EuroTimes October 2022, Volume 27, Issue 8

Patients’ IMPROVING YOUR IQ

NEW TECH CREATES NEW REFRACTIVE OPTIONS. PATIENT INPUT HELPS CHOOSE WHAT’S BEST.

Research Education Innovation

ESCRS’s vision is to educate and help our peers excel in our field. Together, we are driving the field of ophthalmology forward.

Publishers

Publishers Vanessa McCourt

Vanessa McCourt

Operations Director ESCRS

Operations Director ESCRS

Barbara Calderwood

Barbara Calderwood

Mark Wheeler

Mark Wheeler

Executive Editor

Executive Editor

Stuart Hales stuart.hales@eurotimes.org

Stuart Hales stuart.hales@eurotimes.org

Editor-in-Chief

Editor-in-Chief

Sean Henahan

Sean Henahan

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Senior Content Editor

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Kelsey Ingram

Design Director

Design Director

Kelsy McCarthy

Kelsy McCarthy

Designer

Designer Jennifer Lacey

Jen Lacey

Circulation Manager

Circulation Manager

Vanessa McCourt

Vanessa McCourt

Contributing Editors

Contributing Editors

Cheryl Guttman Krader

Cheryl Guttman Krader

Howard Larkin

Howard Larkin

Dermot McGrath Roibeárd O’hÉineacháin

Dermot McGrath Roibeárd O’hÉineacháin

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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 executive editor.

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 executive editor.

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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 1393-8983

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“The secret of getting ahead is getting started.” —Mark Twain

The recently concluded 40th annual Congress in Milan was a refreshing return to a pattern we were familiar with before the COVID pandemic drove us all indoors. This was a fullsize conference showcasing the breadth of research and clinical practice in the field of ophthalmology.

We have come a long way since our annual Congress in Amsterdam last year. There, we were happy to meet in person again but still couldn’t help but be preoccupied with the COVID pandemic. This year, thankfully, wide-scale vaccination and improved treatment meant we could meet with fewer restrictions.

The Congress highlighted our increased awareness of the role ophthalmologists can play in meeting the multiple global challenges we face.

For example, the ESCRS responded very quickly to the Russian invasion of Ukraine. Our ongoing efforts, working with industry, have already provided more than one million euros in support to our Ukrainian ophthalmological colleagues in logistics and medical supplies. The ESCRS sponsored some 300 Ukrainian doctors at the Milan conference.

No issue has broader global ramifications for all of us than climate change. Signs of the enhanced ESCRS commitment to making ophthalmology more sustainable could be seen throughout the conference centre: recycling, reusable water bottles, messenger bikes, and healthy snack options everywhere. Sustainability was also a hot topic at the iNovation Symposium and the Practice Management and Development sessions.

Keeping with the theme of sustainability, the Milan Congress also saw the announcement of the top prize for this year’s John Henahan Essay Contest. You can read George Liu’s

winning essay in this issue, highlighting the contribution ophthalmology makes to climate change and proposals for some workable solutions.

This month’s JCRS Highlights column echoes the theme, with three important articles showing the growing awareness of the problems of climate change and sustainability and the potential of the medical world to improve its practices.

Amid multiple evolving global crises, the task of the ophthalmic surgeon remains the same: to meet the vision needs of individual patients. The past two decades have seen a steady improvement in cataract and refractive surgery results as new techniques and methods for assessing vision continue to evolve.

Our cover article by Howard Larkin looks at patient image quality (IQ), which was the focus of a session at this year’s ASCRS conference in Washington, DC. The take-home? Improving image quality can improve visual function and patient satisfaction. A companion article looks at the role of imaging in the assessment of patients’ IQ.

Look for comprehensive coverage from Milan in our coming issues.

ESCRS PRESIDENT

INTERNATIONAL EDITORIAL BOARD

Thomas Kohnen Chief Medical Editor

José Güell

MEDICAL EDITORS

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 (US), 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)

Paul Rosen

The Congress highlighted our increased awareness of the role ophthalmologists can play in meeting the multiple global challenges we face.

Patients’ IMPROVING YOUR IQ

NEW TECH CREATES NEW REFRACTIVE OPTIONS. PATIENT INPUT HELPS CHOOSE WHAT’S BEST.

The primary reason we perform lens surgery is to improve our patients’ image quality,” noted Daniel H Chang MD.

But reaching refractive goals, especially treating presbyopia, often involves trading multifocality or extended depth of focus (EDOF) for some decrease in image quality (IQ) compared with monofocal lenses. IQ issues, such as induction of higher order aberrations, are also an issue in laser refractive surgery.

IQ problems, such as reduced contrast and increased blur, and dysphotopsias—including glare, halos, starbursts, and light and dark arcs—are a leading cause of patient dissatisfaction with presbyopia-correcting lenses, sometimes requiring explant. They may also require refractive retreatment. And IQ problems can affect visual function required to read or safely walk, drive, or work.

Advances in lens and diagnostic technology have significantly improved presbyopia correction IQ. But patient needs and preferences are still critical for choosing intraocular lenses and other refractive procedures. Understanding IQ and how it affects functional vision is essential to optimising it—and satisfying patients.

CENTRAL IQ

Image quality falls into two categories, central and peripheral, Dr Chang said.

Central vision is the middle 20 degrees or so of the visual field. It requires high resolution and contrast for seeing fine detail and judging depth for everything from reading to working and driving. It is usually the focus of visual testing, and dysphotopsias in this area may be most troublesome.

Just as myopic defocus blurs light, so, too, do light-splitting lenses, producing glare and halos. Light scatter also produces starbursts. Generally speaking, the greater the multifocal or EDOF add, the greater the IQ problems. These issues tend to be more pronounced in diffractive lenses, said Thomas Kohnen MD, PhD.

Peripheral Vision

Visualizing Visual Angle

Visualizing Visual Angle

Dysphotopsia patterns matter, too, Dr Chang said. A lens that produces multiple halos and starbursts may be more bothersome than one that produces a single focused halo or a small area of continuous glare of similar overall intensity.

Design and manufacturing changes have reduced these problems in recent lenses. High-resolution lathing softens diffractive lens ridges, reducing starburst intensity. Filtering high-energy violet light that scatters more reduces halos—and

dysphotopsia complaints. But these changes don’t entirely eliminate IQ concerns.

PERIPHERAL IQ

Peripheral vision is most often measured by perimetry, Dr Chang noted. It ranges from about 10 to 100 degrees off the visual axis. But its quality also is important for visual functions.

courtesy of Daniel H Chang MD, 2022.

These include balance and safe movement, such as seeing steps to avoid falls and motion detection of oncoming cars and pedestrians in traffic.

Therefore, before surgery, patients should be given specific descriptions of possible central and peripheral IQ lens effects to help them decide if the lenses that reduce spectacle dependence are worth it. Be sure to ask patients about their satisfaction with the first lens between surgeries, Dr Chang added.

Outside the central 20 degrees of the visual field, neural rather than optical characteristics are the limiting factors for IQ. In addition to sharply reduced cone photoreceptor density, reduced rod photoreceptor density and the increased number of receptor cells transmitting through each retinal ganglion cell progressively limit resolution and spatial vision, said Susana Marcos PhD.

Still, near peripheral vision is essential for visual functions including detecting motion and distance off axis. The natural crystalline lens is shaped to optimise it optically, while most commercially available lenses optimise mostly central vision. A multiconfiguration aspheric IOL designed by Pablo Artal PhD more closely replicates the optics of the natural lens. This reduces HOAs that can interfere with near-peripheral visual function and improves peripheral defocus and contrast sensitivity. However, the clinical significance of these improvements is unclear.

flat surfaces looking curved. However, it has not been psychometrically validated, Dr Donaldson said.

Eyeland Design Network offers an interactive simulator that scores the intensity, size, and type of halos and glare intensity. Or ophthalmologists can simply ask patients to rate how often they have IQ symptoms and their overall satisfaction with their near, intermediate, and far vision.

Direct measures of visual quality include glare testing, contrast sensitivity, reading speed, and stereoacuity, Dr Donaldson said. These can all be affected by IOL choices and refractive surgery effect. However, judging their clinical significance can be difficult, she added. Often, IQ issues and their functional impacts worsen in dim or low light. Devices that quantitate visual function include the Tracey Technologies iTrace aberrometer and the Nidek OPD-3, which measures point spread function at different pupil sizes and light levels.

Patient-reported outcomes (PROs) should be included in measuring refractive surgery success, said Vance M Thompson MD. These should include dry eye, which can also affect IQ, and visual symptoms such as ghosting, glare, halos, and starbursts. In the two PROWL studies with the US Food and Drug Administration, such symptoms mostly declined over time and were more often resolved than induced by LASIK surgery.

Sharing such results with patients helps them understand what to expect. “We need to close the gap between how we feel about surgical outcomes and how the patient feels,” Dr Thompson said, echoing a February 2022 Journal of Cataract and Refractive Surgery editorial by Dr Kohnen.

“The goal is improvement in quality of life of the patient and satisfaction. We have a variety of lenses available, but we have to figure out which lenses for which patients,” Dr Kohnen stressed.

Negative dysphotopsia typically create a crescent-shaped dark shadow in the far temporal periphery that can be very disturbing, said Samuel Masket MD, and occurs more commonly than thought. In fact, when specifically asked, patients report a nearly 20% incidence early after surgery. This falls to about 3% one year postoperatively, likely due to neuroadaptation, he added. While there is no specific diagnostic test for negative dysphotopsia (ND), the defect or scotoma can be measured and recorded with peripheral kinetic Goldmann visual field testing. The ND scotoma is worse with both eyes open, but symptoms improve when the fellow eye is occluded, either with a patch or a contact lens opaque in the periphery blocking temporally incident light. The contact lens will also improve symptoms when placed on the involved eye. For patients who continue to report bothersome symptoms, a reverse optic capture of the existing IOL or implanting an IOL in the sulcus or one with a groove around the periphery that overlaps the capsule (such as the one Dr Masket designed) resolves or prevents the symptoms.

ASK YOUR PATIENTS

Objective measures such as Snellen visual acuity don’t always tell the whole story, and often reduced visual function due to degraded IQ is the culprit, said Kendall E Donaldson MD, MS. “You’ll get a patient come in with 20/20, and they are so unhappy. So, there is some subjective component by patient report that is sometimes difficult to quantify.”

To distinguish between visual acuity and visual function, “ask the patient,” Dr Donaldson said. Several visual function questionnaires exist, but these are not usually incorporated into clinical practice, she added.

Different questionnaires measure different aspects of function and visual quality. The VF-7 is designed to assess functional improvement after cataract surgery and asks questions about ability to perform daily activities, such as reading, seeing stairs, and driving. The APPLES survey is more specific to IQ, including 21 items about the frequency and severity of glare, halos, starburst, hazy vision, blurred vision, straight line distortions, and

This article is based on a session of Refractive Surgery Day dedicated to patient IQ held at the American Society of Cataract and Refractive Surgery 2022 Annual Meeting in Washington, DC, US.

Daniel H Chang MD is managing partner at Empire Eye and Laser Center, Bakersfield, California, US. dchang@empireeyeandlaser.com

Thomas Kohnen MD, PhD, FEBO is professor and chair, Department of Ophthalmology, Goethe University, Frankfurt, Germany, co-editor of the Journal of Cataract and Refractive Surgery, and ESCRS treasurer. kohnen@em.uni-frankfurt.de

Susana Marcos PhD is David R Williams Director of Visual Science; Nicholas George Professor of Optics, The Institute of Optics; and Professor of Ophthalmology, Flaum Eye Institute at the University of Rochester, New York, US. susana@io.cfmac.csic.es

Samuel Masket MD is founding partner of Advanced Vision Care in Los Angeles, California, and clinical professor of ophthalmology at the Geffen School of Medicine, University of California–Los Angeles, US. avcmasket@aol.com

Kendall E Donaldson MD, MS is professor of clinical ophthalmology and medical director at the Bascom Palmer Eye Institute at Plantation of the University of Miami, Florida, US. kdonaldson@med.miami.edu

Vance M Thompson MD is director of refractive surgery at Vance Thompson Vision in Sioux Falls, South Dakota, and professor of ophthalmology at the Sanford School of Medicine of the University of South Dakota, US. vance.thompson@vancethompsonvision.com

“We need to close the gap between how we feel about surgical outcomes and how the patient feels.”

Vance M Thompson MD

Corneal Mapping Can Help Improve IQ

Corneal topography and tomography can help assess patients’ IQ and guide treatments that can improve it, reported Marcony R Santhiago MD, PhD. While most important in the central cornea, the periphery matters as well, he noted.

Asymmetric astigmatism degrades IQ and is the hallmark of ectatic corneal disease, Dr Santhiago said. It appears as focal changes in keratometry or elevations, irregular curvature patterns, and focal asymmetric corneal thinning. As ectasias worsen, the asymmetry becomes more evident, and IQ worsens. Topography and tomography can also detect induced higherorder aberrations, buttonhole flaps, and asymmetry between the eyes that affect IQ.

Therapeutic refractive surgery can greatly improve poor IQ due to corneal issues. Procedures include topography-guided ablations and phototherapeutic keratectomy for corneal irregularities and opacities. It can help patients with decentration and small optical zones and increase visual acuity in post-LASIK ectasia. “The results are fantastic in terms of increasing IQ and reducing, for example, night vision symptoms.”

Topography-guided procedures are preferable to wavefrontguided because topography is more reliable for mapping highly aberrated or irregular corneas. And the ablation pattern combines hyperopic and myopic approaches to smooth adjacent areas, conserving tissue where it matters most, Dr Santhiago said. For highly irregular corneas, he suggests a two-step treatment, with the first aiming to regularize the cornea only, adding any refractive change as a separate step perhaps six months later.

Corneal topography can help in choosing lenses as well. It can identify patients who may have previous refractive surgery or irregular corneas requiring a special lens power formula to select a conventional or toric lens. Higher-order aberrations, particularly in the central cornea, may suggest the patient is not a good candidate for multifocal lenses. Corneal spherical aberrations, particularly negative aberrations, may indicate a spheric rather than an aspheric IOL.

EPITHELIAL MAPPING

The epithelium can help assess image IQ, said Julie M Schallhorn MD. Because it tends to regress toward a regular shape, it can be thicker or thinner at different points across the cornea, masking corneal irregularities. “The epithelium is not static; it is moving around, filling in the nooks and crannies.”

The epithelium thickens in the central cornea after myopic LASIK and in a donut pattern more peripherally after hyperopic LASIK. “The epithelium tries to undo everything you have done with the laser.” It also may fill in the flatter parts of the cornea around the keratoconus cone and thin over the steeper area, masking the true extent of the cone, Dr Schallhorn added. Because epithelial remodelling is highly variable, Dr Schallhorn recommended epithelial mapping for patients before LASIK or PRK treatment or retreatment—and those with irregular corneas—to assess its potential impact on IQ. “Respect the epithelium. It has a huge impact on image quality.”

WAVEFRONT ANALYSIS

Wavefront and objective scatter index analysis can help distinguish between IQ effects of higher-order aberrations (HOAs) and light scatter, which can help guide treatment, said Karolinne M Rocha MD, PhD. Essentially, HOAs create blur, shape distortions, and halos, while light scatter mostly reduces contrast and increases glare, she said.

Different sources of light scatter, such as cataracts, posterior capsule opacification, and corneal flap interface haze, require specific treatment. Options for correcting HOAs include refractive surgery, corrective lenses, or IOLs that induce spherical aberration (SA), which can also extend depth of focus, but their suitability depends on the SA induced by the cornea. Visual simulators help gauge patients’ response to and tolerance of HOA induction and correction, Dr Rocha said.

Drs Santhiago, Schallhorn, and Rocha spoke at Refractive Surgery Day during the American Society of Cataract and Refractive Surgery 2022 Annual Meeting in Washington, DC, US.

Julie M Schallhorn MD. julie.schallhorn@ucsf.edu

Karolinne Maia Rocha MD, PhD.rochak@musc.edu

Marcony R Santhiago MD, PhD. marconysanthiago@hotmail.com

Extracting the Right Solution

For patients undergoing both cataract extraction and pars plana vitrectomy (PPV) surgery, visual acuity and refractive improvements were similar—whether conducted as a simultaneous, combined procedure or as separate, sequential procedures, according to a study reported by Abdelhalim A Awidi MD.

Since cataract progression typically hastens after PPV and advances quicker in older patients, a simultaneous approach may be suitable for patients more than 60 years of age, Dr Awidi added. This approach can minimise the added risks of intraoperative and postoperative complications associated with increased trips to the operating room.

He outlined three scenarios that require both cataract extraction and PPV. The first is a patient presenting initially with a dense cataract, which, after extraction, subsequently reveals a posterior segment pathology such as epiretinal membrane. This scenario typically results in a sequential cataract extraction and PPV procedure approach. The second is a patient with a known posterior pathology who undergoes PPV surgery and develops a cataract requiring extraction afterwards, as cataracts are one of the most common complications following PPV. The third is a patient presenting with coexisting cataract and retinal pathology. Regardless of procedure timing, improvements in visual acuity and refractive outcomes are significant compared to preoperative measures after two operations, Dr Awidi said.

IMPROVED VISION

In a retrospective study involving 427 eyes in 404 patients over a two-year period, Dr Awidi and colleagues at the Wilmer Eye Institute assessed uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), and spherical equivalent and refractive target before surgery. They observed the patients 1, 3, 6, 12, and 24 months after surgery. The three treatment groups were PPV followed by cataract extraction, PPV and cataract extraction combined, and cataract extraction followed by PPV. Only patients who had an epiretinal membrane or vitreous opacities diagnosis— undergoing either combined PPV and cataract extraction or PPV sequentially before cataract extraction—were included in spherical equivalent and refractive prediction error analyses.

The team saw improvement in UCVA and BCVA of the whole patient cohort at every follow-up visit compared with preoperative measures, Dr Awidi reported. There were statistically significant differences in absolute BCVA among the three treatment groups at 1 and 12 months after combined or the second surgery.

However, there were no significant differences in spherical equivalent or predicted postoperative refractive error between the PPV followed by cataract extraction and the combined surgery groups at 1 and 3 months, or 6 and 24 months, after surgery.

The study also examined the timing of sequential surgeries, as a history of either surgery was an inclusion criteria for the project. Almost two-thirds of patients who underwent PPV first had cataract extraction within one year, and 94% within two years. These figures reflect the rapid progression of cataracts after PPV. Nearly 60% of patients who had cataract extraction first had PPV within one year, and 81% within two years.

“A simultaneous approach could be a suitable option for patients [older than] the age of 60 in elective or emergency situations, as it

Both simultaneous and sequential cataract extraction improve visual outcomes; simultaneous may be better for older patients.

Howard Larkin reports

Image courtesy of AA Awidi, 2022.

Figure 1: Cumulative percentage of eyes undergoing sequential surgery within the specified time frames. PPV/CE = pars plana vitrectomy followed by cataract extraction surgery; CE/PPV = cataract extraction surgery followed by pars plana vitrectomy.

“A simultaneous approach could be a suitable option for patients [older than] the age of 60 in elective or emergency situations.”

avoids the hastened deterioration in vision seen with advanced age that arises with the progression of cataracts following PPV,” he said.

Dr Awidi presented at the American Society of Cataract and Refractive Surgery 2022 Annual Meeting in Washington, DC, US.

Abdelhalim A Awidi MD is a post-doctoral research fellow at the Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, US. aawidi1@jhmi.edu

Image courtesy of AA Awidi, 2022.

Figure 2: Comparison of postoperative month (POM) 1+3 (A), POM6-24 (B) spherical equivalent (SEQ) accuracy and POM1+3 (C), POM6-24 (D) refractive prediction error (RPE) accuracy within ± 0.5 D, 1.0 D, and 2.0 D in eyes with epiretinal membrane and vitreous opacity diagnoses. PPV+CE = simultaneous cataract extraction surgery and pars plana vitrectomy.

Lens-Softening Drug May Offer Presbyopia “Cure”

Phase 2 trials underway for eyedrops intended to restore some accommodation. Howard Larkin reports

Most approved or nearly approved presbyopia drugs work by inducing miosis to extend depth of focus. But the effects last a few hours at most and may interfere with night driving and low-light vision.

By contrast, the experimental compound UNR844 (lipoic acid/ choline ester 1.5% solution, Novartis) works not by affecting pupil size but by increasing the flexibility of the crystalline lens, theoretically restoring some accommodation. The resulting near add is pupil size-independent so it does not reduce incoming light—and the effect may last for months after a few weeks of treatment.

This is why John A

UNR844: Day 150 and 210 DCNVA Impact

Hovanesian MD sees UNR844, currently in phase 2b clinical trials, as a potential breakthrough in presbyopia treatment.

“We want something safe, tolerable, and has long-term benefit, and that’s where this drug is unique,” he said.

DISSOLVING BONDS

The choline component of UNR844 is designed to help penetrate the cornea so the active ingredient, lipoic acid, can reach the aqueous humour and crystalline lens fibres. There, lipoic acid is hydrolysed and reduced into dihydrolipoic acid, which dissolves disulfide bonds thought to be a major contributor to lens stiffening. This also is thought to allow cytosol to again flow freely and may free bound proteins that stiffen the lens.

DCNVA change of logMAR -0.159 compared with -0.079 (0.116) for the placebo group (p = 0.007).

Moreover, UNR844 patients maintained most of their near vision gains 150 and 210 days after they stopped treatment, demonstrating the durability of the drug’s effect.ii

The phase 2b study currently underway involves 600 patients. The primary endpoints are the percentage of patients gaining 10 or more letters of DCNVA and change in bilateral DCNVA from baseline.

A novel compound, UNR844 has the potential to work on patients with early cataract. While it is unlikely to reduce the need for eventual cataract surgery, it may be a semi-permanent solution, he said.

“This is a drug that might actually cure presbyopia. So, it is a pretty exciting prospect for treating this common condition,” Dr Hovanesian concluded.

Dr Hovanesian presented his findings at the American Society of Cataract and Refractive Surgery 2022 Annual Meeting in Washington, DC, US.

i Investigative Ophthalmology & Visual Science. 2016; 57(6): 2851–63. ii Lindstrom RL. ASCRS 2017; Korenfeld MS. Eye, 2021; 35: 3292–3301.

Theoretically, this restores lens flexibility, allowing it to change shape and accommodate. In a mouse model, lipoic acid significantly increased lens viscoelasticity, Dr Hovanesian noted.i

More to the point, the drug appears to work in humans. In a phase 2a study of UNR844 involving 72 patients, 52% of UNR844 patients gained 10 or more letters of distance corrected visual acuity (DCNVA) after 90 days of twice-daily installation compared with 20% of placebo patients. From baseline to day 91, UNR844-treated subjects demonstrated an improved mean

John A Hovanesian MD is in private practice at Harvard Eye Associates in Laguna Hills, California, US, and is a clinical instructor at Jules Stein Eye Institute, University of California–Los Angeles, US. drhovanesian@harvardeye.com

“We want something safe, tolerable, and has long-term benefit, and that’s where this drug is unique.”

Drug-Eluting IOL Haptic Ring May Enable Dropless Cataract Surgery

Controlled-release

implant may reduce eyedrop side effects and compliance risk. Howard Larkin reports

Complications—such as delayed healing and corneal melts—sometimes seen with topical non-steroidal antiinflammatory drugs (NSAIDs) after cataract surgery could be reduced by implanting a drug-eluting ring now in development. By eliminating the need for postoperative eyedrops, the OcuRing (LayerBio) could also guarantee medication compliance and improve patient satisfaction, according to Kenneth J Mandell MD, PhD.

OcuRing provides all the benefits of NSAIDs while reducing the risks associated with topical NSAID administration, which can be greater for people with diabetes, dry eye, or rheumatological disorders, Dr Mandell said—noting these patients make up more than 30% of the target market.

PHASE 1 STUDY

Compatible with most one-piece and three-piece intraocular lenses (IOL), the OcuRing-K is a bio-erodible elastic ring that slips over the end of an IOL haptic and injected with the lens using standard surgical technique. The OcuRing-K contains the NSAID ketorolac, which is sustainably released for several weeks as the implant bio-erodes.

NSAIDs are highly effective in reducing pain and inflammation and decreasing the risk of macular oedema after cataract surgery, Dr Mandell noted. “We picked ketorolac as the active ingredient because of its long history of safety and efficacy in multiple ophthalmic products.”

A phase 1 study involving five patients implanted with OcuRing-K who received no topical NSAIDs found 100% painfree at 1, 7, and 28 days after cataract surgery, Dr Mandell reported. Both pain and inflammation measured at the same intervals were also substantially lower than in a historical comparison cohort treated with topical steroids.

“For the average or moderate-risk patient, we believe OcuRing-K has the potential to be a steroid-sparing monotherapy.”

In the five patients studied, the ring did not move and had no contact with adjacent tissues. All eyes were pristine with no evidence of inflammation, Dr Mandell said. No steroids were applied, and no patient required steroids as a rescue therapy.

The phase 1 study has confirmed OcuRing-K’s safety, efficacy, and compatibility with cataract surgical technique, Dr Mandell said. He plans a randomised phase 2 trial for next year and a phase 3 study for registration in the next two to three years.

Other products in development using the OcuRing platform include sustained release steroids for postoperative inflammation, prostaglandins for lowering intraocular pressure, long-acting NSAIDs to reduce cystoid macular oedema, and posterior capsule opacification (PCO) prevention with multiple potential targets.

Already, the OcuRing platform has shown 30 days sustained release of dexamethasone and moxifloxacin, Dr Mandell said. In a rabbit-eye model of cataract surgery, an OcuRing providing dexamethasone substantially reduced inflammation and PCO formation compared with dexamethasone eyedrops.

Dr Mandell spoke at the Innovators Session at the American Society for Cataract and Refractive Surgery 2022 Annual Meeting in Washington, DC, US.

Kenneth J Mandell MD, PhD is founder and CEO of LayerBio Inc, a clinical-stage biotechnology company based in Lexington, Massachusetts, US, developing the OcuRing and other therapies in ophthalmology. ken@layerbio.com

“For the average or moderate-risk patient, we believe OcuRing-K has the potential to be a steroid-sparing monotherapy.”

Targeting New IOL Wisdom

Acataract patient’s predicted postoperative refraction straddles emmetropia with available intraocular lenses (IOLs)—a 21.5 D lens will leave them at -0.32 D and a 21.0 D lens at +0.14 D. So, which do you choose?

“Surgeons face this all the time and often say, ‘I’ll choose the 21.5 D and leave the patient a little myopic; they’ll be happy, and they’ll get better functional vision even though they want emmetropia.’ I think, I think, I think, right?”, Steven C Schallhorn MD told EuroTimes in an interview.

But if confirmed, the results of a preliminary analysis may show this conventional wisdom is a bit misguided. “Actually, you may be better off if you choose the 21.0 D lens and target slight hyperopia. That’s what the analysis suggests,” Dr Schallhorn said.

INCIDENTAL FINDING

The preliminary conclusion stems from incidental findings of a retrospective study involving 18,648 patients who underwent refractive lens exchange or cataract surgery at Optical Express outlets in the United Kingdom. The study’s main focus was the impact of residual astigmatism on acuity and patient satisfaction, Dr Schallhorn pointed out. “The sphere findings fell out of the analysis. And it even applied to monofocal IOLs.”i

Regarding postoperative sphere, the study found patients were approximately five times less likely to achieve 20/20 uncorrected distance visual acuity and three times less likely to achieve 20/16 if they ended up with slightly myopic than slightly hyperopic, defined in this case as a residual sphere of 0.25 D to 0.5 D plus or minus. “We’re not talking about leaving the patient significantly hyperopic. It is about straddling emmetropia,” Dr Schallhorn noted.

Dr Schallhorn said the finding was not as surprising for multifocal lenses (since the near add might improve distance vision a bit), but it was surprising for monofocal lenses with no add to offset slight hyperopia. “We thought ‘that is quite perplexing; maybe we need to rethink, given most IOLs are available in 0.5 D increments, how we’re targeting the lens power.’”

SEARCHING FOR ‘WHY’

Consistent across all monofocal lens types, refractive and reported satisfaction results seemingly ruled out differences in asphericity as a reason why they might slightly compensate for hyperopia. One possible explanation may be how the brain interprets images that focus slightly behind the macular surface (or slightly hyperopic) more readily than those similarly focused in front of the macula (or myopic).

However, the study was not powered or designed to tease out such distinctions, Dr Schallhorn added. He is now looking at a larger data set focusing specifically on sphere questions in the hope of confirming the earlier findings and isolating factors that may better explain the results.

Nonetheless, the incidental findings from the prior study were statistically significant, suggesting possible merit. “Patientreported outcomes have a lot more variability than clinical measurements, so when they give you a significant result, it’s usually important,” Dr Schallhorn explained.

i Schallhorn SC et al. Journal of Cataract & Refractive Surgery. 2021; 47(8): 991–998.

Patients who ended up slightly hyperopic were also about 30% to 40% more likely to report they were satisfied with their visual results, whether they received a multifocal or a monofocal IOL.

Steven C Schallhorn MD is a Clinical Professor, Department of Ophthalmology, University of California, San Francisco, US. scschallhorn@yahoo.com

Preliminary data suggest patients may be happier with IOLs that leave them a little far-sighted rather than near-sighted.

Howard Larkin reports

“We’re not talking about leaving the patient significantly hyperopic. It is about straddling emmetropia.”

Figure 1: Satisfaction with vision stratified by residual astigmatism (dominant eye) in patients implanted with multifocal IOLs (8,602 patients, three-month follow up).

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Restoring Corneal Transparency

Developing novel cell-based therapies for limbal stem cell deficiency and stromal injury. Cheryl Guttman Krader reports

Extracellular vesicles (EVs) derived from human corneal stromal stem cells (hCSSCs) could form the basis for affordable therapies to prevent or treat stromal scarring in injured corneas, according to Sophie X Deng MD, PhD during a symposium on cell-based therapies for ophthalmic diseases. She described the work addressing limitations surrounding autologous LSC transplantation for LSCD.

Members of the Global Consensus on Management of LSCD Working Group concluded autologous LSC transplantation using the least amount of donor tissue is the preferred method for surgical treatment of unilateral or subtotal bilateral LSCD. They identified the use of ex vivocultivated autologous LSCs as one such approach.

However, a drawback of existing expansion methods for obtaining the transplant material was the use of animal products. To overcome this issue, researchers in Dr Deng’s laboratory, led by Sheyla Gonzalez PhD, developed a xenobiotic-free and feeder-free manufacturing process for LSC expansion in which the limbal biopsy is grown directly on denuded amniotic membrane.

Clinicalpresentationandcellularstructureofaneyebeforeandaftercultivatedlimbalstemcellstransplant(cLSC).Slit-lamp photography under white light (first row) shows a clear cornea in normal eye (first column), abnormal corneal surface in severe limbal stem cell deficiency (LSCD, second column), ocular surface at 6 (third column) and 12 months (fourth column) after cLSC transplant. In vivo laser scanning confocal microscopy of basal central corneal epithelial cells (second row) shows compact corneal basal epithelial cells in high density in normal eye (first column), absence of cells with corneal epithelial cell morphology before cLSC transplant (second column), basal epithelial cells with normal corneal epithelial morphology at both 6 and 12 months after cLSC transplant (third and fourth column). Images from anterior segment optical coherence tomography (bottom row) show central epithelial thickness in normal eye (first column), marked epithelial thinning in LSCD (second column), and restoration of a normal epithelial thickness after cLSC transplant (third and fourth column).

Fifteen patients will receive LSC treatment, and five assigned to a scleral lens control group.

Dr Deng and colleagues also addressed another limitation in LSCD management—the absence of a standardised objective system for diagnosing the disease and grading its severity.

Targeting this unmet need, Dr Deng and colleagues developed a quantitative diagnostic and staging system for LSCD that grades the severity of the condition with a numerical score. The system is a composite of a clinical score and findings from in vivo imaging. The clinical score considers the extent of limbal involvement, extent of corneal involvement, and presence of central axis involvement. The imaging parameters are central cornea basal epithelial cell density, corneal epithelial thickness, cell morphology, and corneal subbasal nerve fibre density.

PHASE I STUDY UNDERWAY

The safety, feasibility, and efficacy of treating LSCD using autologous LSCs cultivated with the xenobiotic-free manufacturing process are under investigation in an ongoing phase 1 clinical trial. As a second objective, the study aims to validate the LSCD diagnostic criteria and quantitative staging system.

The study has a randomised, controlled, open-label design and plans to enrol 20 subjects with severe to total LSCD in one eye.

“Preliminary results show so far that six limbal stem cell grafts manufactured under xenobiotic-free and feeder-free conditions from six limbal biopsies have been successfully transplanted. In addition, there have been no serious adverse events associated with the transplanted cultivated LSCs, and most patients experienced dramatic improvements in subjective symptoms and vision too,” Dr Deng said. The corneal epithelial cell layer with normal cell morphology, basal cell density, and epithelial thickness could be restored after cLSC treatment (as shown in the figure). “This finding is very exciting because this is the first time biological function of transplanted LSCs has been demonstrated and quantified at the cellular level in patients using a set of standardised criteria,” she added. These criteria can be used in future clinical trials as standardised outcome measures that enable objective comparison of efficacy of different LSC therapies, which has not been possible.

“We are still actively recruiting participants for the study. Please refer patients with unilateral LSCD.”

STROMAL SCAR TREATMENT

The development of hCSSC-derived extracellular vesicle-based therapy for corneal stromal scarring holds interest for overcoming the severe shortage of corneal tissue for transplantation. Dr Deng credited James Funderburgh PhD from the

University of Pittsburgh (Pennsylvania, US) for pioneering this field, as his group first demonstrated that CSSCs— which are mesenchymal stem cells within the limbus—have antifibrotic activity.

“In animal models with corneal injury induced by mechanical wounding, Dr Funderburgh and colleagues showed the application of CSSCs reduced scar formation. Phase 1 clinical trials using CSSCs are now being conducted in India,” Dr Deng said.

Dr Funderburgh’s subsequent work validated his hypothesis that EVs from the CSSCs, specifically microRNAs transported in the vesicles, were the key mediator of corneal regeneration. The collaborative work of Dr Funderburgh and Dr Deng further showed that a specific subset of microRNAs might be responsible for the anti-fibrotic function of EVs.

“The evidence indicates EVs from CSSCs are efficient in their ability to reduce corneal scarring and seem to be more stable, safer, and more accessible a treatment for corneal scarring than CSSCs because the EVs can be formulated as an offthe-shelf product,” said Dr Deng.

“However, the CSSCs have a limited replicative lifespan and cannot produce enough EVs for clinical use.”

To overcome this “bottleneck” that prevents the necessary scaling up of EV production, Dr Deng and colleagues set out to create an immortalised CSSC line that could provide an unlimited EV source. Their efforts were successful, as characterisations of the immortalised cells showed the cells maintained the morphology of primary CSSCs, expressed the same cell surface antigens, retained a similar molecular signature, and retained the multipotent differentiation ability into adipogenic, osteogenic, and chondrogenic lineages of the primary CSSCs.

Subsequent research performed in a mouse model of mechanical stromal wounding demonstrated EVs derived from the immortalised CSSCs reduced corneal scarring.

“This work is proof of concept that immortalised CSSCs can produce a large amount of functional EVs and for the feasibility of low-cost, EV-based therapy,” Dr Deng said.

Dr Deng presented this research at ARVO 2022 in Denver, Colorado, US.

Sophie Deng MD, PhD is the director of the Cornea Biology Laboratory, Joan and Jerome Snyder Chair in Cornea Diseases, and co-Chief, Cornea and Uveitis Division at the UCLA Stein Eye Institute, Los Angeles, California, US. deng@jsei.ucla.edu

“This work is proof of concept that immortalised CSSCs can produce a large amount of functional EVs and for the feasibility of low-cost, EVbased therapy.”

CAIRS Gaining Momentum

Procedure offers a safe alternative to DALK. Dr Soosan Jacob reports

Corneal Allogenic Intrastromal Ring Segment or CAIRS refers to the use of any form of allogenic tissue—fresh, preserved, processed donor stroma, or any other alternate allogenic source placed within intrastromal corneal channels.

I started this technique in 2015 as a solution to complications seen with synthetic intracorneal ring segment (ICRS) implantation, such as extrusions and melts. I was pleasantly surprised to see that CAIRS’s other advantages include low risks even with superficial implantation and smaller optic zone, better effect, lower risk of glare and halos, and the possibility of implanting in advanced keratoconus (steeper than 58 D and thinner than 400–450 microns in implantation zone). In addition, synthetic ICRS—even when implanted in an optimal candidate—can, with time, result in overlying corneal melt if continued stromal thinning occurs secondary to progression or eye rubbing. Since CAIRS is allogenic, it becomes part of the host cornea and does not carry this risk.

CAIRS GOES GLOBAL

CAIRS has gained momentum worldwide, with cases conducted in multiple centres in the US, Canada, Australia, Germany, France, Ireland, Lebanon, Turkey, Israel, South Africa, Dominican Republic, and multiple centres in India. An easy technique to prepare CAIRS is to use a special double-bladed trephine (Jacob CAIRS trephine™ [patent pending], Madhu Instruments, India) to punch a de-epithelialised and de-endothelialised donor corneoscleral rim. This gives a ring of stroma that can then be easily cut to the desired length and inserted into a circular femtosecond laser dissected or manually cut channel within the patient’s cornea.

CAIRS can be easily cut by the surgeon with no risk of tissue loss, unlike DMEK. CAIRS is also available from eye banks such as the Alabama Eye Bank, which offers pre-cut segments as well as processed segments. It is, of course, ideal to use optical-grade cornea for CAIRS, but if unavailable, non-optical-grade cornea may suffice if the cornea is not oedematous.

As I have described, customised CAIRS is the latest modification where the segment can be customised to get differential flattening according to individual topography. This helps further optimise results and is especially beneficial in asymmetric keratoconus. It is like progressive thickness synthetic ICRS but with added advantages of greater customisation.

On-the-table customisation offers the advantage of not needing to depend on fixed thickness and arc length combinations. It also negates the need to maintain large inventories, unlike customised synthetic ICRS. Using a degree-zone marker (Jacob degree-zone marker™, Epsilon Eye instruments, US), the surgeon or eye bank can easily create customised CAIRS.

Drawn on a topographical map with the patient’s refraction and topography, plans are then translated to the CAIRS using the degree-zone marker. Customisation is based on the principle that placing a thicker portion of CAIRS under a steeper area gives greater flattening than placing a thinner segment, which makes tailoring the individual topography easier to improve (please see video link).

Various other modifications have now been proposed for CAIRS by different users from around the world. Jack Parker MD (US) has described staining CAIRS with trypan blue and dehydrating it before insertion. Shady Awwad MD (Lebanon) has described the “Jerky Technique”, where prolonged dehydration for 60 minutes in a room with 35–50% humidity results in a jerky-like stiffness to the CAIRS, thereby allowing it to

CAIRS(CornealAllogenicIntrastromalRingSegment):Preoperative (top left), postoperative (top right), and difference (bottom left) keratometric maps of an 11-year-old child who underwent CAIRS with contact lens-assisted corneal cross-linking. Lower right shows slit-lamp image with single CAIRS seen placed inferotemporally. The preoperative uncorrected visual acuity improved from 6/24p (20/80p) to 6/9 (20/30), and the topographic (6.6 D preoperatively to 4.3 D postoperatively), refractive cylinder, and spherical equivalent came down significantly.

be held by a forceps and inserted into the tunnel— much like an INTACS.

I also use a technique of staining the Bowman’s membrane side of the CAIRS, which enables me to implant the thicker and stiffer side towards the pupil while also helping identify and rectify CAIRS twisting during implantation. My team and I have also performed other modifications, such as using cross-linked CAIRS, riboflavin-soaked CAIRS, and instilling riboflavin into the channel.

Our initial experience and pilot study were published in the Journal of Refractive Surgery, and since then, we have done more than 350 cases. The large majority were with simultaneous epithelium-off accelerated corneal cross-linking (CXL) protocol (10 mW/cm2, 9 min). The total number of cases globally is significantly higher.

Even up to a year later (in my experience), reversibility and adjustability remain an advantage, as well as easy combination with cross-linking at the same stage. It also doesn’t take away the ability to perform other adjunct procedures such as topography-guided PRK (TG-PRK), phakic IOL, and refractive lens exchange.

Implanting CAIRS first creates synergy by reducing irregular astigmatism and improving corneal topography so surgeons can minimise tissue removal with TG-PRK and obtain better results with intraocular lens-based procedures. CAIRS is a good substitute for deep anterior lamellar keratoplasty (DALK) in many cases. In combination with thin-cornea cross-linking techniques, it can help delay and/or avoid a DALK completely. CAIRS has an easy learning curve, performed easily even by surgeons not trained in DALK. It also removes risks of intra- and postoperative complications associated with DALK.

The risk of rejection, though theoretically present, has not been significant in my experience. A combined case series between my team and Dr Parker’s yielded just one case (about 0.25% incidence) as compared to a higher rate of 14–64% reported after DALK. In addition, unlike DALK and other more recent stromal additive procedures, the visual axis remains untouched in CAIRS, making it safe even in the rare possibility of a rejection.

To conclude, CAIRS is gaining momentum around the world with not just increasing surgeon interest in learning and adopting this technique but also increased traction among keratoconic patients—who are generally well read about their disease and aware of advantages and disadvantages of various procedures. My hospital has an increasing number of patients walking in seeking CAIRS. That said, CAIRS is not a panacea for all keratoconic patients. Very advanced cases—those with visual axis scarring and those without sufficient corneal thickness even for thin-cornea cross-linking techniques—would still need other procedures such as DALK.

CAIRS has been used for treatment of progressive (TG-PRK) and non-progressive keratoconus, cross-linked ectatic corneas, postLASIK ectasia, and pellucid marginal degeneration. Implantation patterns are well-defined, and surgeons can counsel patients confidently to expect a high chance of improvement in both uncorrected and best spectacle corrected distance visual acuity.

Dr Jacob presented an update on CAIRS at the Cornea Subspecialty Day during ASCRS 2022 in Washington, DC, US.

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 dr_soosanj@hotmail.com.

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CAIRS is gaining momentum around the world with not just increasing surgeon interest in learning and adopting this technique but also increased traction among keratoconic patients.

Monkeypox Update

Early signs include conjunctivitis, blepharitis, and eyelid oedema. Cheryl Guttman Krader reports

As the number of monkeypox cases continues to rise, ophthalmologists have been advised to include this contagious infection in their differential diagnosis of patients presenting with the known ophthalmic manifestations.

The current global monkeypox outbreak began in May 2022, with multiple cases diagnosed in several non-endemic countries. As the number of cases climbed, human monkeypox was declared a global health emergency by the World Health Network on June 22, 2022. A total of 11,001 confirmed cases had been reported in 27 European Union/European Economic Area countries by the last week of July; nearly threefourths occurred in Spain, Germany, and France.

Monkeypox usually begins with lymphadenopathy and constitutional symptoms. Skin lesions generally develop after one to three days, but the rash may appear first, which for most individuals involves the face— including the periocular and ocular skin. Lymphadenopathy may affect the preauricular nodes, as occurs with conjunctivitis caused by other viral pathogens.

According to previous epidemiologic studies, more than 20% of individuals infected with monkeypox experience ophthalmic involvement such as conjunctivitis, blepharitis, and eyelid oedema as early signs.

SIGNS AND SYMPTOMS

The constitutional symptoms of monkeypox include fever, malaise, fatigue, headache, myalgia, and back pain. Sore throat, nasal congestion, and/or cough may be present. The characteristic skin rash appears first as macules and evolves with the formation of papules, vesicles, and then pustules that ulcerate, crust, and heal over a period of a few weeks.

Ophthalmic symptoms tend to develop later in the disease course, which experts report as predictive of a more severe case. These symptoms consist of photophobia and corneal involvement that can be severe with resultant scarring and visual loss.

Of note, previous analyses indicate ophthalmic manifestations in persons with monkeypox are more common in children and unvaccinated individuals than those who have received the smallpox vaccine. However, smallpox vaccine viral strains are also associated with ophthalmic manifestations.

CARE AND PREVENTION

Management for the infection is primarily symptomatic and may include ocular lubricants for the ocular manifestations. Trifluridine has been used to treat other Orthopoxvirusassociated corneal infections, but there is no published information about its use for monkeypox. Ophthalmologists should consider topical antibiotics to prevent secondary infections.

The incubation period for monkeypox ranges from 5 to 21 days (usually 6 to 13). Affected individuals are contagious from initial symptom development until the skin lesions completely heal. The disease is usually acquired through direct, intimate contact with an infected individual but can also occur via exposure to respiratory droplets or fomites contaminated with the virus.

Protection against infection includes wearing gowns, gloves, eye protection, and a fitted N95 mask. Patients known or suspected to have monkeypox should wear a mask, have their lesions covered with a gown or sheet, and isolate in a single-person room. There are no special requirements for air handling, cleaning, or disinfection, but laundry materials that have come in contact with an infected person should be handled with gloved hands.

Sources:

1. Abdelaal A, Serhan HA, Mahmoud MA, Rodriguez-Morales AJ, Sah R. “Ophthalmic manifestations of monkeypox virus”. Eye (Lond). 2022 Jul 27. Epub ahead of print.

2. https://extranet.who.int/publicemergency/

Monkeypox virus Credit: WHO

Gene Treatment for Corneal Clouding from Rare Disease

Mby mutations in a single gene resulting in severe, progressive multisystem disease. In addition to spinal, skeletal, joint, heart disease, and delayed cognitive development, MPS1 causes corneal clouding that often leads to severe visual impairment.

Patients with severe MPS1 mostly used to die before reaching age 10. But many now live longer thanks to therapies, including replacement of the alpha-L-iduronidase (IDUA) enzyme that MPS1 restricts and hematopoietic stem cell transplants.

However, these systemic treatments do not slow corneal opacification—which affects about 80% of all MPS1 patients and up to 98% of those with severe disease. These often lead to blindness as they reach their teenage years.

“As MPS1 patients live longer, vision becomes a critical factor to improve their quality of life,” emphasised Parisa Zamiri MD, PhD. Corneal transplants are the only current treatment alternative. But it is far from ideal. Transplants do not address the underlying disease and often result in severe inflammation and rejection in MPS1 patients. Anaesthesia risk is also high, discouraging repeat treatments.

An experimental genetic therapy may change that. Injected into the cornea, it could restore the body’s ability to produce the missing IDUA enzyme locally, possibly leading to years of clear cornea and restored vision, Dr Zamiri said.

SMALL DOSE, BIG IMPACT

MPS1 leads to deficiency in the IDUA enzyme, which breaks up glycosaminoglycans (GAGs) in cells throughout the body. Without enough IDUA, GAGs accumulate and interfere with cell function. In the cornea, this leads to the formation of abnormal collagen fibrils, fibrosis, and proteoglycan aggregates that cloud the normally transparent stroma.

GB-501 (Graybug Vision) is a gene therapy delivered by an adeno-associated virus that transduces a gene into cells that stimulate IDUA secretion. A single intrastromal injection may result in complete and sustained clearing of corneal clouding associated with MPS1.

The cornea is an ideal site for genetic treatment for several reasons, Dr Zamiri noted. It is readily reached with injections, and genes easily transduce at low titers. Because the cornea is

avascular and immune-privileged, the drug is mostly restricted to local tissues, limiting systemic exposure. And since stromal cells do not divide, a low-dose, small-volume treatment results in a durable cure, she added.

“A small number of keratocytes infected with the virus can continuously produce the drug and keep the cornea clear,” Dr Zamiri noted.

In studies in dogs with varying corneal cloudiness due to MPS1, even the corneas of eyes with advanced disease began to clear within a week of injection, were completely clear within three weeks, and stayed clear for two years, Dr Zamiri said.i Safety has been demonstrated in animal models, with no adverse effects on intraocular pressure, corneal thickness, endothelial cell counts, or blood chemistry. All components of GB-501 also have been previously tested in humans.

Human trials are set to begin next year, Dr Zamiri said. The platform may have the potential for treating other corneal opacities and dystrophies as well.

Dr Zamiri presented at the Innovators Session of the American Society of Cataract and Refractive Surgery 2022 Annual Meeting in Washington, DC, US. i Miyadera K et al. Molecular Therapy. 2020; 28(6): 1455–1463.

Parisa Zamiri MD, PhD is Chief Medical Officer at Graybug Vision, a clinical-stage biopharmaceutical company developing medicines for ocular diseases with locations in California and Maryland, US.

After successful animal studies, human trials set for locally injected viral therapy. Howard Larkin reports

GB-501 demonstrated complete and sustained corneal clearing within 3 weeks GB-501 Retina Visible

Corneal clarity restored in MPS1 dog following single injection of GB-501.

Corneal Endothelial Cell Replacement Moves Forward

Clinical trials beginning for therapies that may treat 100+ eyes per donor cornea. Howard Larkin reports

From Then to Now

Corneal Endothelial Cell Therapy Development Timeline

Clinical Trials

Companies Emmecell Ophthalmics and Aurion Biotech have commenced clinical trials aiming to commercialise cell replacement therapies that could revolutionise corneal endothelial failure treatment. Both therapies involve removing diseased endothelium and injecting cultured corneal endothelial cells into the anterior chamber, where they replace diseased cells.

“This is a real, authentic unmet need,” notes John Berdahl MD. Of the approximately 500,000 people diagnosed annually and the overall 16 million with corneal endothelial disease, only about 70,000 receive endothelial keratoplasties. This is largely due to the limited supply of donor corneas, though not all cases require transplants.

EXPANDING SUPPLY

“The problem is scale,” Dr Berdahl said. “With keratoplasty, one donor cornea can treat one patient. By contrast, using cell expansion and injection, one donor cornea may potentially treat 100 or more patients.”

In addition, endothelial keratoplasties—primarily Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK)—are time-consuming and challenging surgical procedures best performed by experienced corneal surgeons. They are also subject to postoperative complications such as graft detachments and haemorrhages, and recovery can take weeks.

On the other hand, cell therapies theoretically could be injected by most ophthalmologists and reduce the risk of postoperative complications, Dr Berdahl said. Their greater availability, reduced risk, and ease of delivery could benefit not only patients with moderate and severe corneal oedema who now receive endothelial keratoplasty but also patients with early or mild oedema—possibly preventing progression to more severe disease and vision loss.

EARLY RESEARCH PROMISING

The phase 1 and 2 trials planned by the two US manufacturers come after successful first-in-human trials elsewhere. Of the first 11 patients who underwent cell replacement therapy developed by Shigeru Kinoshita MD, PhD and colleagues in Japan, 10 had normal corneal endothelial function, and 10 had significantly improved best-corrected visual therapy five years after treatment.i

Similarly, in Aurion’s 50-patient proof-of-concept IOTA trial in El Salvador, in which Dr Berdahl participated, patients experienced dramatic improvements in visual acuity and reductions in central corneal thickness 6 and 12 months after cell therapy. In another proof-of-concept study by Emmecel, 9 of 21 patients gained three or more lines of best-corrected visual acuity, and 14 had significantly reduced corneal thickness with no treatment-related serious adverse events. Emmecel launched a phase 1 trial in 2021 and Aurion began a dose-ranging trial this year.

“There is only one other commercial cell therapy in existence, and that is the CAR-T family of treatments. Cell therapy is a huge categorical opportunity for medicine, and it’s fun for ophthalmology to be in the lead,” Dr Berdahl concluded.

Dr Berdahl presented at the Innovators Session of the American Society of Cataract and Refractive Surgery 2022 Annual Meeting in Washington, DC, US.

i Numa K, Kinoshita S et al. Ophthalmology. 2021 Apr; 128(4): 504–514.

John Berdahl MD is in private practice at Vance Thompson Vision, Sioux Falls, South Dakota, US, and is a professor at the University of South Dakota Sanford School of Medicine, Vermillion, South Dakota, US. john.berdahl@usd.edu

AI for Eyes

The lack of data available for use in machine learning in ophthalmology greatly limits the clinical value of the diagnostic algorithms the technology provides, warns Professor D Robert Iskander PhD.

“The focus for the future should be on large data sets. Large data sets are expensive, but without them, I would say that machine learning is like a preschool football game,” he said.

TWIN CURSES OF A LOW DATA REGIME AND DIMENSIONALITY

Prof Iskander noted the accuracy of machine learning models increases with the amount of data available. However, data sets in machine learning studies in glaucoma have included an average of only about 200 images, ranging from as few as 60 images, at the low end, to about 3,000 images at the high end.

By contrast, the CIFAR-10 data set—a collection of images used to train machine learning models— consists of 60,000 images split into 10 different classes, with 6,000 images for each.

Moreover, the 10 classes of the CIFAR-10 data set represent a diverse range of images, such as airplanes, cars, birds, cats, deer, dogs, frogs, horses, ships, and trucks. Such classes are much more easily distinguished than the sometimes very subtle changes occurring in the optic nerve of eyes with glaucoma, Prof Iskander observed.

Added to that is the curse of dimensionality, whereby each additional variable exponentially increases the amount of data needed to efficiently separate images into groups. Another of the limitations of working in a small data regime is the potential for overfitting—where a model corresponds too closely to a particular data set to have the same predictive value in a larger and more diverse data set.

TWIDDLING THE KNOBS

The scarcity of data available for machine learning in ophthalmic diagnoses has led some investigators to adopt a range of data manipulation methods designed to enhance an algorithm’s ability to distinguish between groups of images, Prof Iskander said.

As an example, he cited a study conducted by two of his PhD students, Dominika Sulot and Dr David Alonso-Caneiro, which he also co-authored. They investigated glaucoma classification based on scanning laser ophthalmoscopic images using a machine learning technique, with a sample size of only 122 healthy control subjects and 105 glaucoma patients.i

To reduce the complexity of the process, they used a task-specific convolutional neural network. The team also augmented the data set with image transformations and rotations. They achieved their final algorithm using a deep learning ensemble method, combining multiple learning algorithms to provide a more accurate model than any of the constituent learning algorithms.

The team found by using this approach, they could develop an algorithm that could distinguish between normal and glaucomatous eyes with an accuracy of 93%. Prof Iskander noted that while this is an impressive result, he nonetheless likened the approach to tuning a radio while adding more tuning knobs until achieving the desired result.

“My pragmatic interpretation is that even five- or maybe tenfold cross-validation does not guarantee I will end up with this 93% accuracy if we take another set of 100 images. The result is also post hoc—I mean, I had to provide ground truth for this result for the neural network to tell me I was right,” he said.

A WASTEFUL ENTERPRISE

Because of their limited clinical value, machine learning studies in ophthalmology that use small data sets are ultimately little more than academic exercises, mainly useful for training purposes, Prof Iskander said. The proliferation of such studies is therefore an expensive waste of resources. Meanwhile, gathering and labelling data sets of sufficient size—tens of thousands of images—remains a daunting prospect.

“We should also seek real-world solutions that will provide us with an algorithm that can really be used in a machine: for exam ple, in [segmenting] retinal and corneal layers,” he said.

Prof Iskander noted that a search in Google Scholar using the keywords “machine learning” and “ophthalmology” shows the number of studies published on those topics declined from 70,000 articles between 2001 and 2010 to 60,000 articles between 2011 and 2020. This does not follow the usual trend in scientific inquiry, where there is an exponential increase in the number of studies with each succeeding decade.

“Maybe interest in this particular field is waning because people are starting to think that this is not the way to go. And don’t be surprised if you end up with an essentially similar picture if you change the word ‘ophthalmology’ to ‘medicine’,” he added.

Professor Iskander presented at the Artificial Intelligence in Ophthalmology 2022 virtual meeting.

i D Sulot et al, PLoS ONE 16(6): e0252339.

Professor D Robert Iskander PhD, Biomedical Signal processing group, Wrocław University of Science and Technology, Wrocław, Poland. robert.iskander@pwr.edu.pl

Too many studies with too little data in machine learning in ophthalmology. Roibeárd O’hÉineacháin reports

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Innovation in Visualisation During Vitreoretinal Surgery

Benefits of new digitally enabled microscope-integrated intraoperative OCT surgical platform. Cheryl Guttman Krader reports

Adigitally enabled highdefinition, heads-up stereoscopic intraoperative OCT system could help surgeons overcome their fondness for the flatscreen.

The DISCOVER (Determination of feasibility of Intraoperative Spectral domain microscope Combined/integrated OCT Visualization during En face Retinal and ophthalmic surgery) study found surgeons liked the idea of intraoperative OCT (iOCT) for vitreoretinal procedures for both conventional microscope-integrated and digitally enabled platforms. However, they often preferred to use the large, screen- and surgical field-based visualisation of the iOCT data stream.

“Intraoperative OCT is an exciting innovation in vitreoretinal surgery—and previously we showed in the prospective DISCOVER study that it was feasible and useful. However, the study also found surgeons strongly preferred visualising the OCT data on a 2D screen that required looking away from the surgical field compared to using the OCT data injected into the microscope oculars. Therefore, we felt there was a need for a new integrative surgical theatre integrating intraoperative OCT with a 3D heads-up display,” explained Katherine Talcott MD.

INTEGRATIVE TECHNOLOGIES

“A digitally enabled option for high-definition, heads-up stereoscopic intraoperative visualisation is now available, giving an immersive 3D visualisation of both the surgical field and the iOCT data stream. Our study indicates this technology allows for greater surgical visualisation efficiency, as well as other advantages. Additional studies are now needed to better assess patient outcomes, surgeon experience, and overall value of integrative technologies designed to enhance the surgical theatre experience.”

The DISCOVER study is an IRB-approved multi-surgeon case series. Comparative assessment of surgical visualisation efficiency (i.e., the proportion of cases performed with the ocular headsup display in the conventional group or the 3D screen-based visualisation in the digitally enabled group versus cases with the external 2D monitor for each system) was the primary objective of the post-hoc analysis. It included 100 cases performed using

a conventional microscope-integrated iOCT (Rescan 700, Zeiss) and 100 with the digitally enabled iOCT (Artevo 800, Zeiss).

“The Artevo 800 is described as the first 3D-capable digital ophthalmic microscopic. It features a hybrid mode that allows the surgeon to view the surgical field using a 55-inch 4K resolution monitor or through the oculars, and it may offer improved latency and surgical field colour, reduced illumination, and ease of utilising iOCT,” Dr Talcott said.

Although the cases were not randomly assigned to the microscope group—surgeons chose whether to use the conventional or digitally enabled system—the two surgical groups were optimally matched for surgeon and preoperative diagnosis. Data on the characteristics of the conventional microscope-integrated iOCT and digitally enabled iOCT groups showed they were similar with respect to mean patient age (about 65 years for both), most common surgical indications (epiretinal membrane, 35% and 33%, respectively; retinal detachment, 21%, both groups; macular hole, 19% and 20%, respectively), and proportion of cases performed with 23-gauge instrumentation (71% and 67%, respectively).

At the end of each case, surgeons completed a standardised questionnaire designed to obtain information on surgical field

A 3D screen-based visualisation of intraoperative OCT is used during surgery for an epiretinal membrane using a digitally enabled microscope.

visualisation along with impact of iOCT on surgical decisionmaking and surgeons’ perceptions on iOCT utility and ergonomics. The data showed they used surgical field-based iOCT visualisation in 88% of cases performed using the digitally enabled iOCT but only 7.2% of cases performed with the conventional iOCT. Looking at the converse situation, the surgeon looked away from the microscope or the 3D monitor onto the accessory screen in only 12% of cases using the digitally enabled iOCT but in 93% of those performed with the conventional iOCT, Dr Talcott reported.

Safety of using iOCT was good with both platforms—there were no intraoperative complications attributed to it, and the rate of postoperative complications was similar in the two groups. However, the endoillumination level was significantly lower using the digitally enabled system compared to the conventional iOCT (33.4% versus 37.2%, respectively).

ERGONOMIC ADVANTAGES

Ergonomics ratings also showed significant differences favouring the digitally enabled system. In cases performed with the conventional system, 22% were notable for clinically significant back discomfort and 20% for clinically significant headache. The rates for these complaints using the digitally enabled iOCT were 7% and 5%, respectively. The rate of clinically significant neck discomfort was also higher using the conventional iOCT than for the digitally enabled system (4% versus 1%, respectively), although the difference was not statistically significant.

Questions pertaining to iOCT utility showed both the conventional and digitally enabled systems were perceived to have added valuable information in the majority of cases (53% and 60%, respectively). Both the conventional and digitally enabled iOCT systems also impacted surgical decision-making in a sizeable proportion of cases (16% and 21%, respectively).

Other surgeons’ ratings of their intraoperative experience showed a strong preference (83%) for static iOCT acquisition versus real-time acquisition, regardless of the system used. There were no significant differences between the two systems in the percentages of “excellent” ratings given for quality of the widefield view and quality of the macular view. Average macular peel time was also similar in the two groups.

Dr Talcott presented at ARVO 2022 in Denver, Colorado, US.

Katherine Talcott MD is a vitreoretinal surgeon practicing at the Cleveland Clinic, Ohio, US. talcotk@ccf.org

“Our study indicates this technology allows for greater surgical visualisation efficiency, as well as other advantages.”

HUVITZ AD

Improving Vision for Patients with Retinal Degenerative Disease

Oral eicosapentaenoic acid-rich omega-3 supplement demonstrates efficacy and safety. Cheryl Guttman Krader reports

Supplementation with an eicosapentaenoic acid (EPA)-rich omega-3 formulation could be a simple, convenient, and cost-effective therapeutic approach to offer patients with vision loss caused by retinal degenerative diseases.

This was the conclusion of MADEOS, a 24-week, multicentre, randomised, double-blind, placebo-controlled study designed by researchers from the Ophthalmos Research and Educational Institute, Nicosia, Cyprus, led by Dr Tassos Georgiou.

MADEOS included 21 patients with moderate to severe dry age-related macular degeneration or Stargardt disease whose BCVA was between 21 and 55 ETDRS letters. Participants were assigned to use a commercially available supplement containing 3.7 g omega-3 fatty acids (EPA:docosahexaenoic acid = 5:1, Eyetas) or placebo (sunflower oil). The blood ratio of omega-6/ omega-3 (arachidonic acid/EPA) was maintained below two throughout the study.

The supplement was well-tolerated over the study period and associated with a statistically significant gain of six letters in mean BCVA, which increased from 40.93 letters at baseline to 46.93 letters at week 24. Mean BCVA did not change significantly in the control group, and a between-group comparison of mean BCVA change also showed a statistically significant difference favouring treatment with the omega-3 fatty acid supplement. Changes in perceived vision and mood were assessed using a subjective questionnaire and showed a numerical difference favouring the supplement group that was marginally significant.

“There is an unmet need for effective and convenient therapeutic interventions for patients with vision loss from age-related or genetic retinal degenerative diseases. The results of our clinical study suggest that this EPA-rich omega-3 fatty acid supplement may have a positive impact on the quality of life for these individuals,” lead author Katerina Prokopiou PhD told EuroTimes.

Noting that high intake of dietary omega-3 fatty acids or fish has been associated with a reduced risk of developing AMD, whereas clinical studies of omega-3 fatty acid supplementation generated some conflicting results, Dr Prokopiou stated the benefit achieved in MADEOS underscores the importance of the dose and type of fatty acids used.

“Preclinical and clinical data indicate that the dose of omega-3 fatty acids rich in EPA found in the supplement we used is the minimum dose required for a positive effect on vision,” she said.

Dr Prokopiou also indicated that because MADEOS was conducted during the COVID-19 pandemic, the researchers faced challenges with patient recruitment and follow-up.

“MADEOS is a small study, but we believe the results obtained are a good indication of what might be expected in a larger investigation,” she said.

Now the researchers are hoping to conduct larger multicentre clinical studies that would allow stratification of patients based on diagnosis and disease severity.

“In previous observational studies, we noted that the clinical outcome is better when the supplement is administered early in the disease. Although patients with advanced disease can still perceive an improvement in vision using the supplement, patients with milder disease might benefit the most. Preclinical data showing the supplement has a direct protective effect on the photoreceptor layer also suggests that it might be helpful for preserving or improving vision in older individuals—without any macular pathology—who have a natural age-related decline in visual acuity,” Dr Prokopiou said.

Dr Prokopiou presented at ARVO 2022 in Denver, Colorado, US.

Katerina Prokopiou PhD is an Assistant Professor at University of Nicosia Medical School and a Senior Research Associate at Ophthalmos Research and Educational Institute, Nicosia, Cyprus. prokopiou.k@unic.ac.cy

Ocular Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) has many potential ocular manifestations, requiring a vigilant management approach, according to Robert A Avery DO, MSCE.

NF1 is an autosomal dominant condition affecting about 1 in 3,500 live births that causes tumours, or neurofibromas, to grow in nerves throughout the body. About half of NF1 cases are inherited, and the rest arise spontaneously. NF1 is usually evident in children before the age of two years.

Optic pathway gliomas (OPGs) will develop along the anterior visual pathway that includes the optic nerve(s), optic chiasm, and optic tracts in about 20% of NF1 patients, and about a third to a half of these will become sight-threatening. Growths involving multiple nerves known as orbital/periorbital plexiform neurofibromas (OPPNs) may also develop—sometimes leading to significant vision loss and disfigurement.

To detect new symptomatic OPGs, all patients diagnosed with NF1 should have annual ophthalmic exams, including visual acuity and visual field tests, until at least eight years old. Patients diagnosed with OPGs should have more frequent exams soon after diagnosis, including magnetic resonance imaging (MRI). When ocular plexiform neurofibromas are discovered, the child should have a minimum of annual eye exams, although sometimes more frequent depending on the severity and impact on vision, Dr Avery said.

It is not currently possible to predict which neurofibromas will progress to sight-threatening or which OPGs require chemotherapy or other treatment, so ongoing vigilance is essential to preserve sight, he added.

RECOGNISING OCULAR NF1

A common ocular manifestation of NF1 is Lisch nodules, which appear as brownish or coffee-coloured peduncular growths mostly on the lower half of the iris, often appearing between ages three to five years. However, they are primarily useful in diagnosing NF1 and do not affect vision, nor does their presence predict OPGs, OPPNs, or other NF1 conditions, Dr Avery said.

OPGs are the most common NF1 ocular manifestation. They are usually slow-growing, low-grade tumours that form along the optic nerve, chiasm, and optic tracts. OPGs occur in about 15% to 20% of children with NF1 and are usually apparent and fastest growing between ages one and eight years—and seldom require treatment after age eight, Dr Avery said. They may present with early vision loss or optic nerve head atrophy.

Immediately after diagnosis, OPG progress should be monitored every three months with eye exams, including quantitative visual acuity tests and visual fields and MRIs to visualise the optic pathway.

“It’s really hard to tell when vision gets worse with simple assessments like ‘fix and follow the object.’ That’s why we are really pushing for quantitative visual acuity assessments,” Dr Avery said.

For stable cases, monitoring intervals can be extended to every six months for two to three years, he added.

In general, OPG treatment with chemotherapy or other medications aims to preserve vision and is limited to those

patients who need it. Carboplatin and vincristine, or vinblastine, are the most common first-line treatments. Bevacizumab and selumetinib, a recently approved MEK inhibitor, may also shrink OPGs, sometimes dramatically. Surgery is not an option because the tumour is part of the nerve and would result in blindness if removed.

Worsening vision, either central or peripheral, indicates treatment need. Tumour growth may sometimes, but not always, indicate a treatment need. Dr Avery is currently researching MRI volumetrics to get a better idea of when tumour growth predicts vision loss. OCT analysis of changes in retinal nerve fibre layer thickness may also help guide treatment decisions, but its utility and accuracy are still under investigation. Treatment usually begins before the patient is five years old.

OPPNS

Signs of OPPNs include ptosis, proptosis, strabismus, and nystagmus. These occur in about 5% of children with NF1 and usually appear in the first one to three years of life. OPPNs can interfere directly with vision or contribute to amblyopia or glaucoma. Patients with OPPNs should be examined every 3 to 12 months, with more severe cases and children still in the visual maturation process seen more often.

Treatment is indicated to preserve vision, reverse or prevent amblyopia, and improve appearance, Dr Avery said. Surgery is an option in certain cases, though often complicated by the fact plexiform tumours tend to grow back. Selumetinib can decrease tumour size in some cases.

Bulging eyes in NF1 patients may also indicate sphenoid wing dysplasia, in which the bone separating the brain from the orbit is underdeveloped, and the brain pushes the eyes forward. Eye exams should be conducted every 3 to 12 months depending on severity, with surgery to insert a mesh to hold the brain back indicated in some severe cases, Dr Avery said.

Current research includes a phase 3 clinical trial comparing selumetinib with chemotherapy for OPGs. Bevacizumab and other MEK inhibitors may also help, but impact on quality of life and vision is as important as tumour shrinkage. “We are not treating an MRI scan, we are treating a child’s vision,” Dr Avery stressed.

He is also conducting a large-scale study of OPGs for a better understanding of the ones likely to lead to vision loss.

“We hope our new research tools will improve the care of all children with NF1,” Dr Avery said.

Dr Avery presented at the 2022 NF Summit of the Children’s Tumor Foundation in Chicago, Illinois, US.

Robert A Avery DO, MSCE is a paediatric neuro-ophthalmologist at Children’s Hospital of Philadelphia and an associate professor of ophthalmology and neurology at the University of Pennsylvania, Philadelphia, US. averyr@chop.edu

Early detection and frequent monitoring may help preserve vision.

Howard Larkin reports

Nostra Culpa

Our problems, a global issue.

By George Liu MD

The United Kingdom’s National Health Service (NHS) contributes towards 5% of the country’s carbon footprint. They are not alone. If global health services formed their own country, they would be the fifth-largest carbon emitter on the planet. This is a global issue.

In ophthalmology, patients often present with chronic disorders needing multiple consultations (generating travel emissions), and often, surgical procedures are the only solution. Whilst there is a beneficial high turnover of surgical cases in ophthalmology, this also incurs increased waste generation, which is exacerbated by unsustainable practices such as disposable equipment, including substantial amounts of plastic and iron ore. To make matters worse, an NHS investigation showed that children were being exploited to manufacture surgical equipment in Pakistan. So perhaps reusable sterilised equipment is the way forward? Whilst this appears to be the obvious answer, a study in Chicago, Illinois, US, showed that the use of ethylene oxide was likely causing higher rates of cancer in residents living near the sterilisation factory site. Furthermore, disposable equipment is often significantly cheaper to manufacture compared to reusable equipment, which incurs further sterilisation costs. Therefore, how can we safely balance sustainability and public health whilst making surgery financially viable?

Globally, approximately 43 million people are blind. A third of this population is blind due to cataracts—and this figure is set to increase due to the ageing population. However, the only definitive treatment for cataracts is surgery. A technique called Life Cycle Analysis (LCA) quantifies the emissions generated across the life cycle of a product in units of carbon dioxide equivalents (CO2e) and can be used to estimate the impact of cataract surgery. The LCA of a cataract surgery is 181.8 kg CO2e, with the greatest portion (54%) generated from the procurement of supplies. This LCA is the equivalent of driving a car for 500 km, a significant carbon footprint.

Similarly, international ophthalmology conferences also have a major carbon footprint. Transport, venue, catering, workshops, and presentations all contribute towards increased carbon emissions. Again, a balance must be established in an effort to maximise education whilst reining in personal interests such as tourism.

The aggregate of these issues contributes significantly to climate change. The effects of pollution, as studied by King’s College London, show that on high pollution days, there are 673 additional out-of-hospital cardiac arrests and hospital admission for stroke and asthma. If we were to apply these figures to the population of poorer countries, whilst the impact may be the same, their inability to access affordable healthcare generates an international injustice. Therefore, we need to push for global change.

OUR SOLUTIONS, A WORLDWIDE EFFORT

Whilst our community may strive for change, we are limited by our lack of actionable data. However, the recent development of applications, such as “Eyefficiency”, encourages research into the environmental impact of cataract surgery by individual surgical units, thus generating the actionable data needed for change.

Variations in the LCA of cataract surgery depend on the surgeon, but there is no correlation between surgical outcomes and environmental cost, as shown in different locations around the world. Thus, suggesting that opportunities for more sustainable practice are available without having to sacrifice the quality of

care. The Aravind case study showed that cataract surgery was achievable at 5% (23 km by car) of the LCA in the West with no increased risk and significantly reduced waste. However, efforts to pursue a similar case study in the West would be limited by regulations and Western patient perceptions of needing overpersonalised care. More recently, the ophthalmic community has increasingly moved to Immediately Sequential Bilateral Cataract Surgery (ISBCS), which has reduced travel emissions that would normally be incurred from a second cataract surgery. Whilst this is a fair improvement, the combination of the Aravind study and ISBCS would provide the most sustainable outcome.

With the boom in technology during the pandemic, healthcare events are more accessible than ever—from the comfort of one’s own home. Therefore, conferences should be hybrid by default, offering in-person attendance for local delegates and virtual attendance for international delegates. For those in attendance, efforts should be made to offset travel-related emissions. Those using renewable energy should be rewarded with reduced registration fees.

In a similar vein, these advances should be utilised in virtual consultations and other modalities to educate our patients. Ufonia artificial intelligence software conducts telephone postphacoemulsification consultations and greatly reduces anxious patients presenting to “Accident and Emergency” unnecessarily.

Everything exists in fine balance, and we are currently tipping the scale towards an unsustainable future. We should encourage selflessness and sustainability and change our culture of viewing Earth as an infinite resource. We must grasp these opportunities to stop climate change and accept that evolution may include regression in some aspects of our lives. Our response will determine our survival.

This essay was the winner in this year’s ESCRS Henahan Prize Essay Competition. Writers were asked to address the question, “What can the field of ophthalmology do to meet the pressing challenges of climate change, sustainability, and social equity?”

George Liu is a 4th Year Medical Student, Chelmsford, Essex, Tongdean Eye Clinic, UK.

Eyesi Milan

Haag-Streit invited delegates at the annual ESCRS Congress in Milan to attend a “Cataract Surgery Virtual Reality (VR) Training Experience”, and get some hands-on experience with the Eyesi Surgical Simulator. The 20-minute training experience allows delegates to see the surgical field in stereo and high resolution while operating with life-like surgical instruments. Delegates first perform initial warm-up tasks that train hand-eye coordination and microsurgical skill, without involving any pathologies, as an introduction to the simulator. Once warmed up, delegates can perform cataract procedures such as capsulorhexis, hydro manoeuvres, phaco divide-and-conquer, irrigation and aspiration, and IOL implantation. Participants received evaluation scores after the Congress. www.haag-streit.com

LENSAR’S ALLY ENTERS THE CLINIC

Following the US FDA approval of its ALLY Adaptive Cataract Treatment System in June, Lensar announced the clinical launch, with the performance of the first commercial cases in the US. The ALLY system integrates its proprietary imaging technology with an optimised femtosecond laser in a compact system. The integrated system allows the surgeon to perform the entire cataract procedure in an operating room or in-office surgical suite, increasing efficiency and decreasing costs. ALLY includes the company’s proprietary Streamline® software technology. The system uses advanced astigmatic management tools to improve accuracy and precision. Performing the cataract procedure in a single, sterile setting reduces the overall time and improves both the patient and surgeon experience, the company believes. lensar.com/technology/ally-adaptivecataract-treatment-system

HEIDELBERG APPWAY

Also in Milan, Heidelberg Engineering launched AppWay, an AI-powered software app. The company says the app is a “novel gateway solution for secure data exchange that will allow seamless access

to ophthalmic ‘apps’ that aid clinical decisionmaking.” The company has partnered with the AI companies RetInSight and RetinAI to provide eyecare specialists with AI software systems that support retinal diagnostics and therapeutic monitoring. The app is embedded into the

image management platform HEYEX 2, and is designed to provide an innovative workflow solution. This solution facilitates seamless exchange of ophthalmic image data with AI-driven analysis services to deliver additional clinical insights and treatment monitoring tools for enhanced patient care, the company said. For example, clinicians in any practice or clinic can send routine images from their SPECTRALIS platform to the cloud service for a detailed, AI-powered analysis of disease activity and therapeutic benefits. While the patient is still present, the surgeon receives a concise Fluid Monitor report indicating fluid type, distribution, and quantity—in a completely secure, encrypted environment.

“This seamless workflow provides clinicians with easy access to fluid parameters—the most important biomarkers in the routine monitoring of patients with nAMD,” says Professor Ursula Schmidt-Erfurth, Chair of the Department of Ophthalmology and Optometry at the Medical University of Vienna, Austria. www.heidelbergengineering.com

THOMAS KOHNEN European Editor of JCRS

JCRS HIGHLIGHTS

CATARACT SURGEONS MUST DO THEIR PART IN REDUCING WASTE AND POLLUTION

September’s issue of JCRS focused on the role cataract surgeons can play in reducing greenhouse gases and plastic waste. In his editorial, Thomas Kohnen noted that if the healthcare industry were a country, it would be the fifth largest greenhouse gas emitter on the planet. Since cataract surgery is one of the most common surgical procedures performed worldwide, it contributes considerably to healthcare’s environmental footprint. However, there are steps that every medical facility can take to identify and implement ways to reduce waste and carbon emissions in cataract surgery. On an international scope, ESCRS President Oliver Findl announced Mission Zero, an ESCRS commitment to hold the 2023 ESCRS Congress with zero waste to landfills and zero net carbon emissions. The ESCRS Executive Board already took steps towards this goal in planning the 2022 ESCRS Congress in Milan, Italy.

T Kohnen, “Becoming more eye-ficient,” 48(9): 983–984.

WIDE CONSENSUS AMONG OPHTHALMIC SOCIETIES FOR REUSE OF MULTIDOSE CONTAINERS

The issue features a position article on the Ophthalmic Instrument Cleaning and Sterilization (OICS) Task Force’s efforts to reduce topical drug waste with ophthalmic surgery. The Task Force includes representatives of the ASCRS, the AAO, the AGS, and the OOSS. They made three principal recommendations: 1) If proper guidelines are followed, topical drugs in multidose containers can be used on multiple patients in surgical facilities; 2) Topical drugs in multidose containers can be used until the manufacturer’s labelled date of expiration; and, 3) When applicable, patients should be able to bring their partially used medication home for postoperative use. In support of the recommendations, the Task Force cited studies showing that when proper guidelines were followed, reuse of eye medication bottles on multiple patients did not contribute to increased endophthalmitis rates. In addition, they point out using topical medications until their expiration date complies with CDC infection control guidelines. The American Medical Association House of Delegates unanimously adopted a resolution to permit the dispensing of stock medications for post-discharge use and the safe use of multidose eyedrops on multiple patients, which several ophthalmological societies have subsequently endorsed. D Palmer et al., “Reducing topical drug waste in ophthalmic surgery: multisociety position paper”, 48(9): 1073–1077.

AMBULATORY CARE CENTRES REDUCING WASTE MORE THAN HOSPITAL OUTPATIENT DEPARTMENTS

A survey of more than one thousand ophthalmologists conducted in 2019 by the OICS Task Force showed that although most would be willing to reuse surgical devices, supplies, and pharmaceuticals to combat wasteful practices, few were actually doing so. A further review of the survey data shows surgeons operating in ambulatory surgery centres (ASCs) were more likely to have adopted waste reduction policies than those working in hospital outpatient departments (HOPDs). C L Thiel et al., “Differences in reuse of cataract surgical supplies and pharmaceuticals based on type of surgical facility”, 48(9): 1092–1094.

INTERVIEW NEWSMAKER

WITH ROBERT OSHER MD

Perhaps no medical specialty relies on video as part of the learning process as ophthalmology does. Standard cases can be demonstrated, surgeries can be reviewed, and the latest techniques and technology can be highlighted straight from the microscope to the surgeon—from the beginner to the seasoned expert. EuroTimes Editor-in-Chief Sean Henahan caught up with Robert Osher MD, the surgeon who pioneered video recording in ophthalmic surgery and filmed every one of his cases since 1980.

Forty years—that is a lot of videos! The technology has changed considerably over the decades. Can you give an idea of how you got started and what it was like in the early VHS days?

My love affair with video goes back even before VHS. I had finished three fellowships at Bascom Palmer and Wills Eye Hospital, but I still felt very timid and insecure. My dad, a private practitioner in Cincinnati, said, “You’ve completed all these fellowships—come spend just six months with me.” The first cataract surgery I saw there, I was hooked: beautiful, elegant surgery with such happy patients. This was 1980, and he was performing intracapsular surgery.

But I wanted to be in the 1% of phaco surgeons, so I decided to visit every top-notch phaco surgeon in the United States. There were only a handful at that time. Over many months, I visited Dick Kratz and Bob Sinskey on the West Coast, Norm Jaffe and Henry

Clayman in Florida, Jim Little in Oklahoma, and the highlight was travelling to New York to meet the man himself, Charlie Kelman. I spent a lot of time flying around. It took me away from my family and my practice. It was expensive and time consuming. That’s when I had the idea, “I should start a video journal!” We would record the surgeries on 3/4-inch tape, then edit on 1-inch tape. Around that time, I came up with a concept of a video symposium of challenging cases and surgical complications. No one had done this before. Cataract surgeons just showed their perfect cases at the meetings, so the video symposium was a dramatic shift. Both the video journal and the video symposium have stood the test of time. I brought each to Europe almost four decades ago when first invited by Emanuel Rosen and Paddy Condon. I had to carry suitcases full of 3/4-inch tape wherever I went. It was miserable. The video journal would send hundreds of VHS tapes to Europe, with all the attendant problems of different frame rates and colour issues.

Fortunately, the technology improved vastly over the years. We went from VHS to Betacam, SuperBeta, Super VHS, DV cam, digital videotape, digital disk, and ultimately the internet. Now I just carry a few thumb drives to the meetings!

What advantages does video offer in ophthalmology training?

I’ve always loved video education. You can’t teach surgery through a textbook, or from a podium—you have to see it. That is the beauty of the video journal. We can eliminate long delays associated with publishing bringing new ideas, techniques, and technologies to our viewers. We are a free member benefit of nearly every cataract society on the planet. I watch every video from every competition around the world to arrive at our quarterly programmes. For example, the most recent issue focuses on learning Yamane intrascleral haptic fixation and its many variations. The journal is very academic, not allowing advertising or promotion. Our editor board includes George Waring in refractive, Michael Snyder in anterior segment,

Ike Ahmed in glaucoma, and Graham Barret in cataract. We also get extra perspectives from some ESCRS surgeons I respect and admire, including Richard Packard in the United Kingdom, Lucio Buratto in Italy, Ehud Assia in Israel, and Boris Malyugin in Russia. In addition, I’ve just worked with ESCRS surgeons Jorge Alió from Spain and Burkhard Dick from Germany in publishing a book loaded with videos.

Over the decades, you have built up such a vast amount of material, a historical record. What about using this content for research projects such as longitudinal studies of a given topic over time?

The video library is open to our 16 residents who enjoy clinical research. George Waring recently put together an issue on the history and evolution of contemporary refractive surgery, and Mike Snyder organised one on the history of prosthetic iris implantation. The American Academy of Ophthalmology invited me to present a series on the evolution of phaco surgery over the last 40 years, and I’ve been collaborating with the JCRS on a new monthly column. So many historical treasures are in our video library.

What do you think of the trend towards 3D video?

We were involved in 3D video from the early stages. I found it was frustrating because it was impossible to edit in 3D. It also proved challenging to lecture in 3D, with the special screen and the glasses. The technology has been tried multiple times over the years, but never stuck because of cost issues and technical issues.

But technology has evolved with options like Ingenuity and Artevo. The young surgeons without cervical disease are going to benefit from this. For older surgeons like me who have been working for 40 years with a microscope, I’m comfortable, although I’ve been told I’m a “pain in the neck”!

Videography is now a key skill for a young ophthalmologist. Do you have any suggestions for novices?

Yes! First, it is essential to invest in a good camera system with an excellent monitor. It is really important to learn how to stay in focus and centred. A good file system is critical so you can recall cases for editing or for studies. You want to turn the video on at the beginning of surgery and let it run the whole time because you never know when something unexpected will happen. It’s the best way to understand cause and effect to prevent recurrences. And video will forever be the best way to teach residents, fellows, and staff.

Dr Osher is Medical Director Emeritus of the Cincinnati Eye Institute and Professor of Ophthalmology at the University of Cincinnati, Ohio, US. He is founder of the Video Journal of Cataract, Refractive, & Glaucoma Surgery. Dr Osher’s own video productions have won more than 40 international awards at the ASCRS Film Festival and ESCRS Video Competition. His many awards include the Education Award from the ESCRS, the Binkhorst Award and the Innovator’s Award from the ASCRS, and the Kelman Award and the Lifetime Achievement Award from the American Academy of Ophthalmology. Among his recent publications are books Cataract Surgery: Advanced Techniques for Complex and Complicated Cases; What I Say; and The Real ABCs: Achievement, Balance, and Contentment.

The Video Journal is offered as a free member benefit to all members of the ESCRS.

https://vjcrgs.com

| Cataract Surgery

Cataract Surgery and Pars Plana Vitrectomy

Dr Soosan Jacob MS, FRCS, DNB

Pars plana vitrectomy (PPV) is indicated in a variety of situations—such as retinal diseases, vitreous opacities, and cataract complications such as dropped lens material. Cataracts can develop after various vitreoretinal (VR) procedures. For instance, macular hole surgery and primary retinal detachment repair may initiate cataract formation, often placing primary phacovitrectomy as a consideration in these cases.

Clarity of the anterior ocular media is important for proper and thorough vitrectomy and retinal procedures such as membrane peeling. For all these reasons, cataracts often must be extracted concurrently with or after VR surgery.

This article discusses what to know when contemplating cataract surgery in patients where PPV is also required.

CATARACT SURGERY COMBINED WITH PPV

Advances in both phacoemulsification and PPV techniques—such as smaller incisions, valved trocars, and transconjunctival sutureless techniques—and better machines and instruments have made combined surgery easier.

When cataract coexists with VR disorders, the decision for primary phacovitrectomy is clear. But with clear lens and retained accommodation, cataract extraction has some disadvantages. However, PPV alone carries disadvantages such as post-PPV cataract, decreased space, and accidental lens touch during peripheral retina manipulation.

Advantages of combined surgery include cost-effectiveness, convenience, and the rapid visual recovery offered by a single procedure. Surgical advantages include the possibility of more anteriorly placed sclerotomies (reducing retinal tear risk), complete vitrectomy, greater gas fill, and better postoperative tamponade. Decreased risk for macular oedema and post-surgical vitreous traction, complete negation of the risk of vitrectomy-induced cataract with better postoperative clinical and optical coherence tomographic evaluation of retinal disease are other advantages.

BEST CANDIDATES FOR COMBINATION SURGERY

Combined surgery is preferred in patients with risk factors for developing cataract after vitrectomy such as older age, preexisting nuclear sclerosis, and diabetic retinopathy. Patients under consideration of silicone oil or intraocular gas pose this risk too. Even minimal lens opacity can hinder visualisation in

certain situations, e.g., posterior hyaloid or membrane peeling. In such cases, phacovitrectomy is preferable.

Aphakic visualisation allows easier and safer surgery and enhances the ease of posterior vitreous peeling and peripheral visualisation. Clinical and surgical experience, nature of available facilities, and type of VR pathology may be used to decide between combined surgery or PPV alone. The challenges of performing cataract extraction in a vitrectomised eye also need consideration during this decision making. A discussion with the patient about the pros and cons is helpful.

In combined surgery, opt to perform cataract extraction before vitrectomy. A poor red reflex in certain pathologies may challenge the surgeon. Better illumination, capsular dyes, and oblique light from the endoilluminator can help complete the rhexis. A history of previous intravitreal injections should raise suspicion for broken posterior capsule. In these situations, femtosecond laser assisted cataract surgery (FLACS) may be useful for performing rhexis and the Vasavada femtodelineation technique—described for managing posterior capsular weakness/defect in posterior polar cataracts—may be used here.

Cataract Surgery Combined with Pars Plana Vitrectomy (PPV): A) Red reflex may be poor because of VR pathology; B) Sutures applied on corneal incisions before proceeding with vitrectomy; C) The trocars may be placed closer to the limbus after cataract extraction; D) Implanting IOL prior to vitrectomy can cause a blurred view during surgery.

Well-constructed, self-sealing corneal incisions are important, and these should be sutured prior to vitrectomy to avoid iris prolapse while inserting trocars or while indenting the sclera. Avoiding stromal hydration will allow the VR surgeon a clear view. Some other suggested modifications are pre-placed valved trocars and core vitrectomy in eyes with shallow anterior chamber (AC) due to positive vitreous pressure to allow the AC to deepen. As mentioned previously, other surgical modifications include suturing corneal incisions prior to vitrectomy and deferral of IOL placement after vitrectomy completion to allow unhindered visualisation. In the early evolution of phacovitrectomy, the patient was often left aphakic—today, the goal is to get a good refractive outcome, making IOL power calculations important.

Possible postoperative complications include wound leak, increased inflammation, cystoid macular oedema, pseudophakic retinal detachment, silicone oil migration to the AC, IOL calculation errors, and late in-the-bag IOL subluxation. Retinal degeneration may result in complications such as retinal detachment—especially in high-risk patients, such as myopes, where cataract surgery itself is also more challenging. Surgeons should therefore conduct close postoperative retinal examinations. Macular and other retinal pathology may limit postoperative visual acuity despite anatomic success. Expected postoperative visual outcomes should be clearly discussed with patients before surgery to set realistic expectations.

CATARACT EXTRACTION AFTER PPV

PPV and pneumatic retinopexy may cause cataract progression because of gas tamponade, accidental lens touch, hastened nuclear sclerosis, postoperative inflammation, and intravitreal or topical steroids. PPV removes the vitreous sink, enhancing oxygen diffusion from the retinal circulation and resulting in greater oxidative stress to the lens.

Accidental lens touch has been reported in 3.7% of cases and can result in posterior subcapsular cataract, mixed lens opacities, white cataract, or hastened nuclear sclerosis. Cataract surgery has a greater risk of posterior capsular rupture in these cases. Surgeons can identify accidental lens bite during PPV by the rapid development of mature cataract that can result in nucleus drop. Pneumatic retinopexy causes progression of nuclear sclerosis in 95% of eyes after macular hole repair.

LENS-IRIS DIAPHRAGM RETROPULSION SYNDROME AWARENESS

Cataract surgery after PPV is challenging because of low scleral rigidity, greater collapsibility of the eye, absent

support from the vitreous body, a deep AC, and fluctuating anterior chamber depth. Reverse pupillary block on initiating irrigation within the eye results in lens-iris diaphragm retropulsion syndrome (LIDRS), sudden pain, and dilatation of the pupil. Avoid these results by lifting the edge of the iris with a second instrument before initiating irrigation, by lowering bottle height, and in severe cases, by initiating irrigation only after introducing the irrigation port under the iris. Iridotomy and iris hooks are other options to avoid its occurrence. Intraoperative LIDRS may be broken mechanically by lifting the iris edge to equalize fluid pressure on either side of the iris.

Vertically placed instruments, poorly dilating pupils, fragile capsular bags, zonular dialysis, and fluid misdirection are other challenges possible in vitrectomised eyes. Early cataract extraction may therefore be preferred while the nucleus is still soft. For soft nuclei, prolapse and supracapsular phacoemulsification are easier than in-the-bag nuclear disassembly. For denser nuclei, horizontal chopping exerts least stress on the bag and zonules. Tangential cortex aspiration avoids zonular stress.

Newer phacoemulsification machines with active fluidics help maintain a stable AC depth. AC fluctuations can increase the risk of retinal re-detachment. To avoid them, inject viscoelastic with the non-dominant hand before withdrawing the phacoemulsification or I/A probe. A slightly higher powered IOL may be necessary because of the posteriorly displaced bag.

If there is suspicion of a broken posterior capsule from previous retinal interventions, a well-centred and adequately sized rhexis can provide for optic capture. This allows surgeons to avoid hydrodissection and nucleus rotation, with only hydrodelineation performed to retain a protective epinuclear shell. Viscodispersive OVD is used to tamponade the vitreous, followed by gentle slow-motion phaco. Surgeons should opt for bimanual cortex aspiration towards the rent to avoid capsular stress, as capsular bag status will determine IOL placement. As described previously, FLACS may be another option in this situation.

IOL choices in these eyes have been discussed in the May 2022 issue of EuroTimes

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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 dr_soosanj@hotmail.com.

Reducing Topical Drug Waste in Ophthalmic Surgery—A Multisociety Position Paper

With increasing awareness of the healthcare sector’s environmental impact, it has become imperative to take measures to make eyecare environmentally sustainable. International ophthalmological societies are working in collaboration towards this aim—encouraging ophthalmologists around the world to redesign services and adapt processes to reduce the carbon footprint of ophthalmic care.

In the latest episode of the ESCRS Eye Journal Club, we discussed the Multisociety Position Paper from Palmer (et al.), “Reducing Topical Drug Waste in Ophthalmic Surgery”, with Professor Oliver Findl (Austria, President of the ESCRS, board member of the EyeSustain Forum) and Professor David Chang (United States, Past President of the ASCRS, Chair of the EyeSustain Forum). This paper presents three recommendations regarding the safe and responsible use of perioperative topical medications in cataract surgery to reduce unnecessary waste, as endorsed by four Societies—the ASCRS, the AAO, the AGS, and the OOSS.

The recommendations are:

1. Topical drugs in multidose containers can be used on multiple patients in surgical facilities if proper guidelines are followed.

2. Topical drugs in multidose containers can be used until the manufacturer’s labelled date of expiration if proper guidelines are followed.

3. When applicable, patients should be able to bring their partially used medication home for postoperative use.

Prof Chang, one of the paper’s co-authors, discussed the importance of these recommendations, describing how regulatory obstacles were overcome to challenge embedded wasteful policies that lack an evidence base (i.e., discarding eyedrops after an arbitrary period). Agreement between professional societies and regulatory agencies for pharmaceutical use in the operating room reinforces the credibility of the recommendations and assures their adoption. Although these specific recommendations may be more relevant to ophthalmic practice in the United States, Prof Findl highlighted that these recommendations could inspire improvements in the sustainability of eyecare in other settings. In Europe, a wide variation in regulations and practices between countries may require bespoke recommendations which align with the principles outlined in this paper.

The Ophthalmic Instrument Cleaning and Sterilization (OICS) Task Force survey, conducted both in the US and Europe, revealed the majority (98%) of respondents feel it is safe to use eyedrops from multidose bottles on multiple perioperative patients. However, in practice, less than 50% do so, indicating obstacles—including fear of litigation.

Professors Findl and Chang feel the current practice is moving away from postoperative use of antibiotic drops, given the evidence of low rates of endophthalmitis with intracameral antibiotics. At Prof Findl’s institution, dropless cataract surgery has been the practice for nearly 10 years. Meanwhile, studies are underway (the ESCRS EPICAT trial) using intraoperative anti-inflammatory drug delivery to replace the need for postoperative drops. Close collaboration between ophthalmologists and industry should enable further refinements that reduce waste (equipment and medication) in cataract surgery.

The volume of cataract surgeries performed worldwide are such that small refinements may have huge beneficial impacts on the environment. We should all strive to make our practice as environmentally sustainable as possible. Both experts recommend the EyeSustain Forum as a valuable source of information on this topic: https://eyesustain.org

Source: Palmer DJ, Robin AL, McCabe CM, Chang DF; Ophthalmic Instrument Cleaning and Sterilization Task Force. “Reducing Topical Drug Waste in Ophthalmic Surgery: Multisociety Position Paper”. J Cataract Refract Surg 2022 May 20.

Artemis Matsou (Greece), Imran Yusuf (UK)

Good Business Managers Are Good Eye Surgeons

Dr Paul Rosen says the ESCRS has ambitious plans for expansion of the Practice Management & Development Programme

Doctors may not be interested in the business of healthcare, but it has a huge influence on the way we practice and the way we manage our patients. The ESCRS Practice Management & Development Programme was established in 2008 to help to encourage doctors to look at how they can conduct their public and private practice in a different way.

When we started the programme 14 years ago, some people were sceptical about what we were trying to do, but the programme has been a great success and is now firmly established as a core activity for ESCRS.

Being a good ophthalmologist is not just about being a good clinician. It is about maximising the patient experience, as demonstrated by one of our key collaborators Shareef Mahdavi at the ESCRS Practice Management & Development Masterclass at last month’s Congress in Milan, Italy.

It is important to point out the programme embraces all ophthalmologists, including young ophthalmologists in training who need to develop specific skills in areas such as leadership, negotiation, teamwork, finance, and administration.

There has been a perception among eye surgeons that practice management is only relevant to ophthalmologists in private practice, but this is not the case.

I work both in private practice and for the National Health Service (NHS) in the United Kingdom. If you are a clinical leader in a public service organisation, you are fighting for resources—and you need to know how those resources are allocated and how your department needs to be managed to maximise allocated resources.

With that in mind, we have been working over the last 12 months to develop a dedicated educational programme for ophthalmologists which will specifically focus on practice management outside the annual Congress.

We also plan to expand the scope of the programme to include new modules on Artificial Intelligence, Sustainability, and Crisis Management.

Do you have ideas for any stories that might be of interest to our readers?

We had a fantastic programme in Milan, but we want to make the Practice Management & Development Programme more than a once-a-year event.

We have run Practice Management Weekends outside the annual ESCRS Congress in the past, and 2023 will see the ESCRS restart those weekends.

The plan is to have two of those weekends on-site in a major European city, complemented with two online webinar sessions—in other words, four sessions in all.

That will mean we will have a progressive education programme throughout the year. The programme will be refreshed continually and moderated by members of the Practice Management & Development Committee and the ESCRS leadership. We want more interaction with eye surgeons interested in developing their business skills both online and in person.

The ESCRS acknowledges that if this programme is to grow, it cannot be restricted to workshops at the annual Congress, and we must engage with our audience on a year-long basis.

We are also exploring the possibility of establishing an accredited business course for eye surgeons.

This is a complex process that will take time to develop, but we have had encouraging feedback, and we hope to be able to make a major announcement on our progress at the 41st Congress of the ESCRS in 2023 in Vienna, Austria.

Finally, I would like to thank the ESCRS leadership—including our President Oliver Findl—for the support they have given this year and in previous years, as well as the members of the Practice Management & Development Committee who have devoted their time and energy to this programme.

We have made major progress in the last 14 years, and I look forward to even better times ahead.

Paul Rosen is Chairman of the ESCRS Trustees, Chairman of the ESCRS Practice Management & Development Committee, and Past President of the ESCRS.

BioOphthalmology

By Gearóid Tuohy PhD

Clinical study designs for ophthalmic gene therapy may need to be reconsidered following a study showing the migration of vectors from treated to control eyes. The study followed the French Competent Authority granting of a Cohort Temporary Authorization for Use for lenadogene nolparvovec (LUMEVOQ®, GenSight).

The results of a mechanistic study demonstrating the transfer of lenadogene nolparvovec from injected eyes to non-injected eyes of non-human primates suggest the vector might travel through an anatomic route via the optic nerve and chiasm. If formally proven, there may be a need to reconsider clinical study designs in some ocular research—specifically using treated and control studies in separate groups of patients. “The demonstration of a transfer of the lenadogene nolparvovec active substance between eyes has major consequences for designing gene therapy clinical trials and should lead to prioritizing interpatient comparisons whenever possible,” the journal article said.i

The primary focus of the study was Leber hereditary optic neuropathy (LHON), a maternally inherited disorder affecting 1 in 40,000 in Europe, predominantly males. Patients’ central vision loss results from degeneration of the retinal ganglion cell (RGC) layer and optic nerve. For more than 95% of patients, the genetic pathogenesis of LHON involves mutations in genes encoding components of the mitochondrial respiratory NADH-ubiquinone oxidoreductase complex (complex I)—itself involved in the transfer of electrons from NADH to ubiquinone (coenzyme Q). Complex I is composed of 46 subunits, 7 of which are encoded by the mitochondrial genomes ND1-6 and ND4L. Mutations in five mitochondrially encoded subunits include ND1, ND4, ND4L, ND5, and ND6. Three mtDNA mutations (ND4/11778, ND1/3460, ND6/14484) account for more than 90% of cases, with 11778 the most prevalent (>70%). However, there are reports of 16 other pathogenic mtDNA mutations and certain nuclear gene loci. Despite current treatments, visual acuity (VA) outcomes in LHON have been poor, with natural history studies reporting patients legally blind.

ed eyes, suggesting the gene therapy may have travelled from the injected eye. This is a key issue, not only for the phase 3 studies for lenadogene nolparvovec, but potentially for other ophthalmic clinical studies, their clinical design, and the clinical trial costs.

A small non-primate study used a single, human-equivalent injection of lenadogene nolparvovec in the right eye to investigate this further. Three subjects were monitored for three months and another three for six months. Two control animals were monitored for three and six months but received a placebo injection. The results detected vector DNA in all the injected eyes as well as the contralateral non-injected eyes for five of the six subjects in the treatment group. In addition, vector DNA was detected or quantified in the optic chiasm of all six animals.

“Our study is a critical step towards understanding not only how bilateral improvement in vision occurs with unilateral gene therapy but also mechanisms of interocular interactions more generally. Crosstalk between the two optic projections could have ramifications for additional blinding eye diseases,” noted lead author David J Calkins PhD, Professor and Vice Chair and Director for Research at the Department of Ophthalmology and Visual Sciences at Vanderbilt University Medical Center, Nashville, Tennessee, US.ii

“This contralateral effect has not been described in gene therapies with subretinal administration targeting other ophthalmic genetic diseases—specifically in patients with RPE65-mediated inherited retinal dystrophy who participated in a randomised, controlled, open-label, phase 3 trial. Both the nature of the treated disease (neuro-ophthalmic mitochondrial disease) and the intravitreal route of administration may play a role in the development and mechanism of the contralateral effect,” the research team added.iii

Lenadogene nolparvovec is designed as a novel gene therapy for LHON. The French biotechnology company GenSight proposes that 1,100 to 1,200 LHON patients may be seeking therapies for this disorder each year. A large proportion of LHON patients arise from an mtDNA homoplasmic nucleotide transition from guanosine (G) to adenosine (A) at position 11778, resulting in an arginine to histidine substitution in ubiquinone oxidoreductase (NADH) subunit 4 (ND4) of the mitochondrial complex I. Two randomised, double-masked, sham-controlled phase 3 clinical trials—and a long-term follow-up study with a unilateral intravitreal (IVT) injection of lenadogene nolparvovec—showed BCVA improvement in both treated and untreat-

As many clinical studies are in progress—based on a clinical design where each patient may be used as both a treated eye and a “control” eye—significant work will be required to demonstrate how to tease results carefully and methodically.

For more information, see the article in Molecular Therapy–Methods & Clinical Development

Source:

i–iii Calkins et al. “Biodistribution of Intravitreal Lenadogene Nolparvovec Gene Therapy in Nonhuman Primates.” Molecular Therapy–Methods & Clinical Development, 2021 Dec, 23: 307–318. doi: https://doi.org/10.1016/j. omtm.2021.09.013.

“Our study is a critical step towards understanding not only how bilateral improvement in vision occurs with unilateral gene therapy but also mechanisms of interocular interactions more generally.”

EuroTimes looks at the stories behind the names.

ALFRED VOGT 1879–1943

The man behind the palisades. Roibeárd O’hÉineacháin

Alfred Vogt was a Swiss ophthalmologist whose many important contributions to his field of study and practice include the invention of slit lamp microscopy and the description of the ocular structures and pathological signs that bear his name.

Alfred Vogt was a Swiss ophthalmologist whose many important contributions to his field of study and practice include the invention of slit lamp microscopy and the description of the ocular structures and pathological signs that bear his name.

Born October 31, 1879, in the village of Menziken, Aargau, Switzerland, Vogt began his study of medicine in 1899 in Zurich before transferring to the University of Basel. There, while under the mentorship of Prof Karl Mellinger, Vogt published his dissertation about “the detrimental effects of artificial aniline dyes on the eye”.

Born October 31, 1879, in the village of Menziken, Aargau, Switzerland, Vogt began his study of medicine in 1899 in Zurich before transferring to the University of Basel. There, while under the mentorship of Prof Karl Mellinger, Vogt published his dissertation about “the detrimental effects of artificial aniline dyes on the eye”.i

Three years later, he published the first edition of his three-volume textbook on slit lamp microscopy, “Atlas der Spaltlampenmikroskopie des lebenden Auges: mit Anleitung zur Technik und Methodik der Untersuchung” (Atlas of slit lamp microscopy of the living eye: with instructions on the technique and methodology of the examination).

Three years later, he published the first edition of his three-volume textbook on slit lamp microscopy, “Atlas der Spaltlampenmikroskopie des lebenden Auges: mit Anleitung zur Technik und Methodik der Untersuchung” (Atlas of slit lamp microscopy of the living eye: with instructions on the technique and methodology of the examination).

Vogt spent 1920 through 1922 as President of the Swiss Ophthalmological Society. One of his notable acts as president was hosting the first international symposium on slit lamp biomicroscopy in 1922—more than 30 European ophthalmologists (and even one doctor from Japan) attended.

Receiving his medical doctorate in 1904 and starting a private practice in 1906, Vogt was appointed chief of the Aargau Cantonal Hospital by 1909. His alma mater appointed him professor extraordinarius and director of its eye clinic in 1917.ii

Receiving his medical doctorate in 1904 and starting a private practice in 1906, Vogt was appointed chief of the Aargau Cantonal Hospital by 1909. His alma mater appointed him professor extraordinarius and director of its eye clinic in 1917.

Vogt recognised the potential of the slit lamp in studying the eye’s morphology and pathology early on—combining the device with a microscope in 1913 in a period of discovery for the pioneer. For it was also around this time he found using a redfree light revealed the true yellow colour of the macular lutea.

Vogt recognised the potential of the slit lamp in studying the eye’s morphology and pathology early on—combining the device with a microscope in 1913 in a period of discovery for the pioneer. For it was also around this time he found using a redfree light revealed the true yellow colour of the macular lutea.

THE FAMOUS PALISADES

THE FAMOUS PALISADES

Continuing his series of firsts, Vogt became the first ophthalmologist to perform direct examination of the corneal endothelium in 1918. During the course of this work he identified many anatomical structures and pathological signs that bear his name, including the palisades of Vogt, the radially oriented fibrovascular ridges in the limbus that contain stem cells; Vogt’s striae, fine stress lines within the cornea in eyes with keratoconus; and the limbal girdle of Vogt, a corneal opacity that occurs in an arc concentric pattern and is adjacent to the limbus within the palpebral fissure at 3 and 9 o’clock.

Continuing his series of firsts, Vogt became the first ophthalmologist to perform direct examination of the corneal endothelium in 1918. During the course of this work he identified many anatomical structures and pathological signs that bear his name, including the palisades of Vogt, the radially oriented fibrovascular ridges in the limbus that contain stem cells; Vogt’s striae, fine stress lines within the cornea in eyes with keratoconus; and the limbal girdle of Vogt, a corneal opacity that occurs in an arc concentric pattern and is adjacent to the limbus within the palpebral fissure at 3 and 9 o’clock.

His next appointment was professor ordinarius and director of the University of Zurich’s eye clinic in 1923, where he broadened his investigations into vitreoretinal diseases and began treating retinal detachment by sealing the retinal tear—which later led him to publish a major work on retinal detachment. He also introduced the cyclodiathermy technique for treating glaucoma.

The many awards he received during his life included the Donders Medal of the Dutch Ophthalmological Society in 1932, the Cothenius Medial of the Leopoldina in 1939, the Gonin Medal in 1941, and the Gullstrand Medal of the Swedish Medical Society in 1942.

Vogt spent 1920 through 1922 as President of the Swiss Ophthalmological Society. One of his notable acts as president was hosting the first international symposium on slit lamp biomicroscopy in 1922—more than 30 European ophthalmologists (and even one doctor from Japan) attended. His next appointment was professor ordinarius and director of the University of Zurich’s eye clinic in 1923, where he broadened his investigations into vitreoretinal diseases and began treating retinal detachment by sealing the retinal tear—which later led him to publish a major work on retinal detachment. He also introduced the cyclodiathermy technique for treating glaucoma. The many awards he received during his life included the Donders Medal of the Dutch Ophthalmological Society in 1932, the Cothenius Medial of the Leopoldina in 1939, the Gonin Medal in 1941, and the Gullstrand Medal of the Swedish Medical Society in 1942.

Sources:

Frederick W Stocker, Arch Ophthalmol. 1944; 31(2): 172–174.

Sources:

Frederick W Stocker, Arch Ophthalmol. 1944; 31(2): 172–174. Martin Wenzel. “Why Specular Microscopy?”, Specular Microscopy of Intraocular Lenses: Atlas and Textbook for Slit-Lamp and Specular Microscopic Examinations, 2–4. Stuttgart: Thieme, 1993.

Martin Wenzel. “Why Specular Microscopy?”, Specular Microscopy of Intraocular Lenses: Atlas and Textbook for Slit-Lamp and Specular Microscopic Examinations, 2–4. Stuttgart: Thieme, 1993.

i RD Gerste, Ophthalmologica 2021; 244(1): 1–17.

i–ii RD Gerste, Ophthalmologica 2021; 244(1): 1–17.

ii RD Gerste, Ophthalmologica 2021; 244(1): 1–17.

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