOLs can be easily moulded into any desired shape and are flexible enough to allow for injection through very small incisions. Whether hydrophobic or hydrophilic, opacification is a problem with all acylate material lenses. In hydrophobic IOLs, this takes the form of “glistenings”, microvacuoles that result from fluid seeping into the empty spaces within the material’s polymer structure. Optical bench testing indicates glistenings have little effect on modular transfer function (MTF) but significantly increase stray light. In hydrophilic IOLs, opacification is an outcome of calcification, which can result from defects in the material and changes in the aqueous milieu—as may occur during intraocular surgery and in patients with conditions such as uveitis and diabetes. Dr Auffarth and his associates at the university’s David J Apple Laboratory for Ocular Pathology have developed means of testing the susceptibility of lens materials to glistenings and calcification. He noted that over the past 20 years, this type of research has led to the development of virtually glistenings-free hydrophobic acrylic IOLs such as the modern AcrySof IOLs and the Clareon IOLs (Alcon). A non-acrylate material called cross-linked polyisobutylene (xPIB) is now under investigation as an IOL material, Dr Auffarth said. He added xPIB has been FDA approved since 2004 for use in coronary stents, and research has shown it has very good biocompatibility. It has a high refractive index (1.52) and is highly elastic, meaning it could be used for large-optic IOLs implantable through a sub-2.0mm incision. It also induces less chromatic aberration. Moreover, its molecular structure ensures xPIB is not susceptible to glistenings or calcification. Gerd Auffarth: email@example.com EUROTIMES | SEPTEMBER 2021
CATARACT & REFRACTIVE
France Catches Up With 250,000-Case Backlog Safe short circuit for cataract surgery reduces need for anaesthesiologist. Dermot McGrath reports
ataract surgery can be performed safely with a high degree of patient satisfaction without perioperative anaesthetic care, according to a study presented at the online annual meeting of the French Society of Ophthalmology (SFO). Successful, safe surgery can occur in an outpatient or hospital setting under topical anaesthesia. “Our experience has shown that a secure short circuit (SSC) for surgeries of the anterior segment of the eye under topical anaesthesia can be safely and effectively implemented. This corresponds with the increased need for cataract surgery in the wake of the COVID-19 crisis and the ongoing shortage of anaesthesiologists in certain regions,” said Bahram Bodaghi MD, PhD, FEBO. Dr Bodaghi, Professor of Ophthalmology and Visual Sciences at the University of Pierre and Marie Curie in Paris, France, said creative solutions are absolutely necessary to respond to the growing demand for healthcare in a context of demographic and post-COVID-19 pressure. “More than 900,000 phacoemulsification surgeries were carried out in France in 2019, which was reduced by 250,000 in 2020 in connection to COVID-19. The situation is still under stress in 2021, with a net reduction in resources in terms of available anaesthesiologists in both private and public healthcare. The problem has also been exacerbated due to the uneven distribution of ophthalmologists in certain regions in France, particularly rural areas and medical deserts where healthcare providers are severely lacking,” he said.
The French National Authority for Health (HAS) has loosened the regulations regarding the use of anaesthesia for cataract surgery within the last few years, Dr Bodaghi explained. In a recent update, HAS emphasised the choice of technique should be made in consultation between the patient, the surgeon, and the anaesthesiologist. Whatever the choice, HAS recommended a course of care providing for a preoperative anaesthesia consultation as well as intraoperative medical monitoring for all patients to secure care. For the secure short circuit proposed in Dr Bodaghi’s retrospective study, patients were first selected by surgeons before answering a medical questionnaire. They did not have any preoperative evaluation by an anaesthesiologist, received monitoring during surgery by the surgical team, and, in case of a problem, had an intraoperative medical action (IMA) performed. The primary outcome was identifying IMA risk factors among the patients’ medical history, followed by a case-control study. Out of 2,744 screened patients, 1,592 were included. The team found a 5% IMA rate among patients, 81% of which were for intraoperative high blood pressure. In the case-control study, regression analysis revealed a correlation between a history of high blood pressure and insulin-dependent diabetes and IMA. When summing up the findings, Dr Bodaghi said the low incidence of IMA showed the secure short circuit as a safe strategy thanks to rigorous patient selection and an optimised and secure pathway. Bahram Bodaghi: firstname.lastname@example.org
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EUROTIMES | SEPTEMBER 2021
CATARACT & REFRACTIVE
Repeat Biometry Measurements Ocular biometry in adults changes little time over time. Roibeard Ó hÉineacháin reports
xial length (AL) and average keratotomy (KER) measurements appear to change very little over time, suggesting ophthalmologists may not need to repeat ocular measurements prior to cataract surgery as frequently as previously presumed, said Nicholas K Chan MD at the ARVO 2021 Annual Meeting. “These results suggest repeating biometry at one- to two-year intervals during surgical workup may not be a necessity. Rather, the measurements can be used selectively, like in high myopes, for example,” said Dr Chan, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. In the retrospective study, Dr Chan and his associates analysed sequential biometry data in 402 eyes of 201 patients obtained with the IOLMaster® 700 (ZEISS) from January 1, 2016, to September 15, 2020, at the Northwestern Memorial Hospital in Chicago. To be included in the study, patients had to have two biometry measurements over six months apart and be more than 35 years of age. Patients were excluded if they had any other intraocular surgery other than cataract.
SMALL, TIME-INDEPENDENT CHANGE IN BIOMETRY PARAMETERS The study included 119 women and 88 men with an average age of 73 years. The average time between biometry measurements was 21.5 months, average AL was 24.08mm, and the average KER was 43.73D. The mean change in AL between measurements was 0.04mm, and the mean change in KER was 0.10D (p=0.33). Dr Chan noted an analysis using a linear regression model showed no correlation between the length of time between measurements and change in AL or KER. The mean change in AL was 0.04mm among eyes with an interval between measurements of six months to one year, 0.05mm in eyes with a two- to three-year interval, and 0.04mm in eyes with a three- to four-year interval. Eyes with high myopia showed the greatest mean change in axial length (0.07mm), but this was still a small change and not significantly greater than the AL change in eyes with hyperopia (0.04mm), average length eyes (0.04mm), and eyes with moderate myopia (0.03mm). “Axial length and keratotomy changed minimally over time between biometry measurements. The amount of change did not significantly increase with the length of time between measurements, even at large intervals like three to four years, and myopic eyes did not have a significantly greater change in axial length than shorter eyes,” Dr Chan summarised. Nicholas Chan: email@example.com EUROTIMES | SEPTEMBER 2021
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French Study Sheds Light on YAG Complications
Timing of YAG laser treatment implicated in complications. Dermot McGrath reports
lthough Nd:YAG laser capsulotomy remains the gold standard posterior capsule opacification (PCO) treatment after cataract surgery, more data and largescale studies are needed to better understand the risk of complications associated with its use, according to Corinne Dot MD, PhD, Lyon, France. “While the complications of Nd:YAG laser treatment have been known for years, there is still much to learn about the incidence and onset time of such complications—all the more so when one considers YAG capsulotomy is the most common ocular procedure practiced in France after cataract surgery,” Prof Dot said at the online annual meeting of the French Implant and Refractive Surgery Association (SAFIR). Nd:YAG laser capsulotomy complications that cause decreased vision are uncommon but include ocular hypertension (OHT), cystoid macular oedema (CME), retinal detachment, IOL damage, endophthalmitis, iritis, and vitritis. To shed light on the issue, Prof Dot carried out a noninterventional longitudinal cohort study using secondary data from a General Sample of Beneficiaries (EGB) database of patients who underwent Nd:YAG laser capsulotomy between 2014 and 2017 in France. The EGB is a permanent sample representative of 1/97th of the French population. Excluded were patients under 18, those with a history of OHT/glaucoma,
retinal surgery, and medical retina treatment within 12 months of Nd:YAG laser treatment. The study focused on three complications: OHT/glaucoma, retinal detachment, and macular oedema. All three complications were identified in 13.3% of the 6,210 patients included at the oneyear follow-up point after Nd:YAG. The complications occurred within three months for 68% of patients and within six months for 81%. Specifically, the 12-month incidence of OHT/glaucoma, macular oedema, and retinal detachment was estimated to be 9.6%, 6.4%, and 0.4%, respectively, Prof Dot said. “The interval between surgery and Nd:YAG laser treatment showed that complications were more frequent in cases of early treatment—notably, maculopathy if the laser followed within one year of surgery, and OHT/glaucoma if the Nd:YAG laser treatment occurred within two years of surgery,” she said. Summing up, Prof Dot said the data from the French study needed to be evaluated against the natural history of the pathologies in question to understand more about the risk of complications after Nd:YAG laser treatment. “It also highlights the importance of developing and using fibrosis-free IOLs in our cataract surgeries,” she concluded. Corinne Dot: firstname.lastname@example.org
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EUROTIMES | SEPTEMBER 2021
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One-stop-shop Registries in Ophthalmology
Sporting Fewer Limits for Refractive Surgery Dermot McGrath reports
Outcome & Risks
andidates for refractive surgery should be given clear and up-to-date information regarding the potential impact any surgery may have on their occupational status, career choice, and ability to practise certain sports, according to Francoise FroussartMaille MD. “The legal regulations and standards regarding certain refractive techniques are not always clearly defined and vary greatly depending on the specific profession concerned. They are also liable to change over time, so candidates need to check the requirements for each profession and understand it’s only one aspect of the evaluation,” Dr Froussart-Maille said at the online annual meeting of the French Society of Ophthalmology (SFO). In a detailed overview of the limits for refractive surgery in France, Dr Froussart-Maille, an ophthalmologist at Percy Army Training Hospital, Clamart, France, said the overall goal was to explain the possible consequences of each type of surgery to enable candidates to make an informed choice that would not hamper their professional or sporting capabilities. “Refractive surgery can have a functional impact on a patient’s vision in terms of halos, glare, nychthemeral variations in visual acuity, contrast sensitivity, binocular vision, mesopic vision, dry eye, and so forth, all of which may affect their performance,” she said. Since 2017, the procedure to obtain a medical certificate for the practise of most sports in France has been simplified, except for certain combat/contact sports where there is a higher risk of injury and the rules tightened, she explained. “In combat sports, federal restrictions may limit the use of certain surgical techniques deemed riskier, such as LASIK or phakic implants. The retinal risks associated with high myopia may also constitute a contraindication,” she said. For most professions, the patient’s history of intraocular surgery is not part of the required standards. However, specialist advice may be requested after eye surgery in specific trades where safety is an issue, such as drivers, air traffic controllers, or aviation or military personnel, Dr FroussartMaille said. She noted the norms vary greatly from one profession to the next in terms of required postoperative recovery time, initial ametropia, and type of surgery performed. “Some additional exams may be required to assess contrast sensitivity, glare sensitivity, and quality of vision. Refractive treatments for presbyopia such as PresbyLASIK, presbyopic lens exchange, or monovision may also be a potential contraindication for some professions,” she said.
Francoise Froussart-Maille: email@example.com EUROTIMES | SEPTEMBER 2021
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When to Choose LASIK or SMILE? LASIK and SMILE deliver comparable results in head-to-head study. Dermot McGrath reports
atients with myopia and myopic astigmatism have a reason to grin: a head-to-head study presented at the online annual meeting of the French Implant and Refractive Surgery Association (SAFIR) declared both SMILE and femtosecond LASIK as safe, effective, and predictable surgical procedures. “Our results confirm the refractive precision of both SMILE and LASIK, which allow rapid visual rehabilitation for all eyes from the first postoperative day, with all patients reporting an enhanced quality of life after their refractive surgery,” said Catherine Albou-Ganem MD, Clinique de la Vision, Paris, France. Dr Albou-Ganem’s prospective, randomised, double-blind study was carried out at the Clinique de la Vision, on 14 eyes of 7 patients for SMILE and 26 eyes of 13 patients for LASIK. The inclusion criteria were myopia associated with astigmatism greater than 0.75D, regular topography, and corneal thickness of at least 500 microns. All LASIK and SMILE procedures were simultaneous bilateral surgeries. The corneal flap for LASIK was created using the VisuMax femtosecond laser (Carl Zeiss Meditec) with a thickness of 110 microns, followed by topographyguided photoablation (Topolink, Wavelight Allegretto, Alcon Laboratories). All SMILE procedures used the VisuMax laser with a cap thickness between 120 and 140 microns depending on the patient’s corneal thickness and the ametropia for correction. Dr Albou-Ganem said she routinely inspects the same indications for SMILE as for LASIK in terms of the residual stromal bed. “We need to remember there have been some cases of ectasia with SMILE in the literature. I therefore leave at least 250 microns, and preferably more, of residual stromal bed. If the topography does not allow me to perform a LASIK, then I won’t perform SMILE for such eyes either,” she said. The key parameter analysed in the study was visual acuity outcomes from the first day postoperation to three months. In terms of results, the evolution of the refraction was very similar in both groups, with a mean sphere of +0.05D and cylinder of -0.14D for LASIK at three months, and -0.02D and -0.23D respectively for the SMILE group. The uncorrected visual acuity results were also excellent for both groups, Dr Albou-Ganem noted. “They were very much in line with the outcomes presented by Vance Thompson MD at the last ESCRS Congress, which showed the predictability and accuracy of the MRSE correction with SMILE was comparable to or better than LASIK six months after surgery,” she said. Summing up, Dr Albou-Ganem stated the SMILE results for myopic astigmatism were very encouraging, but she still prefers customised LASIK treatments when the cylinder values exceeded the sphere. She said soon, VisuMax software will incorporate cyclotorsion control, which should further improve outcomes for SMILE in astigmatic patients.
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Catherine Albou-Ganem: firstname.lastname@example.org EUROTIMES | SEPTEMBER 2021
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Re-Evaluate Your Refractive Surgery Screening Epithelial thickness mapping adds value for eligibility determinations and surgical planning. Cheryl Guttman Krader reports
CT-derived epithelial mapping appears promising as an adjunctive screening tool for corneal refractive surgery decision making, new research suggests. The research, presented at the 2021 ARVO Annual Meeting, included data for 100 consecutive patients who attended the Cleveland Clinic Cole Eye Institute, Cleveland, Ohio, USA, for corneal refractive surgery. It showed when two masked reviewers had access to epithelial mapping in addition to Scheimpflug tomography, clinical data, and patient history, determinations on candidacy and surgery choice changed in a substantial percentage of cases. J Bradley Randleman MD, Professor of Ophthalmology, Cleveland Clinic Cole Eye Institute, told EuroTimes, “We feel there are significant advantages to using epithelial mapping for patient evaluations, particularly for borderline cases. Using this technology, more patients have been ruled in for surgery than excluded. “However, it is important to point out that epithelial mapping is not used in isolation. Rather, the findings correlated with curvature and elevation patterns from Scheimpflug tomography, and we also consider patient age, corneal thickness, and refractive error,” he continued. Dr Randleman said he began using OCT-derived epithelial mapping for refractive surgery patient evaluations in 2014. He credited work done by Dan Reinstein MD on epithelial remodeling done with high-frequency digital ultrasound and David Huang MD for developing OCT epithelial thickness mapping and demonstrating differences between keratoconic and normal corneas. “After evaluating epithelial mapping with OCT as a screening tool in our own practice, we began using it routinely,” he said. A normal cornea tends to have a gradient of epithelial thickening with slightly greater thickness inferiorly. Therefore, when one sees mild inferior steepening on curvature, it is reassuring to find with thicker epithelium inferiorly. However, seeing central or paracentral epithelial thinning raises concern. This is especially true if there is focal thinning with surrounding epithelial hypertrophy, he explained. EUROTIMES | SEPTEMBER 2021
In the retrospective study, after the reviewers evaluated the epithelial maps, their decisions on surgery candidacy changed for 17% of patients. In 59% of the latter cases, patients previously screened out were deemed eligible for surgery. Among patients who remained eligible for surgery after the epithelial maps reviews, the decision on surgery of choice changed in 21% of cases. In the subgroup of cases for which surgical decisions were unchanged after reviewing the epithelial maps, the information still had an impact, as it increased the reviewers’ confidence in their decision in 49% of cases and decreased their confidence in 18% of cases, Dr Randleman noted. J Bradley Randleman: email@example.com
CATARACT & REFRACTIVE
Three Cheers for Three CCC Simulators
Capsulorhexis training devices differ in their similarity to actual surgery. Roibeard Ó hÉineacháin reports
study in which surgeons evaluated three commercially available continuous curvilinear capsulorhexis (CCC) simulators—SimulEYE, Kitaro, and Bioniko—suggests each simulator has its unique advantages, Nilesh Raval MD said at the ARVO 2021 Annual Meeting. “The SimulEYE and Kitaro models were thought to most closely approximate actual capsular tissue, and surgeons performed the CCC faster on these kits than on the Bioniko model. However, surgeons did create a 5.5mm CCC most accurately on the Bioniko and SimulEYE models,” said Dr Raval, Montefiore Medical Center, Bronx, New York, USA. The study involved seven expert cataract surgeons who performed a simulated CCC using the three devices in a randomised order for a total of three trials on each model. The target size of the CCC was 5.5mm, and the surgeons carried out the procedures under standard operating room conditions using videoenabled Lumera (ZEISS) microscopes, Dr Raval said. He noted the Kitaro simulator has an open-sky configuration and comes with premade corneal incisions. It has a 5.0µm-thin polyester anterior capsule and a reusable artificial nucleus made of resin clay. The SimulEYE kit has a central pupil diameter of 8.0mm and requires a corneal incision and viscoelastic. The Bioniko simulator has a central pupil diameter of 9.0mm and an open-sky design but with a limbal ridge that necessitates a corneal incision. Dr Raval and his associates examined the duration of the procedures, the capsulorhexis size, and the number of capsular forceps manipulations, or “grabs”, required and analysed their findings with multiple regression analyses. They found statistically significant differences among the simulators and across the three trials for all outcome measures. For example, the mean number of grabs the surgeons required to create the CCC was 6.53 with the Bioniko model, compared to 4.90 with the Kitaro model (p=0.01) and 3.90 with the SimulEYE model (p<0.0001). Importantly, however, the Bioniko model is purposefully designed to encourage more capsular grabs. Regarding CCC size, the mean rhexis diameter was 8.0mm with the Kitaro model, compared to 5.24mm with the Bioniko model and 5.11 with SimulEYE model (p<0.0001). Regarding procedure duration, surgeons spent a mean of 41.95 seconds performing the CCC on Bioniko, compared to 32.05 seconds on Kitaro (p=0.02) and 28.90 on SimulEYE (p=0.002). When asked to rate how well each simulator approximated human tissue on a modified Likert scale of 1–7, the surgeons gave the Kitaro and SimulEYE models a mean score of 4.56 and 4.19, respectively, which were higher than the mean score of 1.38 for the Bioniko model (p<0.0001). Overall, while SimulEYE performed better in more categories, each of the three simulators touts its own unique advantages and disadvantages, Dr Raval concluded.
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Sensing Improved Phaco Safety Handpiece with dynamic IOP sensor protects against occlusion surge. Dermot McGrath reports
new phacoemulsification handpiece that includes an integrated pressure sensor may help overcome problems associated with variable infusion and aspiration rates that affect intraocular pressure (IOP) during cataract surgery, according to a study presented at the online annual meeting of the French Implant and Refractive Surgery Association (SAFIR). “This handpiece allows us to operate closer to the real-time physiological IOP of the patient. It also protects against post-occlusion surges and incision leaks and provides automatic detection of the patient eye level (PEL), which is important to calibrate the fluidics accurately in the system,” said Pascal Rozot MD, Clinique Juge, Marseille, France. With the traditional handpiece, pressure alterations at the phaco probe tip travelled to a sensor near the cassette at the speed of sound with adjustments made at the Active Fluidics unit level. Using the ACTIVE SENTRY handpiece, however, the IOP is measured in real-time, intraoperatively, as the new handpiece is equipped with an integrated pressure sensor (Fig 1) and communicates directly with the fluidics regulation system. The result is a faster response to fluctuations in IOP during surgery and greater anterior chamber stability, Dr Rozot explained.
Fig 1: Pressure sensor in the ACTIVE SENTRY handpiece (image from Alcon Lab)
“This handpiece allows us to operate closer to the realtime physiological IOP of the patient.” Pascal Rozot MD Dr Rozot’s prospective non-randomised study compared the performance of the new ACTIVE SENTRY handpiece (Alcon Laboratories) to the classic handpiece on the Centurion Vision System (Alcon). A total of 109 eyes were included and divided into two groups matched for age, sex, and cataract density: 43 eyes for ACTIVE SENTRY and 66 eyes for the classic handpiece. Due to the higher performance of the ACTIVE SENTRY handpiece, aspiration parameters used for the quadrants’ nucleus removal increased by 25%, whereas the IOP could lower to 34mmHg. The parameters assessed included total intervention time, cumulative dissipated energy (CDE), total ultrasound time, fluid use, and total aspiration time. In terms of outcomes, the total intervention time was slightly longer for the ACTIVE SENTRY handpiece group, but the difference was not statistically significant. The total CDE significantly reduced using the ACTIVE SENTRY handpiece (9.41 seconds) compared to the classic handpiece (12.73 seconds). Total ultrasound time was also reduced from a mean of 63.7 with the classic handpiece to 53.8 with ACTIVE SENTRY (Fig 2). Fluidics use reduced, too, with ACTIVE SENTRY (43.35 cc) compared to the traditional handpiece (47.26 cc). Putting the results into context, Dr Rozot said less energy delivered into the eye with ACTIVE SENTRY should equate to safer, more stable surgery. “ACTIVE SENTRY reduced the quantity of fluid used by around 8% with a reduction of up to 25% ultrasound energy delivered into the eye. The new handpiece enables us to work with a physiological IOP and protect against occlusion surge. I think it will be particularly valuable to use in high-risk cases such as high myopes, loose zonules, and floppy iris syndrome where greater anterior chamber stability is required,” he concluded.
Pascal Rozot: firstname.lastname@example.org Declaration of interest: Consultant for Alcon, Johnson & Johnson, Carl Zeiss Meditec, Thea Fig 2: CDE and total US time results
EUROTIMES | SEPTEMBER 2021
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THOMAS KOHNEN European Editor of JCRS
JCRS HIGHLIGHTS VOL: 47 ISSUE: 7
CORNEAL TRANSPLANTATION IN EUROPE For corneal transplantation in Europe, Fuchs’ endothelial dystrophy is the most common indication (vision improvement the leading reason), and DSAEK the predominant technique, according to a study by the European Cornea and Cell Transplantation Registry. In its inaugural report, the international registry, which reports cases from 10 European Union countries plus the UK and Switzerland, identified 12,913 corneal transplants. Most countries were self-sufficient regarding donor tissue. After Fuchs’ (41% of cases), the most common indications were regraft (16%) and pseudophakic bullous keratopathy and keratoconus (both at 12%). DSAEK was the most common technique at 46%, followed by penetrating keratoplasty at 30% and DMEK at 9%. The report provides the most comprehensive overview of corneal transplantation practice patterns in Europe to date, the authors said. Dunker SL et al., “Practice patterns of corneal transplantation in Europe: first report by the European Cornea and Cell Transplantation Registry”, Vol 47, Issue 7, 865–869.
BOWMAN LAYER AND CORNEAL STIFFNESS A study of 26 healthy human corneas in which half had their Bowman layer ablated and the other half their Bowman layer left intact found no significant difference in corneal stiffness in lamella cut to about 160 microns thick. The study analysed stiffness using 2D biomechanical stressstrain extensometry between 0.03 and 0.70 N, according to researchers at the University of Zurich and ELZA Institute, both in Switzerland, and Philipps University of Marburg, Germany. “The presence or absence of Bowman layer did not reveal a measurable difference in corneal stiffness. This may indicate that the removal of Bowman layer during photorefractive keratectomy does not represent a disadvantage to corneal biomechanics,” the authors concluded. Similarly, single-thickness Bowman layer transplants are not able to compensate for biomechanical weakening caused by keratoconus, they wrote. Torres-Netto EA et al., “Contribution of Bowman layer to corneal biomechanics”, Vol 47, Issue 7, 927–932.
NOMOGRAM RESOLVES WAVEFRONT-GUIDED LASIK UNDERCORRECTION A nomogram that guides ablation using manifest refraction sphere rather than sphere determined by Hartmann-Shack aberrometry helps resolve the mild undercorrection of myopia found in the manufacturer’s default specifications for a wavefront-guided LASIK system, according to three researchers. In a series of 84 patients who completed six months of follow up, 162 of 168 eyes, or 96.4%, achieved uncorrected monocular vision of 20/20 or better, improving upon the 83% reported in FDA trials. “[T]his system and nomogram together produce laser corrections whose accuracy is largely limited by the accuracy of manifest refraction,” the authors concluded. “It may be that […] further innovation in engineering is of limited value in improving refractive outcomes.” Maloney RK, Kraff CR, Coleman SC, “Wavefront-guided myopic laser in situ keratomileusis with a high-resolution Hartmann-Shack aberrometer and a new nomogram”, Vol 47, Issue 7, 847–854.
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EUROTIMES | SEPTEMBER 2021
Treating Ocular Surface Disease Easy as MSC? New cell-based therapy promising for OSD treatment. Cheryl Guttman Krader reports
Total application of exosomes in mice accelerates corneal nerve regeneration (after injury) compared to phosphate buffered saline (PBS) treated control eyes.
esenchymal stromal cells (MSCs) and their secreted factors have promising potential for therapeutic use to modulate ocular inflammation or promote ocular surface repair, according to new research presented at the 2021 ARVO virtual conference. “Clinical trials are just getting started to assess the safety and efficacy of these modalities. Much more work is needed to characterise the key mediators and optimal conditions for their production,” said Ali R Djalilian MD, Professor of Ophthalmology, University of Illinois College of Medicine, Chicago, Illinois, USA. Dr Djalilian reviewed findings from studies conducted in culture and animal models that demonstrated the immunomodulatory and regenerative effects of MSCs—or “secretome”—and provided an overview of related clinical research.
PRECLINICAL FINDINGS Dr Djalilian explained that MSCs, found in the cornea and most adult tissues, are suitable for cell-based therapies because they can be isolated and readily grown to billions of cells. Interest in their therapeutic application centres primarily on their immunomodulatory effects. The MSCs also have cytoprotective and trophic effects. Potentially, he said, these multipotent cells could be engrafted into local tissues where they might differentiate into local tissue types. Preclinical studies investigating the therapeutic potential of MSCs include research by Dr Djalilian and colleagues using an animal model of limbal stem cell deficiency (LSCD). The results showed limbal MSCs delivered in a fibrin gel inhibited both neovascularisation and inflammation and modulated macrophagemediated inflammation by promoting the M2-like phenotype involved in repair and inflammation resolution. The team’s work also determined that pigment epithelium-derived factor (PEDF) is one of the key mediators MSCs secreted. Other research focused on use of the MSC secretome, which would offer logistical advantages as a clinical therapeutic agent compared with the MSCs. In a study using the LSCD animal model, Dr Djalilian and colleagues found that topical application of MSC-secreted factors was effective for modulating inflammation, promoting epithelial healing, and helping to restore the corneal phenotype. They also showed in an ex vivo model that treatment with the corneal MSC secretome mitigated corneal endothelial cell loss resulting from phacoemulsification ultrasound-induced injury.
HUMAN TRIALS Clinical studies have already been done investigating MSCs for ocular surface reconstruction. Spanish researchers published positive results after conducting a proof-of-concept clinical trial investigating whether an MSC transplant could treat eyes with corneal epithelial stem cell deficiency. Other studies are underway in India, France, Denmark, and China, Dr Djalilian said. EUROTIMES | SEPTEMBER 2021
Additionally, the team recently launched a phase 1/2 clinical trial that will use cryopreserved allogeneic bone marrow-derived MSCs to treat patients with acute chemical injury or corneal ulcers. The MSCs will be delivered by subconjunctival injection, but the investigators plan to explore alternative routes, including topical MSC administration in fibrin glue and intrastromal injection. The study’s primary objective is to evaluate safety, but the outcomes assessments will also look at epithelial defect closure, stromal healing, and corneal scarring. Dr Djalilian and colleagues have also designed a phase one clinical trial to investigate the use of MSC secretome eye drops in patients with acute or chronic corneal epithelial disease. Recruitment, set to begin later in 2021, will target patients with partial LSCD and neurotrophic keratitis. Again, safety and tolerability are the primary outcomes, but data to gain insight about potential efficacy in the different pathologies is also being collected.
EXOSOME RESEARCH There are also preclinical investigations investigating the potential therapeutic use of corneal MSC-derived exosomes. In studies of these membrane-bound extracellular nanovesicles—which act as MSC regenerative factor carriers—Dr Djalilian and colleagues demonstrated that the exosomes were taken up by human corneal epithelial cells in culture and by corneal epithelium in vivo after topical application in an animal wound healing model. Results from an animal study also showed the exosome treatment accelerated corneal epithelial wound healing. Dr Djalilian reported that macrophages from peripheral blood mononuclear cells exposed to the exosomes adopted the inflammation resolving/less angiogenic M2 phenotype promoted by MSCs. In other research, the team studied the effect of the MSC exosomes on corneal nerves. Their work showed that when added to cultures of trigeminal nerve ganglion cells, the exosomes promoted neurite growth to an extent comparable to that induced by culture supplementation with nerve growth factor. They also showed in an in vivo animal study that topical MSC exosome application significantly accelerated corneal nerve regeneration following mechanical injury. Another study performed with diabetic mice that had developed loss of corneal nerves showed subconjunctival injection of the exosomes promoted corneal nerve regeneration. The exosome-treated animals demonstrated an increase in corneal sensation. “These are small pilot studies, but it is encouraging that we are already seeing clear differences between the exosome-treated and control groups,” Dr Djalilian said. Dr Djalilian acknowledges the funding support from the Department of Defense, National Eye Institute (NIH), and Research to Prevent Blindness for the studies mentioned. Ali Djalilian: email@example.com
Keeping an Eye on COVID-19 Studies show ocular surface a potential portal of entry for COVID-19 virus. Roibeard Ó hÉineacháin reports
he question of whether the eye can be the route of entry for SARS-CoV-2, the virus that causes COVID19, remains controversial. However, recent research shows ocular surfaces, particularly the conjunctiva, are susceptible to SARS-CoV-2 infection. A study presented at the 2021 ARVO virtual conference showed the angiotensin-converting enzyme 2 (ACE2) receptor and the transmembrane protease (TMPRSS2) that enable cells to become infected with SARS-CoV-2 virus were present in conjunctival and corneal tissues in post-mortem human eyes and surgical specimens. “Our key findings were that both ACE2-receptor and TMPPRS2 were prominently expressed in conjunctiva, limbus, and cornea, especially on the surface cells. Together with other studies, our findings highlight the importance of safety guidelines, including eye protection and ocular contact precautions, in preventing the spread of COVID-19,” said Elia J. Duh MD, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. Previous evidence suggesting the eye could serve as a portal of entry for the SARS-CoV-2 virus in the human body includes the conjunctival abnormalities reported in some patients with COVID19 and the detection of SARS-CoV-2 in ocular surface specimens. In addition, epidemiological studies suggest goggles and face shields can help reduce virus transmission in high-risk settings. To determine the presence of ACE2 and TMPRSS2 on the ocular surface, Dr Duh and his associates analysed post-mortem human eyes as well as surgical specimens of conjunctival and corneal tissue and human corneal epithelial lysates using immunohistochemistry and immunoblot assays. Western blotting showed ACE2 and TMPRSS2 were both expressed in corneal epithelial lysates. Immunohistochemical staining for ACE2 receptors was mild to moderate in the corneal epithelial cells, but prominent staining was especially prominent in the superficial epithelial limbus cells. There was also positive staining for ACE2 receptors in the conjunctival cells, particularly in the superficial epithelial cells. Goblet cells had largely negative staining. In addition, there was strong staining for TMPRSS2 in both the corneal epithelium and endothelium. There was intense staining for TMPRSS2 in the multilayered epithelium throughout the entire conjunctival epithelial layer and in the limbus.
OCULAR SURFACE CELLS INFECTED IN LAB The intercellular environment of some ocular surface cells appears to be conducive to viral replication under laboratory conditions, reported Timothy Blenkinsop PhD, Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, USA, in a separate presentation. He noted that in a series of post-mortem eyes of COVID-19 patients, immunohistochemical staining showed the presence of SARS-CoV-2 in the corneal and limbal tissues. However, this still did not show whether the cells were infected by aerosols or a result of systemic infection reaching the eye. To explore that question, his team exposed cultured cornea limbus and sclera cells to the virus. They found evidence of viral replication and RNA sequencing showed signs of SARSCoV-2 present in all three cell types—most pronounced in the limbal cells. In addition, they also found the infected limbal cells exhibited the same gene expression as those associated with SARSCoV-2 infection—such as upregulated gene expression of TNF-α signalling via NF-кB—and an interferon-gamma response. They found similar results using a whole eye stem cell model of eye development that includes many cell types of the eye, such as the cornea, the limbus, the lens, the retina, the RPE, and the CNS. Their research showed that ocular surface cells accounted for 90% of those infected with an area of limbus carrying the bulk of the infection. Gene expression changes found by way of single-cell RNA sequencing demonstrated increased expression of TNF-α compared to less infected cells from the stem cell whole eye model and uninfected colonies. Infected cells also exhibited lower expression of interferon-gamma pathway genes compared to uninfected colonies. “Together, these data suggest the human eye can be directly infected by SARS-CoV-2 and implicates limbal cells as an alternative portal for viral entry,” Dr Blenkinsop said.
Professor Elia J. Duh: eDuh@jhmi.edu Timothy Blenkinsop: firstname.lastname@example.org EUROTIMES | SEPTEMBER 2021
Beyond Vision 2020 New trends in population eye disease research can drive better care globally. Howard Larkin reports
s demand for eye services grows with an aging world population, new strategies in eye research can help drive improvements in eye care that better address global need and inequality, according to panellists at the Association for Research in Vision and Ophthalmology 2021 Annual Meeting (ARVO). To a large extent, the recent shift to epidemiology datadriven eye care policy results from the work of the Vision Loss Expert Group (VLEG). This coalition of more than 100 ophthalmologists and optometrists around the world has transformed eye disease data collection and analysis from an ad hoc exercise into a scientific tool, according to Rupert Bourne BSc, FRCOphth, MD, VLEG coordinator, head of the Glaucoma Service at Cambridge University Hospital, and director of the Cambridge Eye Research Centre, UK. Before 2010, the World Health Organisation (WHO) released infrequent updates on the prevalence of blindness and vision impairment, reporting sporadic, often incomplete studies supporting no-sex, limited age, and cause disaggregation, Dr Bourne said. Since 2010, VLEG has conducted a systematic, regular review of the published and grey literature used to create The Global Vision Database, which now has more than 500 population-based eye surveys. This supports new analysis every five years to note changes in prevalence rates worldwide and individual countries and regions. Multiple studies offering microdata are particularly important for age fitting and sex disaggregation, which in turn supports accurate modelling of the current, unmet need and developing needs, Dr Bourne said.
BURDEN OF DISEASE Sophisticated statistical modelling and prevalence estimates also support and validate the Global Burden of Disease (GBD) study, which is particularly important for mobilising resources to address medical needs of all types. The GBD applies disability weights to prevalence, yielding disability-adjusted life years (DALYs). This important health metric allows for burden of disease analysis across 369 disease and injury categories for allocating resources to address it. The latest GBD report, published in 2019, showed DALYs ranking for blindness and vision loss as nineteenth and fifteenth among all causes for populations 50 to 74 years old and 75 years and older, respectively. These impairments ranked lower than the ninth and tenth place ranking for hearing loss, though together when considered as “sensory loss”, they rank fifth and sixth of all causes of disease burden in these age groups—an even higher disease burden than diabetes. “The burden [of vision loss] is still very high despite the relatively low disability weight ascribed to it by the GBD,” Dr Bourne said. According to VLEG’s latest five-year study in 2020, more than 600 million people around the world are blind or at least mildly distance-vision impaired, while another half a billion are near-vision impaired, Dr Bourne reported. Cataract is the leading cause of blindness, and uncorrected refractive error the EUROTIMES | SEPTEMBER 2021
leading cause of moderate to severe vision impairment. Diabetic retinopathy is the one cause where age-standardised blindness prevalence rates have increased over the last 30 years. (Lancet Global Health, February 2021)
REFINING DATA COLLECTION Non-visually significant ocular morbidities—such as latent glaucoma or conjunctivitis—also contribute to the global burden of eye disease by increasing the need for prevention and monitoring, noted Nathan Congdon MD, MPH, glaucoma specialist and Ulverscroft Professor of Global Eye Health at Queen’s University Belfast, Northern Ireland, UK. He is conducting a review to estimate how much this increases the need for eye care globally. Among current needs are standardisation of terminology and robust definitions so the impact of these conditions can be better measured and addressed, Dr Congdon said. “Healthcare planning to serve the population must take into account the full burden of need for eye care. We can’t fight what we can’t see and don’t know.” Population-based studies contact people who might not otherwise be using medical services and are important to complete the need and burden picture, said Tasanee Braithwaite MPH, MRCP, FRCOphth, DM, Consultant Ophthalmologist at Guy’s and St Thomas’ Hospital, London, UK. She discussed new STROBEVision extension guidelines for standardising the design, conduct, and reporting of such surveys. Addressing social determinants of health in studies and analysis is yet another critical factor for successfully addressing vision and eye health equity, said Jinan Saaddine MD, MPH, medical epidemiologist at the Vision Health Initiative of the US Centers for Disease Control and Prevention, Atlanta, Georgia, USA. Factors including neighbourhood conditions, access to health services, and social status (including race and ethnicity, education, and economic stability) profoundly affect health risks and inequities and must be taken into account in policy development. But better data is only the first step, noted Serge Resnikoff MD, PhD, visiting professor at the University of New South Wales, Sydney, Australia. With more than one billion people affected by vision-impairing conditions that in principle are easily addressable, “an absolutely massive upscale of services is really needed very urgently,” he said. Advances in how vision impairment is defined—including adding near vision impairment to the ICD coding system—helps better define the scope of the problem, Dr Resnikoff added. But much more remains to be done to ensure universal coverage is truly universal, leaving no one behind.
Rupert Bourne: email@example.com Nathan Congdon: firstname.lastname@example.org Tasanee Braithwaite: email@example.com Jinan Saaddine: firstname.lastname@example.org Serge Resnikoff: email@example.com
Pathways to Ocular Lymphatic Outflow Mechanism of subconjunctival blebs confirmed in live humans. Howard Larkin reports
ngiographic studies and optical coherence tomography (OCT) have found structural evidence suggesting lymphatics drain aqueous humour from subconjunctival blebs used to lower intraocular pressure in glaucoma surgery and treat various eye diseases via drug delivery, Alex Huang MD, PhD reported at the Association for Research in Vision and Ophthalmology 2021 Annual Meeting. In a study of 10 patients, angiographic imaging of subconjunctival blebs revealed sausage-shaped outflow pathways previously thought to represent lymphatics. Simultaneous OCT imaging showed semilunar valves or flaps that are a lymphatic hallmark, said Dr Huang, Associate Professor at the Doheny Eye Institute and the Stein Eye Institute at the University of California–Los Angeles, USA. This study provided multimodal outflow/structural imaging evidence confirming the hypothesis that lymphatics drain blebs in live humans, Dr Huang said. Potential implications include the ability to regulate bleb outflow by encouraging or discouraging outflow using drugs affecting the lymphatic system, he added. “If we can understand this better, we could improve the treatment of eye diseases.”
ANIMAL AND HUMAN STUDIES Subconjunctival blebs are intentionally created in traditional glaucoma drainage surgery as well as minimally invasive glaucoma surgery (MIGS) devices such as the XEN Gel Stent (Allergan) and the PreserFlo MicroShunt (Santen). Additionally, they develop during subconjunctival drug delivery. Blebs may also occur spontaneously as chemosis due to fluid overload, infection, inflammation, or head and neck surgery, Dr Huang noted. So how does fluid exit blebs? Mechanisms suggested include leaking into the orbit or through blood vessels. But observation of patients undergoing subconjunctival haemorrhage and dye injections in studies show dispersion through irregular pathways with
“If we can understand this better, we could improve the treatment of eye diseases.” Alex Huang MD, PhD alternating wide and narrow points resembling sausage links, suggesting the lymphatic system is involved, Dr Huang said. In animal studies using two-photon microscopy and OCT from colleague Goichi Akiyama MD, PhD, Dr Huang found bicuspid valves in the direction of subconjunctival outflow, providing additional evidence of lymphatic involvement. Using molecular markers, they were also able to confirm bleb-related outflow pathways expressed specific lymphatic but not blood vessel markers. (Fig 1) In his human study, Drs Huang and Jong Young Lee MD injected indocyanine green and subconjunctival lidocaine in macular degeneration patients preparing for intravitreal injection. This enabled ocular surface lymphangiography, which revealed outflow pathways in seven patients. Simultaneous OCT showed the variable lumen diameter and the presence of valve-like structures along outflow pathways. In comparison, aqueous angiography imaging of trabecular outflow (which visualizes veins, not lymphatics) demonstrated even-calibered pathways without valves that took typical venous Y-shaped branching. Understanding the mechanism is important because pharmacological manipulation of lymphatics could make glaucoma surgery more successful by increasing outflow—or make subconjunctival drug delivery more effective by reducing outflow, Dr Huang concluded. Alex Huang: firstname.lastname@example.org or email@example.com
Figure 1: Lymphatic Coursing Through a Bleb A) A subconjunctival bleb was created by injecting fluorescent dextrans (green). B/C) Immunolabeling for a lymphatic-specific marker (Prox1; red) demonstrates a lymphatic meandering through the bleb substance, servicing as an outflow pathway for the bleb.
EUROTIMES | SEPTEMBER 2021
Envisioning Better Neovascular Eye Disease Treatment Pathways to new therapeutic targets and sustained drug delivery systems. Roibeard Ó hÉineacháin reports
esearch continues to reveal potential new therapeutic targets for retinal and choroidal vascular disease while advances in biotechnology bring new means of delivering vascular endothelial growth factor (VEGF) suppression, says Peter Campochiaro MD, FARVO, Wilmer Eye Institute, Baltimore, Maryland, USA. “In the future, sustained delivery of anti-VEGF agents and sustained expression of anti-VEGF proteins by gene transfer will largely replace repeated intraocular injections. They will combine with sustained activation of TIE-2 in patients with suboptimal outcomes from sustained VEGF suppression,” Dr Campochiaro predicted in his Proctor Award Lecture delivered at the ARVO 2021 meeting.
THE ROAD TO ANTI-VEGF THERAPY Since the late 1990s, laboratory and clinical studies have shown VEGFs’ importance in the molecular pathogenesis of these diseases. Ultimately, this led to the use of intravitreal anti-VEGF agents as the first treatment for neovascular age-related macular degeneration (AMD). What has greatly facilitated that process for AMD, he said, was the generation of animal models. For example, mice with disrupted Bruch’s membrane develop consistent ingrowth of vessels from the choroid or subretinal space at Bruch’s membrane sites, called type 2 CNV, which is the most common type of CNV in AMD patients. Studies using animal models showed aflibercept—a potent, specific VEGF binding protein—strongly suppressed choroidal neovascularisation. The VIEW 1 and VIEW 2 clinical trials confirmed those findings, showing aflibercept provided a strong improvement in visual acuity and anatomic benefit, leading to its FDA approval.
DIABETIC RETINOPATHY ROAD BUMPS Oxygen-induced retinopathy in mice mimics many diabetic retinopathy features, such as retinal non-perfusion and retinal neovascularisation. Research using this model has demonstrated that two hours after the onset of retinal hypoxia, there is a marked increase in the transcription factor hypoxia-induced factor-1 alpha (HIF-1α) in the inner retina followed by increased VEGF expression in the same cells four hours later. Other research showed a marked increase in retinal neovascularisation in adult mice that underwent injections of an adenoviral vector expressing VEGF and induced expression of angiopoietin 2 (Ang-2), a TIE-2 inhibitor HIF-1α upregulates. HIF-1α inhibitors markedly suppressed ischemia-induced retinal and choroidal neovascularisation at Bruch’s membrane rupture sites. “These data indicate HIF-1α plays a central role in the development of both choroidal and retinal neovascularisation. In ischaemic retinopathies, retinal vessel closure causes retinal hypoxia that activates HIF-1. That stimulates transcription of multiple vasoactive proteins and their receptors,” Dr Campochiaro noted. It was not known whether retinal hypoxia contributed to diabetic macular oedema (DME), which can occur independently of retinal neovascularisation. However, supplemental inspired oxygen reduced DME, demonstrating how retinal hypoxia contributes. The READ-2 multicentre trial showed intravitreal ranibizumab provided significant improvement in visual acuity compared to focal laser therapy—the previous standard of care for DME. The RISE and RIDE multicentre trials showed ranibizumab injections provide large, sustained improvements in visual acuity and antiVEGF injections became standard care for DME. EUROTIMES | SEPTEMBER 2021
MAPPING OUT DELIVERY STRATEGIES Dr Campochiaro reported how there are multiple strategies under investigation that may provide a more sustained suppression of VEGF with fewer interventions, thereby easing patients’ treatment burden and improving outcomes. Furthest along is the Port Delivery System (PDS), an implantable refillable reservoir for ranibizumab delivery. In the phase three ARCHWAY trial, eyes implanted with the port delivery system and given ranibizumab refills or exchanges every six months had equal visual outcomes to eyes receiving monthly injections. Gene therapy for choroidal and retinal vascular diseases is also on the horizon. In a clinical trial in which neovascular AMD patients underwent subretinal injections of RGX-314—an AAV8 vector that expresses an anti-VEGFfab similar to ranibizumab—there was good RGX-314 expression, stable or improved visual acuity, and leakage suppression at the longest time point for which data are available (three years for cohort 3 and 1.5 years for cohorts 4 and 5). Suprachoroidal injection provides a new non-invasive route of delivery that allows gene therapy in an outpatient setting. Clinical studies are also underway testing the efficacy of suprachoroidal RGX-314 injection for neovascular AMD and diabetic retinopathy.
INVESTIGATING NEW THERAPEUTIC TARGETS Dr Campochiaro noted recent phase two clinical trials indicate the addition of TIE-2 activation to VEGF-suppression provides supplementary benefits in treating DME. The TIME2 trial demonstrated that ranibizumab plus AKB9778—an inhibitor of vascular endothelial-protein tyrosine phosphatase that activates TIE-2—provided greater DME reduction than aflibercept alone. In the RUBY trial, a combination of aflibercept and an anti-Ang-2 antibody also provided greater DME reduction than aflibercept alone. In those trials, there was no difference in visual outcomes because they included patients with chronic DME and poor visual potential. The BOULEVARD trial investigated faricimab, a bi-specific antibody that blocks VEGF and Ang-2, in patients with treatment naïve DME and better visual potential. It showed those who received faricimab had better visual recovery as well as better control of macular oedema. By contrast, the YOSEMITE and RHINE trials showed faricimab had a greater reduction in macular oedema but no additional visual benefit at nine months compared to aflibercept. In summary, retinal and choroidal vascular diseases are prevalent causes of vision loss, which were previously treated with ablative treatments that provided minimal benefit. Presently, they are treated by repeated injections of anti-VEGE neutralising proteins that provide substantial benefit when given frequently and regularly. But in clinical practice, undertreatment is common and leads to poor outcomes. In the future, these diseases will be treated by one of a variety of approaches that provide sustained VEGF suppression. This will be sufficient for most patients, but in those with incomplete response, it will be supplemented by agents that activate TIE-2 or target other hypoxia-regulated vasoactive proteins not yet validated in clinical trials.
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Device for retinitis pigmentosa safe at two years, restores some functional vision and visual function. Howard Larkin reports
resenters at the Association for Research in Vision and Ophthalmology 2021 Annual Meeting reported a 44-channel retinal prosthesis safe after 24 months (NCTNCT03406416). The device—which was placed in the suprachoroidal space in four patients with advanced retinitis pigmentosa—also improved patient performance on functional vision and visual function tests. In the 24 months after the uncomplicated implant surgery, all four patients showed only minor movement in their optical coherence tomography (OCT) imaging, most of which was rotational. The most significant rotation was up to 17 degrees in one eye, but it did not affect device function, according to Penelope Allen MBBS, FRANZCO, Associate Professor and Vitreoretinal Surgeon at the Centre for Eye Research Australia, East Melbourne. OCT, fundus photography, and clinical exams all confirmed the location of the devices behind the patients’ macula and the absence of retinal trauma. No serious adverse events occurred during two years of follow up. The study builds on a previous device (NCTNCT01603576), adding 20 channels and a wider field of view to the current device. The aim was to develop a bionic eye usable at home and safer—and easier—to implant when treating people with inherited retinal disease, Dr Allen said. “The devices are stable after an initial settling period. The arrays remain functional, and we believe this is due to the stability of the surgical approach.”
EUROTIMES | SEPTEMBER 2021
After 16 weeks of vision rehabilitation training, the patients were assessed on three laboratorybased visual function tasks and three functional vision tests, said Maria Kolic, orthoptist and senior clinical trial coordinator at the Centre for Eye Research Australia. With the device on, three of the four participants could discriminate moving bar speeds ranging from 7 to 30 degrees per second. Average pointing error across all visits on square location was significantly less for all four participants, at 10.3 ± 3.3 degrees with the device on versus 27.7 ± 8.7 degrees with the device off. Two of the four participants had measurable grating acuity of 0.033 cycles per degree. On average, the device improved participants’ ability to locate objects on
the table-top search, detect and touch the doorway on the doorway detection task, and detect and avoid more obstacles during obstacle avoidance task. On the real-world Functional Low-Vision Observer Rated Assessment instrument, all four participants showed improvements with the device on compared to off; and the three participants who continued follow-up appointments showed increased improvement, particularly within the first six months, and they held stable for the remainder of the two-year trial, reported Lewis Karapanos MD, also of the Centre for Eye Research Australia. Participants also self-reported improvements in mobility, functional vision, and quality of life. The Australian National Health and Medical Research Council and commercial partners Bionic Vision Technologies funded the research. Penelope Allen: email@example.com Maria Kolic: firstname.lastname@example.org
EUROTIMES | SEPTEMBER 2021
Did COVID-19 Put a Lockdown on Intravitreal Injection Adherence? Study shows vision does not suffer with short lapses in care. Cheryl Guttman Krader reports
n-person appointments and treatments met obvious delays and cancellations due to COVID-related lockdowns. A retrospective study of this impact at an intravitreal injection clinic found that while missed appointments were common, the average treatment delay was short and not associated with significant vision loss. However, the analyses did confirm longer lapses in care could potentially compromise outcomes and reinforce racial disparities in healthcare. “Our study shows that for patients treated with intravitreal injections, enhancing visit adherence can lead to better visual outcomes. Strong patient-provider relationships [that foster] effective communication and patient education are fundamentally important for patient adherence to follow-up,” said Vivian Paraskevi Douglas MD, DVM, MBA, Research Fellow at Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, USA. Presented at ARVO 2021, the study included 353 patients with 1,086 visits scheduled from December 1, 2019, through June 10, 2020. The patients in the cohort were predominantly Caucasian, and most were receiving treatment for wet agerelated macular degeneration. A review of appointment status by month showed that the rate of completed visits fell dramatically during the first two months of the lockdown period. Most missed visits were cancellations rather than “no show” patients. Approximately three-fourths of the cancellations during both the lockdown and pre-lockdown periods were patient-initiated rather than provider-initiated. Rates of cancelled and “no show” appointments were higher among African American patients compared to Caucasians.
The researchers noted that the latter finding could be partially explained by African Americans being disproportionately affected by COVID-19. Ensuring minority populations receive education about the importance of visit adherence is instrumental going forward. Dr Douglas added, “Providing culturally and linguistically appropriate health information and community engagement efforts can lead to health equity promotion and improved health outcomes, including visual outcomes.”
VISION OUTCOMES During the lockdown period, the average delay in care was 2.34 weeks, and it was similar among subgroups classified by indication for intravitreal injection. In the overall cohort, there was no significant visual acuity loss during the lockdown, and the mean change in visual acuity was not significantly different between patients who completed their scheduled appointment and those who missed one or more. However, plots of individual patient outcomes versus time delay in care showed associations between longer delays and greater visual deficits. The effect was greater in patients with wet age-related macular degeneration or branch or central retinal vein occlusion and more moderate in patients treated for diabetic eye disease.
Vivian Paraskevi Douglas: email@example.com
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How Beneficial is Remote DR Care? New telemedicine technologies could improve monitoring and care. Howard Larkin reports
rowth in telemedicine technology use spurred by the COVID-19 pandemic could revolutionise diabetic eye care. Remote monitoring made possible by home-OCT and wide-field fundus cameras could do a better job of detecting and diagnosing diabetic retinopathy (DR) and diabetic macular oedema (DME) earlier, allowing treatment before vision is permanently lost, said Tunde Peto MD, PhD at the Association for Research in Vision and Ophthalmology 2021 Annual Meeting. DR and DME are particularly pernicious because, by the time they appear, symptoms are advanced to the point where vision loss is often irreversible, noted Dr Peto, Queen’s University Belfast, Northern Ireland, UK. This makes regular monitoring of diabetic patients essential. Other ocular issues common in diabetic patients include dry eye, anterior segment disease, and cataracts, she noted. Yet even before the pandemic, “good quality diabetic eye care was not universally available,” Dr Peto said. According to a DR Barometer study conducted in 41 countries, nearly half of providers reported they did not use written protocols for managing diabetes-related vision loss, 21% of ophthalmologists said they had not trained in DR or DME diagnosis and treatment, and 27% of patients never discussed eye problems with their doctors until they already had symptoms. The pandemic likely made this situation worse by cancelling non-urgent examinations and diverting ophthalmic personnel to COVID clinics. On the plus side, the pandemic encouraged development of remote monitoring, drivethrough clinics, effective triage of who needs to be seen in person, and protocols to limit infection exposure risk in office visits. These developments are likely permanent changes and could improve diabetic eye care, Dr Peto said.
SLO/OCT model ・ SLO model
REDESIGNING PATIENT FLOW However, minimising contact while maintaining care quality requires reinventing patient flow and the role of every care team member, Dr Peto said. Questions include what resources are now in place and whether current team members can perform virtual interviews and triage and collect images remotely. “Do we need more technicians; do we need more nursing assistants? How do we get buy-in from everyone … and what would be the ideal solution look like now and in a year’s time?” Dr Peto asked. Virtual clinics are excellent, but they take time to run and read the images appropriately, Dr Peto said. In designing them, consider both the patient benefit and medico-legal issues, as the images produced are available for all to see. Also, make sure the team is up to the task and trained well to provide the best care to patients. Then run a “holiday test.” If the system doesn’t work when the primary physician is absent, it needs strengthening, she said.
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Scanning AI and Robotics Solutions
A robotic technician and artificial intelligence diagnostics combo shows potential to automate screening for eye disease. Roibeard Ó hÉineacháin reports
oupling a robotically aligned optical coherence tomography (RA-OCT) system with a deep learning algorithm to classify images can enable a semiautomated approach for screening for posterior eye disease, reports Ailin (Irene) Song MD/MHSci student at Duke University School of Medicine, Durham, North Carolina, USA. “The eye is a difficult organ to examine for non-eye doctors. We have developed a platform combining artificial intelligence and robotics to acquire and classify eye images. This is a potential platform for eye screening in settings where eye exams are otherwise challenging,” Ms Song told the ARVO 2021 Annual Meeting. The RA-OCT system—originally developed by Drs Mark Draelos and Joseph Izatt (Duke BME) and refined by Dr Ryan McNabb— consists of a custom robotic-aligning, swept-source OCT (RA-OCT; 1040nm) system with a low mass (2.4kg) sample arm that has 70mm-diameter achromatic lenses with 3D-printed optomechanics to provide a clinically relevant 32-degree view of the retina. When patients undergo testing with the RA-OCT system, they sit on a chair without forehead strap, chin rest, or any kind of head restraint. The system’s face- and pupil-tracking cameras triangulate the eye and pupil motion, which the robotic arm and OCT system compensate for in real-time. To interpret the images, Ms Song and the others in Anthony Kuo’s (MD, Associate Professor of Ophthalmology at Duke University) research group used transfer learning to adapt a pre-existing convo-
lutional neural network to train a deep learning algorithm to classify OCT images as normal or abnormal. They trained and validated their model on two publicly available OCT datasets and two of their own RA-OCT volumes. Altogether, the training and validation datasets included 87,697 OCT images, of which 59,743 were abnormal. The top-performing deep learning model had a training accuracy of 96% and a validation accuracy of 99%. For external testing, the research group performed posterior segment imaging with the RA-OCT system in 21 patients with a broad range of retinal diseases and 22 healthy volunteers over the age of 18 at the Duke Eye Center between August and October 2020. They used the top-performing deep-learning model to distinguish between healthy and abnormal eyes. They found that compared to clinical diagnoses, the model correctly labelled 18 out of 22 normal averaged B-scans and 18 out of 21 abnormal averaged B-scans. For pathology detection in this testing set, the model had high levels of accuracy, sensitivity, and specificity, Ms Song said. In addition, for the correctly predicted scans, saliency maps identified the areas that contributed most to the deep learning algorithm’s predictions, which also matched the regions of greatest clinical importance, she added. Ailin (Irene) Song: email@example.com
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Portable Retina Imaging Smartphone ophthalmoscope attachment enables patient services in atypical situations. Cheryl Guttman Krader reports
n innovative smartphone-based direct ophthalmoscope for optic nerve imaging can provide a low-cost and convenient option for enabling patient access to care in atypical settings, suggests a study conducted during the COVID-19 pandemic. The study compared acquisition time for images obtained using the D-EYE digital retinal camera attached to an iPhone 6 versus a standard ophthalmic imaging platform (Optos). A retrospective analysis of the study was presented at the ARVO 2021 virtual Annual Meeting. Patients included in the study had visual acuity of 20/20 to 20/50 in at least one eye. Imaging was performed on 76 dilated eyes of 38 patients and 34 undilated eyes of 17 patients. Imaging time for both devices was captured using internal timers and totalled for both eyes of each patient. For the dilated group, imaging time per patient averaged 14.32 seconds using the smartphone attachment and 99.11 seconds using the standard system. For the non-dilated group, the mean imaging time per patient was 26.94 seconds using the smartphone and 103.94 seconds with the Optos instrument. For both the dilated and nondilated situations, the difference in acquisition time favouring the smartphone technology was highly statistically significant. Gloria Wu MD—Adjunct Clinical Instructor, Department of Ophthalmology, UC San Francisco School of Medicine, California, USA—told EuroTimes she began using the smartphone ophthalmoscope during the COVID-19 pandemic since patients were afraid to come into the office but were willing to be seen in the parking lot or sitting in their cars. “While we are back to seeing patients in the office, I find the D-EYE attachment is excellent for bedside imaging of hospitalised patients as well as those in the office—whether these patients are in a wheelchair, had neck surgery, or immobilised for another reason,” she said. “I am always watching out for novel technology that uses what we have available to capture retinal images. I believe all
“I believe all physicians should be looking for ways to provide more portable services and enable telemedicine so patients can benefit from easy access to technology and care.” Gloria Wu MD
physicians should be looking for ways to provide more portable services and enable telemedicine so patients can benefit from easy access to technology and care. These strategies will also help us meet the challenge of perfecting artificial intelligencebased care solutions.” Dr Wu observed the D-EYE, introduced in 2014 and costs $400, only fits an iPhone 6 or 7, so she had to buy a refurbished iPhone 6 to use the ophthalmoscope. “It took our technicians just an average of seven minutes to learn to use the device and would take an ophthalmologist just one or two minutes. Users need to have a steady hand, and then it provides very good quality video from which we can crop images,” she said.
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EUROTIMES | SEPTEMBER 2021
Rapid Diagnosis in the Palm of the Hand Growing role in diagnosis and monitoring of infant and young child eye conditions. Howard Larkin reports
and-held OCT (HH-OCT) provides a unique in vivo view of the eye’s early development, enabling rapid diagnosis of paediatric ocular conditions ranging from differential aetiology of nystagmus to early-onset retinal dystrophies and optic nerve diseases such as glioma, glaucoma, and optic nerve hypoplasia, Irene Gottlob MD, FRCOphth said in a presentation reviewing work by her group and others at the Association for Research in Vision and Ophthalmology 2021 Annual Meeting. HH-OCT allows the technology to be used effectively on infants and young children by adjusting the hand-held device to the child’s position. “Very small children, even premature children, can be examined,” said Dr Gottlob, University of Leicester, UK. This enables viewing in real-time the development of the retina only previously known through sporadic histology samples. For example, the growing differentiation of retinal pigment epithelium and photoreceptor cells, and development of the foveal pit as well as thickening of the outer nuclear layer under it, can readily be tracked as the retina matures, Dr Gottlob noted. Development continues until at least age 12, if not adulthood, and closely parallels development of the visual cortex and visual acuity, she added.
Image 2: Left: Schematic representation of the different grades of foveal hypoplasia. Middle: Examples of original OCT images for each grade. Right: Prediction of future visual acuity for 42 children with nystagmus. OCT scans obtained at a mean age of 19.8 months and visual acuity at a mean age of 44.1 months when children could reliably cooperate with visual acuity tests. Mild grades of foveal hypoplasia correspond to best visual acuities while grade four foveal hypoplasia with a foveal appearance similar to peripheral retina corresponds to worth visual acuities. (Rufai SR, et al. Can Structural Grading of Foveal Hypoplasia Predict Future Vision in Infantile Nystagmus?: A Longitudinal Study. Ophthalmology. 2020 Apr; 127 (4): 492-500. doi: 10.1016/j.ophtha.2019.10.037. Epub 2019 Nov 4. PMID: 31937464; PMCID: PMC7105819)
RETINAL AND OPTIC NERVE IMAGING
In retinoblastoma, OCT can be used to increase diagnostic accuracy and clinical staging, resulting in changes in management in 15% of cases in one study, Dr Gottlob said. Retinal or optic nerve abnormalities are also visible in the following cases: microcephaly; optic nerve drusen; and optic nerve hypoplasia. Optic nerve changes can be monitored in optic nerve gliomas and childhood glaucoma. In glaucoma, corneal changes and iridocorneal angle changes can also be observed. Optic nerve head pits and related retinal disruptions are also easily seen on OCT, Dr Gottlob said. She also pointed out that optic nerve abnormalities are visible in children with congenital fibrosis of the extraocular muscles, which confirms this disease affects wider parts of the eye and not only the extraocular muscles.
Image 1: The hand-held OCT probe is pointed to the child’s eye, enabling scans in children who cannot cooperate with standard OCT machines with chin-head rests.
Irene Gottlob: firstname.lastname@example.org
DIFFERENTIAL DIAGNOSIS IN NYSTAGMUS Nystagmus is associated with foveal hypoplasia often clearly visible on OCT, Dr Gottlob said. Albinism and aniridia display similar “typical” foveal hypoplasia patterns, with the foveal pit shallow or missing. Achromatopsia can be distinguished on OCT by its “atypical” foveal hypoplasia, including pathological continuation of the inner retinal layers, disrupted inner segment/outer segment junction, and “punched out” hyporeflective zones where central photoreceptors should be that grow with age. Retinal dystrophies can be identified by abnormal lamination of the outer retinal layers, Dr Gottlob said. Retinal pigment epithelium (RPE) may not be distinguishable from photoreceptors compared with normal control images. A grading system for foveal hypoplasia based on OCT images shows increasing severity corresponding to reduced visual acuity, Dr Gottlob said. This system was able to predict future VA, demonstrating the technology’s diagnostic and prognostic utility.
Left: Cornea, anterior segment, and optic nerve changes seen in childhood glaucoma on OCT with increased corneal thickness, abnormal iridocorneal angle, and deeply excavated optic nerve. Right: OCT of age-matched control child. (Figure courtesy of Dr AV Pilat)
EUROTIMES | SEPTEMBER 2021
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Eye on Nutrition
Interest in nutritional intervention spurs career-long research, yielding transformative findings. Cheryl Guttman Krader reports
uriosity has an interesting way of influencing lives. For Paul S Bernstein MD, PhD, a clinician-scientist, academic curiosity led to a focused clinical and basic science research career understanding of the role specialised nutrients play in retinal physiology and macular disease protection. Speaking at the ARVO 2021 virtual meeting as the recipient of the Mildred Weisenfeld Award for Excellence in Ophthalmology, Dr Bernstein reviewed his work to delineate the biochemistry and biophysics of retinoids, carotenoids, and very-long-chain polyunsaturated fatty acids (VLC-PUFAs). He also described the translational implications of the findings from the laboratory investigations of these compounds, which are essential for retinal health. Vice-Chair for Clinical and Basic Science Research, Moran Eye Center, University of Utah, Salt Lake City, USA, Dr Bernstein began his lecture by explaining the importance of ocular nutrition research. “The underlying cause of many eye diseases logically points to nutritional interventions, and they often have fewer side effects than pharmacological interventions. Patient compliance with nutritional interventions can be excellent, they are often relatively low cost, and there can be strong patient and clinician interest in such interventions. This is something that attracted me to this field ever since I started work on my PhD in the 1980s.”
SEEING THE PROBLEM He described his doctorate research on retinoid chemistry in the eye that identified how an enzyme catalyses the isomerisation of all-trans-retinoids to 11-cis-retinoids—later named RPE65— which led to the modern description of the visual cycle. “This basic science work has been successfully translated into the clinic. Clinical trials are investigating whether pharmacological inhibition of RPE65 has a benefit for Stargardt disease and AMD. Even more importantly, RPE65 gene therapy is an FDA-approved treatment for a form of Leber congenital amaurosis,” Dr Bernstein said.
CONCENTRATING ON CAROTENOIDS After receiving his PhD and joining the Moran Eye Center, Dr Bernstein turned his research focus to the basic biochemistry of understanding how and why carotenoids uniquely concentrate in the human eye. This work led to the identification of the binding proteins that drive the retinal deposition of lutein, zeaxanthin, and meso-zeaxanthin; retinal mapping of the localisation of lutein and zeaxanthin; and the determination that RPE65 likely mediates the isomerisation of lutein to meso-zeaxanthin. The lab went on to create a transgenic “macular pigment” mouse that could serve as an animal model for studying ocular carotenoids in human eye disease. Experiments using this mouse showed carotenoid delivery to the retina enhances visual function and inhibits A2E formation. “Thus, we show there could be potential benefit from carotenoid supplementation to patients with recessive Stargardt disease (STGD1),” he said. Dr Bernstein also led the development of non-invasive methods for in vivo measurement of carotenoids in the eye and skin. Having subsequently shown ocular carotenoids were present at birth at a level correlating with maternal serum zeaxanthin, he serves as the principal investigator for an ongoing clinical study investigating the effects of adding lutein and zeaxanthin to prenatal supplements.
SHIFTING FOCUS Most recently, Dr Bernstein has turned his attention to VLCPUFAs. He explained that these compounds, which are not present in an ordinary human diet, are unique to the retina and a few other tissues in the body. Thought to provide membrane fluidity and structural integrity for photoreceptor disks, VLC-PUFAs are precursors for neuroprotective elovanoids in the RPE. Dysfunction of the enzyme responsible for in vivo synthesis of VLC-PUFAs from shorter chain dietary PUFAs leads to autosomal dominant Stargardt-like macular dystrophy (STGD3). Having developed sensitive methods for measuring VLC-PUFAs in the retina, Dr Bernstein and coworkers showed these compounds also deplete in eyes with AMD and diabetic retinopathy (DR). Using a synthetic VLC-PUFA developed in conjunction with colleagues from the chemistry department, the team conducted experiments in animal models of STGD3 that demonstrated its oral delivery led to increased VLC-PUFA levels in the retina and positive functional effects. “Supplementation with VLC-PUFAs or their precursors deserves further exploration in clinical trials, possibly even in a future AREDS3 trial. We speculate that nutritional supplement with VLC-PUFAs could also be a nutritional approach to treating STGD1,” Dr Bernstein said.
PRACTICING HEALTHY HABITS In addition to his work as a basic science and clinical researcher, Dr Bernstein is a practicing clinician. He concluded his lecture by sharing the advice he gives to patients about ocular nutrition. “I still advise all of my patients to eat an ‘eye-healthy’ diet with lots of fruits, vegetables, and fish. I certainly encourage an AREDS2 supplement with 10mg lutein and 2mg zeaxanthin for individuals at high risk for AMD, but I advise them to wait on other singlenutrient supplements and herbals until more data are available. And I certainly encourage patients to support and participate in high-quality nutritional clinical studies and basic science research.” Paul S Bernstein: email@example.com EUROTIMES | SEPTEMBER 2021
Battling Toxic Adverse Events
Targeted cancer therapies can have sometimes sight-threatening side effects. Howard Larkin reports
he advent of therapies that target signalling pathways involved in cancer growth has driven reduced mortality in a broad range of cancers, contributing to an overall decline of 15% in a decade. Yet, these small molecule and monoclonal antibody therapies also frequently produce unwanted adverse effects, including ocular toxicities, said Alison H Skalet MD, PhD at the Association for Research in Vision and Ophthalmology 2021 Annual Meeting (ARVO). “It is critically important to be aware of the insidious, subacute, and late presentation of toxicities in these patients. For ophthalmologists, it is important to be aware that ocular toxicities are emerging as among the most common adverse events with targeted therapies for cancer, and some of these toxicities are vision-threatening,” said Dr Skalet, Chief of Ocular Oncology at the Casey Eye Institute at Oregon Health & Science University, Portland, Oregon, USA. The issue is unlikely to subside. Ongoing advances in genomics and molecular biology continually unveil new potential targets for cancer therapy. This has resulted in an explosion of new drugs developed in the past decade, with more in the pipeline.
TARGETING SIGNAL INHIBITORS AND IMMUNOTHERAPY Targeted therapies include agents that address specific driver mutations, leading to dysregulated signal transduction and those targeting overexpressed pathways in cancer cells, such as VEGF. Immune system-enhancing immunotherapies, such as checkpoint inhibitors that enable T-cells to attack cancer cells, are also included, Dr Skalet said. She noted small molecules address not only cell surface receptors but intracellular pathways as well. They are often delivered orally, and many can cross the blood-brain and blood-retina barriers. By contrast, the much larger monoclonal antibodies do not enter cells or cross barriers and are typically given by infusion. Because these agents target disrupted cell processes, researchers initially assumed they would be non-toxic to normal, functioning cells. However, this has not proven to be the case, Dr Skalet said. “Targeted agents exhibit the same frequency and severity as traditional cytotoxic agents, although the nature of the toxic effects is different.” Chemotherapy side effects often include alopecia, myelosuppression, nausea, and vomiting, Dr Skalet said. Targeted therapies more often produce vascular, dermatologic endocrine coagulation as well as immunologic, pulmonary, and ocular toxicities. Recognising and managing these adverse effects is essential, she added. Dr Skalet distinguished between on-target and off-target adverse effects. On-target toxicities are “class effects” shared by all agents, such as hypertension with VEGF and rash with EGFR inhibitors, and must be managed proactively. Off-target effects occur when drugs inhibit unintended targets with similar structures. While creating drugs more specific to the intended target is desirable, it is not always possible, so any toxic effects that appear must be addressed.
are sight-threatening. In a 2015 study of 16 targeted anticancer agents, the most common ocular adverse events were blurred vision and severe conjunctivitis. And, there was a higher incidence of ocular toxicity with small molecule agents than with antibodies. (Fu et al. Oncotarget 2017.) Among the most severe ocular adverse events for signal inhibitory agents is severe periorbital oedema with imatinib, a tyrosine kinase inhibitor. Vision disturbances, including trailing lights, occur with crizotinib, an ALK inhibitor. EGFR inhibitors—including erlotinib, gefitinib, afatinib, cetuximab, and panitumumab—are associated with surface toxicities such as keratinocyte hyperplasia with necrosis, the disappearance of follicles, and inflammation. Dry eye, conjunctivitis, keratitis, corneal ulceration, and abnormal lash growth were observed, Dr Skalet said. MEK inhibitors—including trametinib, selumetinib, binimetinib, and cobimetinib—suppress the development of retina cells and retinal pigment epithelium. They are associated with retinal vascular occlusion and what is known as MEK inhibitorassociate retinopathy, which is usually mild and self-limiting and presents within a week of the first dose. It can include central serous retinopathy, serous retinal detachment, cystoid macular oedema, and thin choroid. It is thought to result from hyperpermeability of the RPE leading to breakdown of the blood-retinal barrier, Dr Skalet said. BRAF inhibitors (such as vemurafenib, dabrafenib, and encorafenib) are associated with uveitis and cutaneous malignancies—primarily well-differentiated squamous cell carcinomas and keratoacanthomas, which occur in up to 25% of users. Immune checkpoint inhibitors also can promote ocular toxicity as part of a systemwide autoimmune reaction spurred by their use. Ocular reactions occur in about 1% of patients and can involve everything from the anterior surface, the posterior segment, and the sclera and orbit. The most commonly reported effects are dry eye, uveitis, and myasthenia gravis. Typically, these are managed with corticosteroid therapy, and occasionally immunotherapy must be interrupted, Dr Skalet said. The ipilimumab antibody is associated with anterior and posterior uveitis, Graves-like ophthalmopathy, and optic neuritis, which may cause rapidly progressing and permanent vision loss. Reactions can develop while patients are on steroids and months after treatment concludes, Dr Skalet noted.
JOIN THE CANCER TEAM While most targeted therapy ocular adverse events are self-limiting, some are sight-threatening. Therefore, ophthalmologists’ involvement in multidisciplinary collaborative cancer care teams is warranted, Dr Skalet said. Steps to consider for patients initiating therapy with drugs known for ocular manifestations include a baseline ophthalmic evaluation. Familiarity with the wide range of potential ocular events and how to manage them is also essential, she concluded.
COMMON OCULAR TOXICITIES While most ocular toxicities are mild to moderate and require little or no intervention, some can cause significant vision loss or EUROTIMES | SEPTEMBER 2021
Alison Skalet: firstname.lastname@example.org
Spotting Opportunity with Inclusive Vision Science Researchers with vision loss add value to person-centred science.
ncluding colleagues with vision loss and blindness on research teams can increase the impact and relevance of vision science, especially now both basic research and clinical practice are moving towards person-centred models. Researchers, including several with visual impairment or blindness, shared their perspectives on the value persons with sensory disabilities can add and how they can be better integrated into research programmes, at the ARVO 2021 Annual Meeting. What the research questions are, what the data are, how they are analysed and written up, and who actually conducts the research— all profoundly influence the research product, said Mahadeo Sukhai PhD, who is a congenitally blind biomedical research scientist, and now director of research and chief accessibility officer at the Canadian National Institute for the Blind, Toronto, Canada. “If we don’t understand our researchers and our research population, we are literally blinded to the things we are figuring out,” he said. For the fully sighted, including researchers with visual disabilities not only offers the opportunity to gain insight and relevance in studies, but it can also be a valuable personal learning experience, said Walter Wittich PhD, CLVT, associate professor at the School of Optometry of the University of Montreal, Canada. “Here is a fascinating opportunity to learn something new, to go about discovering your own misconceptions, your own biases, your own moments of stereotyping someone else, and see if you can challenge yourself.”
VOICE AT THE TABLE Reflecting on his experience supervising his first blind PhD candidate, Dr Wittich noted the student is intimately familiar with being visually impaired, and he recommended talking to them as much as possible. Find out what it is like, how they cope, and, importantly, what they do and do not need. Natalina Martiniello PhD, CVRT, who recently earned her PhD in visual impairment and rehabilitation with Dr Wittich, and who is now a research associate at the University of Montreal and president of Braille Literacy Canada, agreed. “People with visual impairment are not just the clients and the patients we serve and study but also the experts and colleagues we work alongside.” Her personal experience as a blind person has helped Dr Martiniello in her research developing evidence-based strategies for working-age and older adults with vision loss to learn braille. “Inclusion and accessibility really are beneficial to everyone. Inclusion is all about who has a voice at the table.” Yet despite these perhaps obvious benefits, the inclusion of persons with disabilities in health research—especially for visual impairment—is woefully low, said Bonnie Swenor MPH, PhD, assistant professor at Wilmer Eye Institute and founder and director of the Disability Health Research Center (both at Johns Hopkins University, Baltimore, Maryland, USA). A recent study she conducted of National Institutes of Health grants in the USA found less than 2% of principal investigators reported any
kind of disability, with visual disability as the smallest group. The total proportion of principal investigators with disabilities actually fell from 1.9% to less than 1.2% in the decade ending in 2018, reported Dr Swenor, who is visually impaired. The study implies “there is a gap, and we are not paying attention to it,” she said.
FACING THE CHALLENGE Perhaps the biggest obstacle to including visually impaired people in research programmes is people simply do not know how to go about it, Dr Wittich said. He recommended reaching out to colleagues who have experience and contacting the disabilities office found in most universities. Most of all, be prepared to negotiate frankly when determining what supports each individual needs. With Dr Martiniello, this included adding extra time to work through encountered barriers when using research platforms not necessarily designed to meet international accessibility standards. It also included 3D printed models of the visual cortex to learn vital anatomy tactilely. “It’s about good supervision. Communicate; talk to your student about what they need,” Dr Wittich said. Respect the dignity of disabled colleagues and recognize they have the same differences of ability, resilience, and social identity as anyone, Dr Wittich added. And just because they have personal experience doesn’t mean they are not serious about science, though this is a common bias, Dr Swenor said. The technical nature of much of the research and educational materials in vision science can be especially challenging for visually impaired colleagues, said Gordon Legge PhD, professor of psychology at the University of Minnesota, Minneapolis, USA, and the director of the Minnesota Laboratory for Low-Vision Research. Wet labs, specialised optical equipment, and graphic data present particular obstacles. Drawing on his own experience on both sides of the inclusion process, Dr Legge reiterated the need for supervisors to mentor and advocate for visually impaired researchers within the institution. “You have to be a little bit proactive,” he said. The situation has significantly improved since Dr Legge, who is visually impaired, applied to college decades ago. He was discouraged by most universities from taking science or engineering. He ended up at the Massachusetts Institute of Technology (MIT), where they pledged to make it work—and they did.
Natalina Martiniello: email@example.com Bonnie Swenor: firstname.lastname@example.org Walter Wittich: email@example.com Gordon Legge: firstname.lastname@example.org Mahadeo Sukhai: Mahadeo.Sukhai@cnib.ca EUROTIMES | SEPTEMBER 2021
EVERYTHING YOU ALWAYS WANTED TO KNOW ABOUT....
Posterior Capsular Rent First in a multi-part series on PCR explains how to anticipate, prevent, and manage this complication in the most effective manner. Dr Soosan Jacob MS, FRCS, DNB
posterior capsular break is a complication that may occur in the best of hands during cataract surgery—both in the phacoemulsification and extracapsular cataract extraction stages. Varying incidence ranging from 0.2% to 14% has been reported depending on factors such as systemic, orbital, and ocular characteristics of the patient, type of cataract, experience of the surgeon, and the available operating facilities. Vitreous loss may occur in up to 5% of cases. Improper management of the posterior capsular rent (PCR) can lead to further complications and less than desirable visual results.
RISK FACTORS Systemic risk factors for PCR include a short neck, obesity, inability to cooperate or lie still, dementia, old age, respiratory difficulty, and use of systemic drugs such as tamsulosin. A poorly positioned patient with chin turned downwards and iris not parallel to the floor can result in a poor red reflex, as can a contralateral tilt to the head or a deep-set eye, which can LEGEND FOR FIGURE: result in pooling of fluid IOL scaffold technique: and disturbing light reflexes. A) Intravitreal triamcinolone acetonide is used to stain vitreous. Vitrectomy performed. B) A three-piece IOL is injected under the nuclear fragments. A patient lying low on the C) Phacoemulsification with the IOL acting as a scaffold. trolley makes the surgeon D) Pars plana vitrectomy is performed for any residual vitreous prolapse and aspirating residual cortex by alternating between cut and aspirate modes. lean forward to operate with The IOL is then transferred to the sulcus. resultant discomfort and diflow scleral rigidity, vitrectomised eye, high myopia, liquefied ficulty during surgery. vitreous, weak zonules, a floppy bag, small pupil, and pseudoLikewise, a poorly placed drape obstructs a clear view. Excess exfoliation. Media opacities such as post-anaesthetic epithelial fluid in the fluid collection bag, a tight speculum, a tight/shalhaze, corneal scars, asteroid hyalosis, or vitreous haemorrhage low orbit (either anatomical or secondary to retro), or peribcan all increase PCR risk. ulbar injection can lead to increased vitreous pressure, causing The type of cataract also affects the incidence of PCR: for the posterior capsule to bulge instance, posterior polar cataracts, white or hard brown cataforward and increase the racts, intumescent cataracts, and traumatic or paediatric catarisk for PCR. Deep-set eyes, racts all have a higher risk. prominent nose and brows, Poor quality of instruments, machines, or the operating small palpebral aperture, and microscope; machine malfunction; and inexperienced persons strong Bell’s phenomenon assisting or adjusting machine parameters/tubing can also cause difficulty in manoeuaffect the incidence of PCR. Finally, surgeon experience also vring instruments. affects the rate with a higher risk earlier in the learning curve. Ocular conditions can Improper surgical technique for almost any step can lead to a increase the risk of PCR. cascading effect in increasing the difficulty of surgery, ultimateThis includes a shallow or ly culminating in a PCR or other complications if not managed deep anterior chamber, appropriately. A poorly constructed wound can result in anteEUROTIMES | SEPTEMBER 2021
EVERYTHING YOU ALWAYS WANTED TO KNOW ABOUT.... rior chamber shallowing, iris prolapse, intraoperative pupillary constriction, iris trauma, and difficult surgery. Similarly, a small rhexis can cause capsular blowout, difficult nucleus, and cortex management in addition to risking rhexis and PC tears. Uncontrolled movements of the phaco probe, poor foot-pedal control, mismatch between fluid inflow and outflow, postocclusion surge, going too close to the anterior or posterior capsule, and accidental purchase of capsule by the phaco or irrigation/aspiration (I/A) probe are some other causes for PCR.
IMMEDIATE RESPONSE TO A PCR
The first thing to not do is to pull out the phaco or I/A probe, as this disturbs the intraocular pressure equilibrium, causing the PCR to enlarge and the vitreous to prolapse out. The surgeon should instead remain in foot position one and inject dispersive viscoelastic through the side port with the non-dominant hand while holding the dominant hand steady. Once the dispersive viscoelastic tamponades the break, stabilizes any remnant nuclear fragments, and fills the AC, the probe may gently be withdrawn. The next step is to analyse the situation, as further management depends on when the PCR occurred, the surgeon’s experience in managing such situations, the availability of required machines and instruments, and the presence of vitreoretinal backup.
STAGE AT WHICH PCR OCCURS PCR most commonly occurs towards the end of phacoemulsification—while removing the last nuclear fragment, during cortex aspiration, or polishing the PC. PCR during hydrodissection can result in the entire nucleus sinking. Posterior polar cataracts with inherent weakness in the PC are especially predisposed to this. Post-traumatic cataracts, postvitrectomised eyes, or eyes with a history of intravitreal injections may have unnoticed/iatrogenic posterior capsular breaks that may extend to sudden increase in pressure from the hydrodissection wave. Very small incisions, high viscosity, viscoelastic blocking
egress of fluid, mature cataracts that fill the entire capsular bag, a small rhexis, rapid hydrodissection, or sudden use of large volume of fluid can cause the nucleus to float up against the anterior capsular rim. This creates a seal, which causes an accumulation of fluid within the capsular bag that ultimately leads to capsular block syndrome (CBS) and PC blowout. Multiple gentle injections of small volumes of fluid, tapping the nucleus gently to break the seal and allow entrapped fluid to escape, and depressing the posterior lip of the incision are manoeuvres that allow excess fluid to exit. This is also important in myopic eyes, microincision coaxial phaco, and bimanual phaco, where the incisions are smaller. Femtosecond laser-assisted cataract surgery (FLACS) creates gas bubbles within the lens, which, unless released, add to the intralenticular pressure during hydrodissection, risking CBS and capsular blowout. Attempts at nucleus rotation in the presence of a compromised capsule can also result in nucleus drop. If the PCR involves retained nuclear fragments without vitreous loss, the management depends on the size and hardness of the remaining nucleus. A large nucleus or hard fragment can be brought out after conversion to extra-capsular cataract surgery. A small fragment or a soft nucleus may be emulsified within the anterior chamber, taking care to avoid chamber fluctuations and vitreous prolapse by using dispersive viscoelastic and slow-motion phacoemulsification. The IOL scaffold technique described by Agarwal et al. can be used where a foldable IOL is pre-placed within the AC—over the iris and under the nuclear fragments so the IOL haptic occludes the pupil and prevents fragment drop, vitreous prolapse, or PCR enlargement. To be continued in next issue. Dr Soosan Jacob is Director and Chief of Dr Agarwal’s Refractive and Cornea Foundation at Dr Agarwal’s Eye Hospital, Chennai, India, and can be reached at email@example.com.
EUROTIMES | SEPTEMBER 2021
Under Attack Clare Quigley reports from the cyber trenches
And then there was the cyberattack. One Friday morning, I was walking down the basement corridor towards the locker room to drop off my cycling gear. Michelle, one of the clinical nurse managers, stopped me. It was all over the media, apparently: a cyberattack had struck, targeting the whole Health Service Executive—or HSE, the Irish public health service. I did not realise what this meant, but it rapidly became more apparent. We could not turn on the computers. Over the last year or so, there had been a valiant effort to transition to an electronic medical record. We had gotten familiar with the software slowly. Clinics initially did not run so smoothly, of course, while we were getting used to navigating the program. Where should I fit in the central corneal thickness? How do I add a nice diagram? Some of the teams, including those I worked with recently in the anterior segment, were especially keen on the new system. They were early adopters to the electronic record software. And so, the usual thick brown charts were being phased out, to be replaced by slim chartlets and an electronic record. But what happens then, when we cannot turn on the computers? Patients arrived for clinic, for surgery, but we could not access any of their electronically stored data. Some of them we knew well from frequent visits. Some of them, not so well. Some of them knew their treatment, their drops, their history. Some of them, but not all of them. “Can you tell me why you are here today?” I would ask. “Unfortunately, with the cyberattack, we do not have access to your electronic file. Can you tell me your background history?” This got old pretty quickly. At the top of my (now paper) clinical note, I got in the habit of writing *cyberattack* just to highlight to everyone looking back over the file that the interaction had taken place without any access to the patient’s electronic record. In the clinics, imaging was still possible, so we could get OCTs for our patients. But we could not turn on the computers. So, we trooped up and down the corridor, to and from the photography department, to look at images on the OCT machines. Additionally, during the few weeks of the cyberattack, we could not look at past scans. So, I would see a patient in clinic who had a vein occlusion, or wet AMD, and have only the snapshot of
today’s visual acuity and OCT to base a decision on; continue injections, or what to do? “Is your vision better, worse, or the same?” I would ask. Patients were understanding of the situation. I made sure to continue to write *cyberattack* somewhere on my notes. There were personal costs too. I had been given a work laptop, that I liked and had become dependent on. Whenever there was a Zoom meeting or conference, I used it, as the microphone on my personal laptop was broken. Otherwise, my old laptop worked well, so I had not replaced it yet. But now we were told any work device had to be returned to the IT department for cleaning. So, I surrendered my potentially compromised HSE laptop and went out straightaway that weekend to buy a new laptop. I had to have a working microphone; important online exams, including the EBOD, were looming. The layers of disruption seemed without end. I heard about problems with getting paid. The finance department would not have access to our overtime hours. We usually clock in and out, and our on-call hours make a significant contribution to our pay cheques. The same for the nurses, who do on-call too. There was a decision to pay us an average salary, which seemed fair. Then it started to affect my fellowship applications. At this early stage in the process of finding a fellowship, getting my credentials recognised is mandatory, a relatively convoluted process at the best of times. But now, when I contacted the hospitals that I worked in previously, the HR departments informed me they could not verify my work history there, as they had no access to their records. Several plaintive phone calls and letters ensued. The non-clinical administrative challenges were immense. For a few weeks, we were all working on paper, transported back to the 1970s. Eventually, all devices were cleaned, and a new server arrived. We could turn on the computers again. Warily we got back to usual. I wonder about the people who attacked our health service and the damage they caused. Delayed chemotherapy and surgery, more advanced cancers. Deaths. A decision to target us in the middle of a pandemic. I hope we catch them, and the crimes we charge them with correspond somehow to the suffering caused.
“I hope we catch them, and the crimes we charge them with correspond somehow to the suffering caused.”
EUROTIMES | SEPTEMBER 2021
NEWS IN BRIEF SCHWIND INNOVATION AWARD SCHWIND eye-tech-solutions received a “SME Innovation Award” following a survey by the independent Deutsche Gesellschaft für Verbraucherstudien (DtGV). SCHWIND achieved success in one of the most innovative fields of investigation, healthcare, and lifesaving, securing a top spot among the top 10% of SMEs in its industry. The company scored particularly well due to granted patents for its SCHWIND ATOS femtosecond laser.
Photographs courtesy of Andrea Leonardi, Department of Neuroscience, Ophthalmology Unit, Orthoptic and Assistant in Ophthalmology School, University of Padua, Italy.
FDA APPROVAL FOR VERKAZIA The US FDA approved Santen’s Verkazia™ for the treatment of vernal keratoconjunctivitis (VKC) in children and adults. Verkazia (cyclosporine ophthalmic emulsion, 0.1%) is indicated for the treatment of vernal keratoconjunctivitis (VKC) in children and adults.
EYEHANCE IN EUROPE The TECNIS Eyhance Toric II IOL with TECNIS Simplicity Delivery System from Johnson & Johnson is now available in Europe. The lens and delivery system provide treatment for cataract patients with astigmatism. The technology provides good distance vision as well as better intermediate vision than what conventional monofocal IOLs provide, the company says.
RAYNER CHANGES HANDS VERITAS LAUNCH Johnson & Johnson announced the global availability of the VERITAS Vision System during the 2021 in-person annual meeting of the American Society of Cataract and Refractive Surgery (ASCRS). Features of the phacoemulsification system include Hybrid Fluidics Technology to minimise post-occlusion surge and provide chamber stability, and Intelligent Occlusion Sensing Technologies that automatically respond to occlusions, the company reports. The system is built on the WHITESTAR Technology platform and also includes significant ergonomic improvements.
CVC Capital Partners VIII acquired a majority stake in UK-based Rayner, a leading manufacturer and developer of IOLs and associated pharmaceuticals, from private equity firm Phoenix Equity Partners. Rayner, which developed the world’s first IOL in 1949, now makes IOLs and other products available to about 300,000 patients in more than 80 countries through its subsidiaries and distribution networks.
LENSAR DEMONSTRATES NEW CATARACT SYSTEM Also at the annual ASCRS meeting in Las Vegas in 2021, LENSAR hosted in-person demonstrations of its next-generation femtosecond laser ALLY™ Adaptive Cataract Treatment System. LENSAR expects to submit a 510(k) application for regulatory clearance of ALLY in the first quarter of 2022, with a commercial launch planned for later in 2022.
EUROTIMES | SEPTEMBER 2021
12th EuCornea Congress
EURETINA 2021 Virtual 9 – 12 September Virtual Meeting https://www.euretina.org/
EURETINA 2021 Virtual 9 – 12 September Virtual Meeting https://www.euretina.org/
39th Congress of the ESCRS 8 – 11 October Amsterdam, the Netherlands https://www.escrs.org/
25 September Virtual Meeting https://www.eucornea.org/
SFO Autumn E-Congress 6 November Virtual Meeting https://www.sfo.asso.fr/
AAO 2021: Re/Create
12 – 15 November New Orleans, Louisiana USA https://www.aao.org/annual-meeting
EUROTIMES | SEPTEMBER 2021
8 – 11 October 2021 RAI Amsterdam, The Netherlands
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In addition to HP-guar, SYSTANE® HYDRATION contains Hyaluronic Acid (HA), resulting in a dual-polymer formula that provides longlasting hydration protection and relief for those suffering from moderate, chronic dry eye.4,6,8 As part of the full SYSTANE family of artificial tears, these formulations reflect the continual innovation you expect from Alcon products and enable you to customize dry eye relief to serve your patients’ individual needs and sustain their loyalty.
Pack shot is for illustrative purposes only.
*Compared with hyaluronic acid alone. See instructions for use, precautions, warnings and contraindications. 1. MarketScope LLC. 2019 Dry Eye Products Market Report: A Global Analysis for 2018 to 2024. St. Louis, MO: MarketScope LLC; 2019. 2. Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II Report executive summary. Ocul. Surf. 15(2017):802-812. 3. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017;15:575-628. 4. Davitt, WF, Bloomenstein M, Christensen M, Martin AE. Efficacy in patients with dry eye after treatment with a new lubricant eye drop formulation. J Ocul Pharmacol Ther. 2010;26(4):347-353. 5. Springs, C.L. Novel hydroxypropyl-guar gellable lubricant eye drops for treatment of dry eye. Adv Therapy 27, 681–690 (2010). 6. Rangarajan R, Kraybill B, Ogundele A, Ketelson H. Effects of a hyaluronic acid/hydroxypropyl guar artificial tear solution on protection, recovery, and lubricity in models of corneal epithelium. J. Ocul. Pharmacol. Ther. 2015;31(8):491-497. 7. Christensen MT, Martin AE, Bloomenstein M. A comparison of efficacy between Systane Ultra and Optive lubricant eye drops when tested with dry eye patients. Optometry. 2009;80(6):315. 8. Rolando M, Autori S, Badino F, Barabino S.Protecting the ocular surface and improving the quality of life of dry eye patients: a study of the efficacy of an HP-guar containing ocular lubricant in a population of dry eye patients. J Ocul Pharmacol Ther. 2009;25(3):271-278. ©2021 Alcon