OZURDEX® (dexamethasone intravitreal implant) acts fast1,2 and lasts3–5 with less treatment visits compared with anti-VEGFs.5 Effective DME treatment doesn’t have to be a burden.6
The most commonly reported adverse events reported following treatment with OZURDEX® are those frequently observed with ophthalmic steroid treatment or intravitreal injections (elevated IOP, cataract formation and conjunctival or vitreal haemorrhage respectively). Less frequently reported, but more serious, adverse reactions include endophthalmitis, necrotizing retinitis, retinal detachment and retinal tear. This advert is consistent with the UK marketing authorisation. Licences may vary by country, please refer to your local country SmPC. DME, diabetic macular edema; IOP, intraocular pressure; VEGF, vascular endothelial growth factor. 1. Lo Giudice G et al. Eur J Ophthalmol 2018;28(1):74–79. 2. Veritti D et al. Ophthalmologica 2017;238(1–2): 100–105. 3. Escobar-Barranco JJ et al. Ophthalmologica 2015;233(3–4):176–185. 4. Allergan. OZURDEX® Summary of Product Characteristics. 5. Kodjikian L et al. Biomed Res Int 2018:8289253. 6. Boyer DS et al. Ophthalmology 2014;121:(10):1904–1914.
OZURDEX® (Dexamethasone 700 micrograms intravitreal implant in applicator) Abbreviated Prescribing Information Presentation: Intravitreal implant in applicator. One implant contains 700 micrograms of dexamethasone. Disposable injection device, containing a rod-shaped implant which is not visible. The implant is approximately 0.46 mm in diameter and 6 mm in length. Indications: Treatment of adult patients: with macular oedema following either Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO), inflammation of the posterior segment of the eye presenting as non-infectious uveitis and visual impairment due to diabetic macular oedema (DME) who are pseudophakic or who are considered insufficiently responsive to, or unsuitable for non-corticosteroid therapy. Dosage and Administration: Please refer to the Summary of Product Characteristics before prescribing for full information. OZURDEX must be administered by a qualified ophthalmologist experienced in intravitreal injections. The recommended dose is one OZURDEX implant to be administered intra-vitreally to the affected eye. Administration to both eyes concurrently is not recommended. Repeat doses should be considered when a patient experiences a response to treatment followed subsequently by a loss in visual acuity and in the physician’s opinion may benefit from retreatment without being exposed to significant risk. Patients who experience and retain improved vision should not be retreated. Patients who experience a deterioration in vision, which is not slowed by OZURDEX, should not be retreated. In RVO and uveitis there is only very limited information on repeat dosing intervals less than 6 months. There is currently no experience of repeat administrations in posterior segment non-infectious uveitis or beyond 2 implants in Retinal Vein Occlusion. In DME there is no experience of repeat administration beyond 7 implants. Patients should be monitored following the injection to permit early treatment if an infection or increased intraocular pressure occurs. Singleuse intravitreal implant in applicator for intravitreal use only. The intravitreal injection procedure should be carried out under controlled aseptic conditions as described in the Summary of Product Characteristics. The patient should be instructed to selfadminister broad spectrum antimicrobial drops daily for 3 days before and after each injection. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Active or suspected ocular or periocular infection including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. Advanced glaucoma which cannot be adequately controlled by medicinal products alone. Aphakic eyes with ruptured posterior lens capsule. Eyes with Anterior Chamber Intraocular Lens (ACIOL), iris or transscleral fixated intraocular lens and ruptured posterior lens capsule. Warnings/Precautions: Intravitreous injections, including OZURDEX can be associated with endophthalmitis, intraocular inflammation,
increased intraocular pressure and retinal detachment. Proper aseptic injection techniques must always be used. Patients should be monitored following the injection to permit early treatment if an infection or increased intraocular pressure occurs. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy between two and seven days following the injection. Patients must be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay. All patients with posterior capsule tear, such as those with a posterior lens (e.g. due to cataract surgery), and/or those who have an iris opening to the vitreous cavity (e.g. due to iridectomy) with or without a history of vitrectomy, are at risk of implant migration into the anterior chamber. Implant migration to the anterior chamber may lead to corneal oedema. Persistent severe corneal oedema could progress to the need for corneal transplantation. Other than those patients contraindicated where OZURDEX should not be used, OZURDEX should be used with caution and only following a careful risk benefit assessment. These patients should be closely monitored to allow for early diagnosis and management of device migration. Use of corticosteroids, including OZURDEX, may induce cataracts (including posterior subcapsular cataracts), increased IOP, steroid induced glaucoma and may result in secondary ocular infections. The rise in IOP is normally manageable with IOP lowering medication. Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex and not be used in active ocular herpes simplex. OZURDEX is not recommended in patients with macular oedema secondary to RVO with significant retinal ischemia. OZURDEX should be used with caution in patients taking anticoagulant or anti-platelet medicinal products. OZURDEX administration to both eyes concurrently is not recommended. Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, consider evaluating for possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids. Interactions: No interaction studies have been performed. Systemic absorption is minimal and no interactions are anticipated. Pregnancy: There are no adequate data from the use of intravitreally administered dexamethasone in pregnant women. OZURDEX is not recommended during pregnancy unless the potential benefit justifies the potential risk to the foetus. Lactation: Dexamethasone is excreted in breast milk. No effects on the child are anticipated due to the route of administration and the resulting systemic levels. However OZURDEX is not recommended during breast-feeding unless clearly necessary. Driving/Use of Machines: Patients may experience temporarily reduced vision after receiving OZURDEX by intravitreal injection. They should not drive or use machines until this has resolved. Adverse Effects: In clinical trials the
most frequently reported adverse events were increased intraocular pressure (IOP), cataract and conjunctival haemorrhage*. Increased IOP with OZURDEX peaked at day 60 and returned to baseline levels by day 180. The majority of elevations of IOP either did not require treatment or were managed with the temporary use of topical IOP-lowering medicinal products. 1% of patients (4/347 in DME and 3/421 in RVO) had surgical procedures in the study eye for the treatment of IOP elevation. The following adverse events were reported: Very Common (≥ 1/10): IOP increased, cataract, conjunctival haemorrhage*. Common (≥1/100 to <1/10): headache, ocular hypertension, cataract subcapsular, vitreous haemorrhage*, visual acuity reduced*, visual impairment/ disturbance, vitreous detachment*, vitreous floaters*, vitreous opacities*, blepharitis, eye pain*, photopsia*, conjunctival oedema*, conjunctival hyperaemia. Uncommon (≥1/1,000 to <1/100): migraine, necrotizing retinitis, endophthalmitis*, glaucoma, retinal detachment*, retinal tear*, hypotony of the eye*, anterior chamber inflammation*, anterior chamber cells/flares*, abnormal sensation in eye*, eyelids pruritus, scleral hyperaemia*, device dislocation* (migration of implant) with or without corneal oedema , complication of device insertion resulting in ocular tissue injury* (implant misplacement). (*Adverse reactions considered to be related to the intravitreous injection procedure rather than the dexamethasone implant). Please refer to Summary of Product Characteristics for full information on side effects. Basic NHS Price: £870 (ex VAT) per pack containing 1 implant. Marketing Authorisation Number: EU/1/10/638/001. Marketing Authorisation Holder: Allergan Pharmaceuticals Ireland, Castlebar Road, Westport, Co. Mayo, Ireland. Legal Category: POM. Date of Preparation: May 2019. UK/0288/2019
Adverse events should be reported. Reporting forms and information can be found at https://yellowcard.mhra.gov.uk/ Adverse events should also be reported to Allergan Ltd. UK_Medinfo@allergan.com or 01628 494026 JOB CODE: INT-OZU-2050217 DATE OF PREPARATION: DECEMBER 2020
Publishers Therese Dolan, Operations Director ESCRS Barbara Calderwood, Divisional Director Engagement Associations and Communities MCI UK Mark Wheeler, Finance Director MCI UK Editor-in-Chief Sean Henahan Senior Content Editor Kelsey Ingram Design Director Kelsy McCarthy Designer Jen Basel Circulation Manager Vanessa McCourt Contributing Editors Cheryl Guttman Krader Howard Larkin Dermot McGrath Roibeard Ó hÉineacháin Contributors Leigh Spielberg Gearóid Tuohy Priscilla Lynch Soosan Jacob Colour and Print W&G Baird Printers Advertising Sales Roo Khan MCI UK Tel: +44 203 530 0100 email: email@example.com
A EUROPEAN OUTLOOK ON THE WORLD OF OPHTHALMOLOGY
04 Pursuing the Holy Grail of Presbyopia Treatment
CATARACT & REFRACTIVE 07 In Your Lane—
GLAUCOMA 19 Meditation
Between Glaucoma and CSFP
22 Preventing Glaucoma Blindness
23 Differentiating NTG
25 New Testing Paradigms 26 Glaucoma Treatment
08 LACS vs Manual
ESCRS EuroTimes is not responsible for statements made by any contributor. These contributions are presented for review and comment and not as a statement on the standard of care. Although all advertising material is expected to conform to ethical medical standards, acceptance does not imply endorsement by ESCRS EuroTimes. ISSN 1391-8983
12 Preparing for Presbyopia
09 Weighing the Evidence for UV Filters in IOLs
10 Novel Presbyopia Correcting IOL
11 Seeking the Solution for Accommodating IOL Success Pharmacotherapy
13 Modular IOLs Enter Clinic 14 New Biometry 15 Adjusting IOL Power
21 The Vulnerable Balance
Ophthalmology and Society
Published by the European Society of Cataract and Refractive Surgeons, Temple House, Temple Road, Blackrock, Co Dublin, Ireland. No part of this publication may be reproduced without the permission of the managing editor. Letters to the editor and other unsolicited contributions are assumed and subject to editorial review and acceptance.
Drops First in Line
28 Everything You Ever
Wanted to Know About Posterior Capsule Ruture SB Rupture
30 BioOphthalmology 31 Industry Briefs 32 Calendar of Events
in the Eye
CORNEA 16 A New Era for CXL 17 Viewing Cosmetic Eye Colour Change with a Different Lens
As certified by ABC, the EuroTimes average net circulation for the 10 issues distributed between February and December 2019 was 47,863
EUROTIMES | OCTOBER 2021
EDITORIAL A WORD FROM RUDY NUIJTS MD, PHD
GUEST EDITORIAL You better start swimmin’ or you’ll sink like a stone For the times they are a-changin’ Bob Dylan Rudy MMA Nuijts
Emanuel Rosen Chief Medical Editor
INTERNATIONAL EDITORIAL BOARD Noel Alpins (Australia), Bekir Aslan (Turkey), Roberto Bellucci (Italy), Hiroko Bissen-Miyajima (Japan), John Chang (China), Béatrice Cochener-Lamard (France), Oliver Findl (Austria), Nino Hirnschall (Austria), Soosan Jacob (India), Vikentia Katsanevaki (Greece), Daniel Kook (Germany), Boris Malyugin (Russia), Marguerite McDonald (USA), Cyres Mehta (India), Sorcha Ní Dhubhghaill (Ireland) Rudy Nuijts (The Netherlands), Leigh Spielberg (The Netherlands), Sathish Srinivasan (UK), Robert Stegmann (South Africa), Ulf Stenevi (Sweden), Marie-José Tassignon (Belgium), Manfred Tetz (Germany), Carlo Enrico Traverso (Italy)
EUROTIMES | OCTOBER 2021
am pleased to be asked to write an editorial for EuroTimes coinciding with the 39th annual Congress of the ESCRS in Amsterdam. The pandemic is still with us, but unlike last year when our annual meeting was entirely virtual, this year we will be able to have a hybrid meeting. The programme is once again packed with a wonderful array of symposia, free papers, special lectures, courses, and posters. The virtual component will assure that those who cannot attend in person can listen in and share in the discussions. EuroTimes, as always, will provide extensive coverage in coming issues. The ESCRS is proud to be one of the first European medical societies to go back to face-to-face congresses since the feedback from our members and industry overwhelmingly stated they missed the personal interaction that cannot be achieved during purely virtual congresses. One of the hot topics at this year’s conference will be the treatment of presbyopia. Sometimes known as the holy grail of ophthalmology, this is the theme of this month’s EuroTimes. You’ll find interesting articles about new shape-changing IOLs, femtosecond laser-induced refractive index change, and pharmacological approaches now entering clinics. We will incorporate lessons learned from the pandemic, such as the use of telemedicine to streamline daily practice. But there are even The ESCRS is larger issues facing ophthalmology proud to be one we need to address. The United Nations estimates at of the first European least 2 billion people in the world medical societies to have vision impairment or blindgo back to face-toness. Most (90%) of the 1.1 billion face congresses people with vision loss live in lowand middle-income countries. More than half of the globe’s blind people are women and girls. Loss of sight is estimated to cost the global economy $411 billion in productivity each year. All of this came into focus as all 193 members of the United Nations General Assembly adopted a resolution dubbed “Vision for Everyone”. The resolution, the first ever on vision from the UN, commits the international community to provide access to eye care for the people living with preventable sight loss by 2030. The resolution acknowledges quality eye care as critical in helping the UN achieve sustainable development, an end to poverty, improved education, and reduced inequality. The resolution asks for international financial institutions and donors to provide targeted finances in tackling preventable sight loss—particularly for developing countries. This is a significant milestone, and the ESCRS, not least through its Charitable Committee, is ready to support making eye care services more widely available while becoming an integral part of universal healthcare. Continuing the global theme, this month also includes World Sight Day, October 14th. Sponsored by the International Agency for the Prevention of Blindness, the goal is to focus on global eye health. Ophthalmology exists within the world at large. We need to examine current questions of race and gender within our field. We are also not immune from the effects of climate change. We need to re-evaluate our methods and determine ways to minimise waste and think about a sustainable approach to ophthalmic surgery as we strive to meet what we know will be an ever-increasing demand for our services.
Rudy MMA Nuijts MD, PhD is Professor of Ophthalmology, University Eye Clinic Maastricht, The Netherlands firstname.lastname@example.org
OPHTEC | Cataract Surgery
NEW CTF/TCT optic designed to: P REDUCE GLARE & HALOS1 P TOLERATE THE KAPPA ANGLE2 P TOLERATE DECENTRATION 3 P TOLERATE MISALIGNMENT 4 1) 2) 3) 4)
PRESBYOPIA & ASTIGMATISM CORRECTION REINVENTED We look forward to meeting you at the ESCRS in Amsterdam!
The misalignment tolerance and the use of segments instead of concentric rings reduces photic phenomena, helping patients to adapt more naturally to their new vision. The central zone of 1.4 mm in diameter is larger than most available mIOLs and allows a wider tolerance so that the visual axis passes through the wider central segment avoiding visual disturbances. In cases of tilt or misalignment, the patient can still benefit from good near and far vision, as the segmented zones allow a balanced far/near light distribution in a steady optical platform. Broader Toric meridian designed to be more tolerant of misalignment. White paper: Evaluation of a new toric IOL optic by means of intraoperative wavefront aberrometry (ORA system): the effect of IOL misalignment on cylinder reduction. By Erik L. Mertens, MD Medipolis Eye Center, Antwerp, Belgium
SPECIAL FOCUS: PRESBYOPIA TREATMENT
Pursuing the Holy Grail of Presbyopia Treatment Rich pipeline suggests new options are on the horizon and beyond. Cheryl Guttman Krader reports from ASCRS Refractive Day 2021
early two billion people on Earth are presbyopic, and the number continues to increase. With a variety of investigational approaches for treating presbyopia advancing along the regulatory approval pathway, the question arises: Where do we stand now with regard to presbyopia treatment? Delivering the Steinert Refractive Lecture at the ASCRS in Las Vegas, USA, Marguerite B McDonald MD, borrowed a quote from Winston Churchill that she said offers the perfect answer. “‘Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning,’” Dr McDonald quoted. In her presentation, Dr McDonald highlighted the limitations of currently available presbyopia treatments and other abandoned treatments. Most of her talk reviewed pharmacological, surgical, and contact lens-based approaches in clinical development.
TOPICAL DROPS Pharmacological approaches to treating presbyopia with topical drops are represented by an array of products based on pupil constriction to increase depth of focus, and a single modality aimed to soften the crystalline lens to improve accommodation. Currently, eight companies are developing a pupil constricting agent for treating presbyopia, and most contain pilocarpine. “What is new about these treatments is that they contain a much lower concentration of pilocarpine than what was ever used for glaucoma, and they formulate it in sophisticated delivery vehicles,” Dr McDonald said. Of the pilocarpine-based drops, AGN190584 (Allergan) is farthest along the pathway to regulatory approval as its New Drug Application is undergoing US FDA review. AGN-190584, administered bilaterally once daily for 30 days, was investigated in two phase-three clinical trials that enrolled 750 patients. Both studies met their primary endpoint, showing that a significantly greater proportion of patients using AGN-190584 versus placebo-treated controls gained at least three lines of mesopic high contrast binocular distancecorrected near visual acuity at three hours. EUROTIMES | OCTOBER 2021
The near vision benefit was achieved without any negative impact on distance vision. The most common side effects associated with AGN-190584 were headache, conjunctival hyperaemia, and blurred visual acuity, each occurring in less than 3% of treated patients. The adverse events were generally mild and did not lead to treatment discontinuation, Dr McDonald said. CSF-1 (Orasis), another pilocarpine-based agent, achieved positive results in a phase two study where it was administered twice daily. Two phase-three studies investigating CSF-1 with 600 patients are now underway. MicroLine (Eyenovia) sprays pilocarpine onto the eye with microarray print technology (Optejet). At the completion of a smaller phase-three trial evaluating pilocarpine concentrations of 1% and 2%, 70% of patients indicated interest in using the product if it was approved. There are phase three registration trials planned for 2021. Another company, Kedalion Therapeutics, also uses novel technology (AcuStream) to deliver pilocarpine for treating presbyopia. A phase two study is investigating 1% and 2% pilocarpine concentrations. Pilocarpine is a component in a two-drug kit being developed as a treatment for presbyopia (Ocuphire). This approach combines a low dose of pilocarpine (0.4%) administered in the morning with an evening dose of phentolamine 0.75% (Nyxol)—a moderate and long-acting nonselective alpha-adrenergic antagonist. “The combination synergistically activates the iris sphincter muscle and inhibits the iris dilator muscle. It also allows for the active ingredients to be used in lower concentrations, which may decrease the likelihood of adverse events,” Dr McDonald explained. A phase two study including 152 patients met its primary endpoint and key secondary endpoints and showed the combination treatment had a favourable safety profile. There are plans for phase three registration trials. PRX-100 (Lenz Therapeutics, formerly Presbyopia Therapies) pairs aceclidine, a parasympathomimetic cholinergic muscarinic receptor agonist, with tropicamide to induce strong miosis without accommodative distance blur. It demonstrated efficacy in a phase two study. Further development stalled while the company reorganises. BRIMOCHOL™ (Visus Therapeutics) is a fixed combination agent designed to gain synergistic efficacy with a possible safety benefit. It contains carbachol (a potent cholinergic
SPECIAL FOCUS: PRESBYOPIA TREATMENT miotic agent) and brimonidine, which may help prevent the redness associated with all miotics. The brimonidine preserves pupil dilation, may inhibit ciliary muscle contraction, and whitens the eyes. A phase two study is comparing two BRIMOCHOL formulations against carbachol monotherapy. One other combination topical treatment for presbyopia (EyeFocus) contains a miotic, an alpha-1 agonist, one or more histamine-1 antagonists, and an NSAID (OSRX). UNR844 (lipoic acid choline ester, Novartis), the lens softening agent, acts to hydrolyse the disulphide bonds between crystalline lens proteins. In a phase two trial enrolling early presbyopes (ages 45 to 55 years) treated twice daily for three months, UNR844 was associated with modest improvements in near vision compared to placebo along with dysgeusia and headache in 5% and 3% of users, respectively. “While the trials investigating UNR844 are attempting to reverse presbyopic lens changes, it seems this agent would more likely be used in younger patients as a preventive strategy,” Dr McDonald said. “The long-term safety of using this treatment for decades and whether the treatment works consistently across the entire lens are questions that need to be answered.”
SURGICAL APPROACHES Thermal keratoplasty treatments for presbyopia using the holmium:YAG laser or radiofrequency energy have been available in the US for years but were never widely adopted. Optimal Keratoplasty (Opti-K, NTK Enterprises), which has the CE mark and was under investigation in a US clinical trial, seems to overcome the drawbacks of previous approaches, Dr McDonald said. Performed with an infrared thulium fibre laser under topical anaesthesia, Opti-K is a non-invasive, rapid procedure that causes minimal discomfort and involves no downtime. Although the treatment effect regresses completely in one to two years as the presbyopic refraction changes, Opti-K can be safely repeated, unlike other thermal keratoplasty procedures. “Opti-K also avoids the risks of other existing surgical treatments for presbyopia that are associated with the need
for flap creation, stromal implant placements, and epithelial barrier disruption,” Dr McDonald said. “A drop of topical steroid administered at the end of the procedure is the only postoperative medication needed. Among almost 1,400 eyes treated in clinical trials, there have been no cases of an induced cylinder of greater than 1D or loss of BSCVA of two lines or more at the one-year follow-up.” Looking further into the future, Dr McDonald discussed laserinduced refractive index change (LIRIC, Clerio Vision), a femtosecond laser technique in development to alter the refractive index of the cornea, intraocular lenses (IOLs), and contact lenses. Achieving change in a highly localised fashion, the cornea treatment modifies collagen fibril density without causing tissue ablation. One-month data from nine patients showed significant improvement in near vision and clear corneas with no light scatter, wound healing response, or inflammation. “With this non-invasive treatment, there is no need for postoperative antibiotic or steroid drops. Animal studies show it has almost no effect on corneal nerves, suggesting it may be unlikely to cause dry eye,” Dr McDonald said. Applied to an IOL, LIRIC can convert a monofocal optic to a multifocal design or vice versa. It is also being developed to create diffractive contact lenses. “Because tear film mucus and debris accumulate in surface echelettes, presbyopia-correcting contact lenses have been trapped in the ’90s with a refractive design. LIRIC enables diffractive technology because it embeds the echelettes within the lens and can create a lens with any add power, not just the limited choices of existing contact lenses,” Dr McDonald said.
Marguerite B McDonald MD is a Clinical Professor of Ophthalmology at New York University Lagone Medical Center, New York, USA email@example.com
EUROTIMES | OCTOBER 2021
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CATARACT & REFRACTIVE
In Your Lane— Ophthalmology and Society
Outgoing AAO leader calls for social as well as professional engagement. Howard Larkin reports from ASCRS in Las Vegas, USA
he past 18 months have been a time of testing filled with lessons for future growth, David W Parke II MD said at the ASCRS opening ceremony. In his final address to the membership, Dr Parke, who departs this year as CEO of the American Academy of Ophthalmology, urged ophthalmologists everywhere to become more fully engaged in their communities. Responding to issues outside of eye care that affect public health, which includes not only the COVID-19 pandemic but related issues such as racism and the rise in drug abuse and depression, is essential to fulfilling the Academy’s professional mission of protecting sight and empowering lives, Dr Parke said. “We ultimately will only thrive if our communities thrive.”
COVID LESSONS The speed and magnitude of the pandemic’s onset revealed many weaknesses and some strengths in the preparations of the profession and society at large. It was not just a story of case numbers and deaths but of innumerable lives altered forever, Dr Parke said. “Even though we now know the SARS-CoV-2 virus made it to the United States by late December 2019, the first confirmed US case was on January 28, 2020. It was still business as usual,” he remarked. But by March 1, there were 30 confirmed US cases, ballooning to more than 10,000 by March 18. Initial mortality estimates were in the 2% to 3% range, prompting people to wipe down mail with disinfectant while waiting for hospitals to run out of ICU beds and ventilators. By May, 75% of hospitals reported exhausted stocks of essential personal protective equipment (PPE). “It was not unreasonable fear. We were all facing the detonation of a global pandemic with uncertain but substantive mortality, no known treatments, and a nation running out of even basic masks and gloves,” Dr Parke said. The only actions immediately available to combat the pandemic were to reduce transmission rates and preserve scarce PPE for frontline workers, Dr Parke said. So, on March 18, 2020, the AAO board recommended ophthalmologists cease providing non-urgent care to accomplish those ends. While the statement called on individual practitioners to use their own judgement, “in an amazing show of professional unity, this statement was endorsed within days by most major organisations in ophthalmology, including ASCRS, the Cornea Society, and the American Glaucoma Society. Within days, most other specialties issued similar statements, as did the US Surgeon General and the CDC,” Dr Parke said. As a result, most elective procedures and routine care shut down for months. Along with stay-at-home orders, the measures did slow the transmission rate. AAO advised on April 17 that practices could reopen based on local conditions. An abrupt and global shutdown reversed on a regional and gradual basis. Some parts of the specialty, such as paediatric ophthalmologists, were affected more, while others, such as retina specialists, were affected less. During the shutdown, some ophthalmologists took training in life support to help out on the front lines. Others caught up on training, with CME requests increasing by 73%. Still, by the end of the year, surgical volumes were back to pre-pandemic levels or even a little higher, Dr Parke noted. “If we knew in March 2020 what we know now, the March AAO statement might have been more nuanced,” Dr Parke said. But the episode contains an important leadership lesson.
“There are times when decisions must be made without the comfort of having all the data you’d like and without the luxury of lengthy debate,” he said. “In those circumstances, decisions must be guided by principles. Chief among them is that preserving human life and safety is paramount.”
COMMUNITY RESPONSE During the pandemic, other social issues emerged, including the murder of George Floyd in police custody and the subsequent rioting and unrest. These events prompted the AAO board to condemn racism, Dr Parke said. The statement drew three kinds of responses. The overwhelming majority supported the position, Dr Parke said. Then there were “absolutely heartbreaking notes from Black colleagues of bias and racism they experienced in the profession.” Last were a not insubstantial number who said it was none of the Academy’s business, and it should “stay in your lane.” However, in 2017 AAO had begun an outreach programme to encourage more minority participation in ophthalmology, which had only 6% minority representation in a country with a 30% minority population. This is a health as well as a social issue because studies show patients who can identify with their doctors are more likely to go to appointments and adhere to treatment, improving health outcomes, Dr Parke noted. Definitely in ophthalmology and medicine’s lane. “The borders between eye health and public health, our community and the larger community, and our professional principles and socioeconomic principles are very blurred,” Dr Parke said. Always, actions should be guided by the goals of protecting sight and empowering lives, he advised.
Dr Parke is the outgoing CEO of the American Academy of Ophthalmology. He served for 17 years as president and CEO of the Dean McGee Eye Institute and Edward L Gaylord Professor and Chair of the Department of Ophthalmology at the University of Oklahoma College of Medicine, USA. EUROTIMES | OCTOBER 2021
CATARACT & REFRACTIVE
LACS vs Manual Cataract Surgery New technology can improve some surgeries, but manual may be more efficient. Howard Larkin reports from ASCRS in Las Vegas, USA
wo busy surgeons made a case for laser-assisted cataract surgery (LACS) or conventional manual cataract surgery in a spirited debate at this year’s conference. Making a case for LACS, John J DeStafeno MD argued that extracapsular manual surgery is excellent, but the key to improving cataract surgery is embracing new technology. “Where would we be right now if we didn’t embrace developments in intraocular lenses? Pharmacology? Corrective lenses? LASIK? Phacoemulsification?” Dr DeStafeno asked. When discussing LACS, surgeons often ask if it makes cataract surgery any safer or quicker, or if it promotes better healing, reduces endothelial cell loss, or provides better vision, he explained. “The key when you are looking at new technology for your practice is do you think it makes you a better surgeon, is it something you want to have in your toolbox?” For Dr DeStafeno, the answer is yes. “I like it for small pupils, pseudoexfoliation, [reducing] phaco energy, deeper orbits, and corneal diseases like Fuch’s dystrophy and patients with retinal issues.” LACS allows him to do more with less, Dr DeStafeno said. “I can use less trypan blue, fewer blade-based LRIs. I can do it all in one.” That includes capsulorhexis, lens fragmentation, surgical wounds, arcuate incisions, and even marks on the cornea or capsule for aligning toric lenses more accurately. LACS can reduce long-term complications like phimosis from working in a small capsulorhexis. It also helps avoid the risk of iris expansion rings, reduce corneal oedema, and avoid TASS by not injecting dyes, he said.
“The key when you are looking at new technology for your practice is do you think it makes you a better surgeon, is it something you want to have in your toolbox?” WHAT ABOUT COST? Concerns about LACS include not enough volume to support a machine purchase and expensive disposables for a procedure not covered by insurance. Some surgeons also do not treat astigmatism and fear increased complications—though Dr DeStafeno said he has experienced very few complications with LACS. Dr DeStafeno outlined a few ideas for making LACS financially viable. One is to lease lasers. “They have roll-on, roll-off; they have great lease packages with very affordable minimums.” An alternative way to decrease the LACS cost burden is by incorporating the technology into premium services. “Offer LACS to presbyopia-correcting or toric IOL patients. Insurance also does not cover preoperative-screening OCTs, topography, wavefront aberrometry, etc., and practices do charge for theseservices,” Dr DeStafeno said. “You can also add free laser enhancements and extended postop care.” EUROTIMES | OCTOBER 2021
But the bottom line is technology can make surgery better, Dr DeStafeno said. “Don’t struggle with that deep orbit. Don’t struggle [by] looking through a fishbowl all the time. … Expand your toolbox. Be part of making it better, just like we did with phaco. Embrace technology. Make it work for you,” he urged delegates.
KEEP IT SIMPLE Arguing for manual surgery was R Luke Rebenitsch MD. “I like to make things simple,” he said. He cited a study by the ESCRS involving 16 centres in 10 countries and more than 2,800 surgeries that found no improvement in either visual or safety results for LACS over manual surgery. Posterior capsule complications, absolute biometry prediction error, and postoperative complications were all equivalent. “If anything, there was a trend toward worse distance corrected vision. Maybe that’s from the prostaglandin release. Another study found little difference in capsulorhexis strength.” Endothelial cell loss may be slightly less in LACS, averaging 55.43 cells per mm2 more cells compared with manual surgery in one large meta-analysis, Dr Rebenitsch allowed. “Is it clinically relevant? Probably not for most cases.” Concerning cost, a French Ministry of Health study involving 1,476 eyes in 907 patients found equivalent outcomes between FLACS and manual surgery with €10,703 saved per manual patient (Lancet 2020; 395: 212–224). In his own practice, Dr Rebenitsch had a laser break down after more than 1,000 laser cases, forcing a return to manual surgery. “What I found was we were doing one less eye per hour with femto.” A little more anaesthesia and pretreatment with NSAIDs also were required for femto. “So, I just thought, ‘are we throwing away time? Time is money.’ We’re paying for the laser and we’re losing time,” Dr Rebenitsch said. Better ways to improve safety include using augmented reality microscopes, dispersive OVD, phaco-choppers, non-longitudinal ultrasound, and glutathione-enriched irrigation, Dr Rebenitsch said. Manual surgery is more efficient and decreases the cost for equivalent outcomes, he concluded.
John J DeStafeno MD is a cataract and corneal specialist at Chester County Eye Associates, West Chester, Pennsylvania, USA and clinical instructor at Wills Eye Hospital, Philadelphia, USA firstname.lastname@example.org R Luke Rebenitsch MD has an ophthalmologist practice in Oklahoma City, USA Dr.Luke@ClearSight.com
CATARACT & REFRACTIVE
Weighing the Evidence for UV Filters in IOLs Dermot McGrath reports from the French Society of Ophthalmology Annual Meeting
lthough intraocular lenses have incorporated filters to block harmful ultraviolet (UV) rays since the 1980s, the debate about exactly which wavelengths of visible light should be blocked continues to animate the scientific community. Speaking at the virtual annual meeting, Professor Corinne Dot MD, PhD, FEBO, said that while all modern IOL platforms block harmful UV light, there are major differences in the ultraviolet transmission characteristics of the wide range of lenses currently on the market. “We know there are key differences between the implants thanks to studies such as that by Dr Carmen Garcia-Domene [Optom Vis Sci. 2018 Dec; 95(12): 1129–1134], which looked at eight different IOLs with UV blockers. The real question is whether the differences in the filtering capacity of the lenses are clinically significant,” she said. Reviewing the history of UV filters in IOL technology, Prof Dot said the goal of the filter on the implant is to essentially reproduce the natural filtering characteristics of the crystalline lens. “In the 2000s, it was demonstrated that certain parts of the blue light spectrum were more toxic for the retina compared to other blue light wavelengths, which are important for biorhythms and sleep patterns. This gave rise to yellow implants that block blue light in the spectrum of 400 to 430 nm, which is supposedly the most toxic to the retina,” she said. Prof Dot identified three main types of filters in current use: ultraviolet filters (white IOLs) available since 1985 that block all UV from 300 nm to 400 nm; yellow implants that block all UV and part of the blue light spectrum, available since 2003; and the more recent violet light-filtering IOLs that block violet light in the range 300 to 400 nm and part of the blue light spectrum. Prof Dot said pooled findings from the Beaver Dam and Blue Mountains Eye studies showed the AMD risk increased by a factor of 5.7 after five years for aphakic patients who received cataract surgery compared to those with implants incorporating a UV filter. “It clearly shows the interest of having UV blockers, even after a certain age,” Prof Dot said. The picture is more complicated when it comes to establishing the utility of using yellow blue-light filters in IOLs for macular protection. “A 2018 Cochrane review [Downie et al, Cochrane Database Syst Rev. 2018;5] which included 57 randomised control trials from 17 countries and more than 5,000 eyes, concluded macular protection was not clearly established for using a blue-light filter, nor was its influence on the development of AMD or its progression,” she said. However, a subsequent publication by the same authors pointed out that most of the trials included in the initial review had a very short follow-up of fewer than three months, and drawing conclusions about AMD risk was therefore impossible.
“We know there are key differences between the implants thanks to studies such as that by Prof Carmen Garcia-Domene.” “Companies have no real commercial interest to conduct long-term investigations, hence register or institutional studies might represent the best avenue to shed light on these important questions. We also need to bear in mind that AMD is a complex multifactorial disease, with tobacco, genetic factors, diet, and other environmental factors all playing a potential role,” she said. Prof Dot cited a recent single-centre retrospective study in Finland of more than 11,000 eyes which looked at two groups of patients with either yellow blue-filtering or standard white IOLs implanted after cataract surgery from 2007 to 2018 with an average age of 75.4 years (Achiron et al, Ophthalmology, 2021 Mar; 128(3): 410–416). “No benefit was found in yellow blue-filter IOLs versus standard white IOLs for the incidence of AMD after surgery—or on the outcome of patients already being treated for AMD in terms of number and interval of intravitreal injections or on the evolution of AMD. However, Finland is not a sunny country, so there is a real interest in conducting similar studies further south,” she observed. For potential toxicity from LED lights, Prof Dot said there was no present evidence that they pose a risk to the retina. “LED may be uncomfortable for some but are not considered dangerous at this point, so there is no real interest in extending LED filters to IOLs,” she explained. In terms of sleep quality, a recent meta-analysis showed it improves significantly after cataract surgery irrespective of whether a blue-light or UV filter is used (Zheng et al, Int J Ophthalmol. 2017 Nov 18; 10(11): 1734–1741). Summing up, Prof Dot said the standard UV filter has proven its utility and is available on all implants on the market. For yellow IOLs with a blue-light filter, she said their utility is hypothesis-based rather than evidence-based. Violet filters have very few studies, as they are a recent addition to the market, but they offer an intermediate profile between UV filters and blue-light filters that may serve as a fitting compromise for those sceptical of yellow IOLs.
Corinne Dot MD, PhD, FEBO is Professor of Ophthalmology, Val de Grâce, Paris and head of the department of ophthalmology, Desgenettes Hospital, Lyon email@example.com. or Corinne.firstname.lastname@example.org EUROTIMES | OCTOBER 2021
CATARACT & REFRACTIVE
Novel Presbyopia Correcting IOL Efficacy and safety results from pivotal trial show the non-diffractive EDOF lens meets its design goals. Cheryl Guttman Krader reports from ASCRS in Las Vegas, USA
he novel, non-diffractive extended depth of focus Vivity IOL (Alcon) provided superior distance-corrected intermediate and near vision, a greater range of vision, and non-inferior best-corrected distance vision in a recent multicentre trial, reports Cathleen McCabe MD. Dr McCabe was the investigator at one of the 11 centres participating in the pivotal trial that led to US FDA approval of the Vivity IOL. “Having a non-diffractive EDOF lens that does not split light, provides excellent quality of vision with a visual disturbance profile equal to the monofocal lens, and is built on the rotational stability of the AcrySof platform has allowed me to expand the number of patients I can offer a presbyopia-correcting solution to at the time of cataract surgery,” she told EuroTimes. “Now, patients who I would consider borderline candidates for a diffractive presbyopia-correcting IOL can be given the opportunity to experience a range of vision independent of glasses. Such patients include those with a few drusen or retinal pigment epithelium changes, a small non-foveal-affecting epiretinal membrane, borderline thinning, early changes in the nerve fibre layer, concern about a risk of glare, or haloes postoperatively.” The Vivity IOL design includes a novel “X-Wave” wavefrontshaping technology that aims to provide a continuous extended range of vision with a visual disturbance profile similar to the aspheric monofocal AcrySof IQ SN60WF IOL. “Built on the AcrySof platform, the Vivity looks like the SN60WF—but the central 2.2 mm of the Vivity optic stretches and shifts the wavefront without light splitting to provide an extended focal range rather than multiple focal points,” Dr McCabe explained. Point spread function analyses show the area of precisely focused light for the monofocal SN60WF lens is around distance but extends to the intermediate range and includes some functional near vision for the Vivity lens, she added.
PIVOTAL TRIAL PERFORMANCE The pivotal trial randomised 221 cataract patients to bilateral implantation with the Vivity IOL or the AcrySof IQ monofocal IOL. Refractive predictability was good in both study groups. Among first implanted eyes, the rate of achieved MRSE ≤0.5D of emmetropia was 91.6% for the Vivity IOL and 86.5% for the aspheric monofocal IOL. The study met its key endpoints chosen to demonstrate the Vivity IOL fulfilled American National Standards Institute criteria for EDOF IOLs. In testing conducted six months postoperatively, the Vivity IOL demonstrated a greater range of monocular defocus compared to the aspheric monofocal IOL. In addition, the Vivity IOL was statistically superior to the control lens in mean photopic monocular distance-corrected intermediate visual acuity (DCIVA) and non-inferior for best-corrected distance vision. Additional analyses showed that 72.9% of first eyes implanted with the Vivity IOL vs 25.2% of first eyes receiving the aspheric EUROTIMES | OCTOBER 2021
monofocal IOL achieved monocular DCIVA of 0.2 logMAR or better. Mean photopic monocular distance corrected near visual acuity measured at 40 cm was also statistically superior in eyes implanted with the Vivity IOL compared to the control group. Patient experiences with visual disturbances were collected using the validated Questionnaire for Visual Disturbances (QUVID). At six months, no patients reported severe glare and only 0.9% in both groups reported severe halos. The severe starburst rates were 3.8% for the Vivity IOL and 2.7% for the monocular lens.
“Now, patients who I would consider borderline candidates for a diffractive presbyopia-correcting IOL can be given the opportunity to experience a range of vision independent of glasses.” “Most patients in both groups indicated being ‘not bothered at all’ by haloes, starbursts, or glare, and there were no statistically significant differences between groups for these outcomes,” Dr McCabe said. Responding to a question about contrast sensitivity results, Dr McCabe said data from monocular testing in the pivotal study showed the Vivity IOL associated with a meaningful decrease in contrast sensitivity compared with the monofocal IOL at only a single spatial frequency. “It is hard to know what this difference means clinically, but as a surrogate measure for understanding the relevance, the percentages of patients who reported not experiencing or being bothered by blurred or hazy vision were the same or higher in the Vivity group compared to the control,” she explained. “In addition, patients in the Vivity group reported having ‘good’ or ‘very good’ vision in both bright and dim light at the same rate or at a higher frequency than the patients implanted with the monofocal lens. “These data correspond with the experience of my patients implanted with the Vivity lens who report being happy with their quality of vision and not bothered at all by blur, haze, or visual disturbances.”
Cathleen McCabe MD is the Medical Director, The Eye Associates, Bradenton, Florida, USA email@example.com
CATARACT & REFRACTIVE
Seeking the Solution for Accommodating IOL Success New IOL harnesses ciliary muscle movement. Cheryl Guttman Krader reports from ASCRS in Las Vegas, USA
novel accommodating IOL (AIOL, Opira, ForSight VISION6) proved safe and stable, providing continuous “monofocal quality” vision across the functional near range in a recent clinical study, according to Ayman Naseri MD. Dr Naseri presented data from a study of 29 patients who were followed for two years after bilateral cataract surgery with implantation of a monofocal IOL in one eye and the Opira AIOL in the fellow eye. The surgeries were performed without any attempt to correct astigmatism. For distance correction, mean Snellen intermediate and near visual acuity in the Opira AIOL eyes was approximately 20/20 and 20/25, respectively. This was superior to the outcomes in the monofocal IOL eyes. Consistent with the visual acuity results, the monocular defocus curve from testing performed at two years showed the Opira AIOL had an extended range of focus across a large dioptric range, Dr Naseri said. He also shared the first data report from the follow-up of up to two years for nine patients who had bilateral Opira AIOL implantation. He noted refractive outcome accuracy improved in this cohort because the surgeries occurred after refining the AIOL’s A-constant. Without correction, mean binocular visual acuity at two years was better than 20/20 at distance, 20/20 at intermediate, and approximately 20/25 at near. The distancecorrected outcomes were even better, and data demonstrating achieved objective accommodation will be presented in the future, he said. To highlight the performance of the Opira AIOL and show it addresses the functional limitations of existing presbyopia-correcting IOLs, Dr Naseri presented a graph showing the binocular defocus curves of the Opira AIOL and several commercially available multifocal presbyopia-correcting IOLs. “The defocus curve for the Opira AIOL is based on just nine patients, but in many ways, our lens is demonstrating exactly what we are looking for in the holy grail search for an accommodating IOL—true accommodation throughout a range of visual function. We are very excited about continuing its development.”
DESIGN RATIONALE Dr Naseri proposed dependence on the capsular bag to mediate accommodative effort has been a limiting factor hampering successful AIOL development. He explained that interpatient variability in capsular bag elasticity and volume—combined with fibrosisinduced capsular bag changes that occur over time—creates an unpredictable environment leading to unpredictable outcomes. “We believe the right approach is to directly harness ciliary muscle movement to drive shape change in an accommodating IOL,” Dr Naseri explained. The Opira AIOL is a ciliary muscle-driven, capsule-fixated, dynamic shape-changing device. Its accommodative mechanism
is based on direct ciliary body engagement without zonular support or capsular bag intermediaries. Made of silicone, the Opira AIOL is injected through a clear corneal incision and haptic-fixated within the capsulorhexis. It has a dynamic anterior surface and a static posterior lens available for toric correction and postoperative adjustment. “The Opira accommodating IOL spans from ciliary muscle to ciliary muscle, and when the ciliary muscle moves in a centripetal fashion with accommodative effort, the Opira AIOL changes shape on its anterior surface, similar to what happens in the young phakic eye,” Dr Naseri explained.
ADDITIONAL DETAILS The current iteration of the Opira AIOL requires insertion through a 3.9 mm incision, but the company is targeting to reduce the minimum incision size to 3.0 mm. The lens is being made to fit eyes with varying dimensions, and lens size is chosen based on preoperative measurements taken with ultrasound biomicroscopy. Proper sizing is important for the performance of the Opira AIOL, Dr Naseri emphasised. Proper sizing of the capsulorhexis is also important regarding IOL implantation. So far, surgeons have achieved successful outcomes using either a manual technique or femtosecond laser for the capsulorhexis. “It may be an issue if the capsulorhexis size is radically off target, but we think capsulorhexis creation will be relatively straightforward,” Dr Naseri said. Asked about the potential for uveitis-glaucoma-hyphaema syndrome with the accommodating IOL, Dr Nasir acknowledged this complication is a potential concern with any lens that sits in between the iris and the anterior capsule. Unlike sulcus-based lenses that are positionally fixated and stabilised by ciliary/sulcus structures, the Opira AIOL is capsule-fixated, which mitigates the risk of IOL movement and tissue erosion. Its safety profile is excellent for the patients with two years of follow-up, but additional data from longer follow-up in more patients are needed to fully answer the question, and he suggested specific lens design features should mitigate the risk. “I think many clinicians would agree the sulcus is a pretty safe place to put a lens that doesn’t move and has no sharp edges. The Opira AIOL has a very smooth surface, and it is very stable in the eye,” Dr Naseri said. He reported posterior capsule opacification is common because the Opira AIOL does not have much peripheral intracapsular hardware. Many patients have undergone Nd:YAG capsulotomy without any adverse effect on their functional results. Ayman Naseri MD is president and chief medical officer of ForeSight VISION6; Professor of Ophthalmology, University of California, San Francisco, USA firstname.lastname@example.org EUROTIMES | OCTOBER 2021
CATARACT & REFRACTIVE
Preparing for Presbyopia Pharmacotherapy Expectations are for a near-term approval, more options to follow, and marked market demand. Cheryl Guttman Krader reports from ASCRS in Las Vegas, USA
harmaceutical treatment for presbyopia is on the horizon, and ophthalmologists can anticipate significant patient interest in this topical therapy that offers a solution for those who want to be rid of reading glasses. “Topical drops for treating presbyopia are a whole new class of therapeutics that will explode over the next few years. Ophthalmologists need to embrace these medications, which look very promising in clinical trials,” said Eric D Donnenfeld MD.
PHARMACEUTICAL APPROACHES Dr Donnenfeld divided the developing medications for treating presbyopia into three categories: miotic-based drops that contain pilocarpine, carbachol, or aceclidine as their active ingredient; combination therapies that include a miotic; and lens restoration drops. The miotic-based drops increase the depth of focus by reducing pupil size. According to criteria set by the US Food and Drug Administration, gaining market approval will require that these medications demonstrate efficacy for improving near vision by at least three lines without causing any distance vision loss. “Placing a pinhole at the iris expands the depth of field without impairing the peripheral field, but it can also make the eye more myopic,” Dr Donnenfeld explained. Among the miotic-based medications in the clinical trial pipeline, AGN-190584 (Allergan) may be the first to market as its New Drug Application is currently under FDA review. AGN-190584, which contains pilocarpine 1.25%, was investigated in two phase-three studies where it was dosed once daily in both eyes for 30 days. The study results showed the treatment was associated with statistically significant gains in distance-corrected near visual acuity of at least three lines in mesopic conditions without loss of five letters or more in corrected distance visual acuity. CSF-1 (PresbiDrops, Orasis) is another pilocarpine-based product, but it contains a lower concentration of pilocarpine, 0.4%, and has an oil-based, preservative-free vehicle formulation. Phase two study results comparing CSF-1 with a vehicle showed promising efficacy, safety, and tolerability, and two phase three trials investigating CSF-1 are underway. MicroLine (Eyenovia), which has also advanced into phase three studies, contains pilocarpine 1% or 2% delivered via a spray jet system (Optejet). “This proprietary drug delivery system evenly disperses a microdose of 7 μL onto the cornea, and its effect has been reported to last three to four hours,” Dr Donnenfeld said. Lenz Therapeutics is developing an aceclidine-based drop. In a clinical trial, the medication was associated with maintaining an average pupil size of 2 mm for up to seven hours. The combination therapy category includes brimochol (Visus), a fixed combination of carbachol and brimonidine. Carbachol is a longer-acting miotic than pilocarpine, and brimonidine has multiple actions able to enhance efficacy and safety. EUROTIMES | OCTOBER 2021
“Brimonidine prevents pupillary dilation, inhibits ciliary body contraction, and whitens the eyes to prevent ocular redness induced by the miotic. In addition, by reducing aqueous production, brimonidine decreases carbachol turnover and increases its bioavailability,” Dr Donnenfeld explained. “Phase two trials are about to begin.” Ocuphire is developing another combination approach using phentolamine (Nyxol) and pilocarpine 0.4%, but the two medications are dosed separately. Phentolamine, an α-1/2 antagonist, is given at night, and pilocarpine in the morning. “In an initial study, the combination approach showed almost 24 hours of effectivity,” Dr Donnenfeld said. The lens restoring drop, known as UNR844 (lipoic acid choline ester, Novartis), acts to increase the flexibility of the crystalline lens by oxidizing disulfide bonds. A phase two dose-ranging study of UNR844 is underway.
DEFINING THE PATIENT POOL As an issue estimated to affect more than 2 billion people worldwide, including 123 million Americans, and with consequences that affect quality of life in multiple ways beyond cosmesis, presbyopia is a big problem, Dr Donnenfeld said. “Glasses, contact lenses, and surgical solutions for presbyopia have important drawbacks. Miotic presbyopia drops are safe, effective, and reversible, which is want patients want,” he said. Dr Donnenfeld described several groups of “best candidates” for miotic drops. They include emmetropes who are likely uncomfortable with vision correction surgery, hyperopes who will benefit from improvement in near and distance vision, and post-LASIK emmetropes who have already made a significant investment to achieve glasses-free vision. “Pupil-constricting drops may also help to address high-order aberrations and glare and halo for post-LASIK patients with those issues,” Dr Donnenfeld said. Pseudophakic patients are another set of candidates. Patients with a monofocal IOL could use presbyopia drops instead of readers. The drops could also be of interest to patients with presbyopia-correcting IOL who want more near vision than their implant provides. Contraindications for miotic drop use include high myopia and a history of retinal tears. Anticipating high demand for the presbyopia drops, Dr Donnenfeld said, “The volume of patients coming in will stress our offices. Ophthalmology needs to work together with optometry to offer these medications.” Eric D Donnenfeld MD is a Clinical Professor of Ophthalmology, New York University Medicine, New York, USA. He is a founding partner of Ophthalmic Consultants of Long Island, New York. He is past president of the ASCRS. email@example.com
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Modular IOLs Enter Clinic
Versatile systems offer opportunities for achieving refractive outcomes and more. Cheryl Guttman Krader reports from ASCRS in Las Vegas, USA
odular IOLs that allow for postoperative adjustments could offer many advantages to the cataract surgeon and their patients according to Sumit Garg MD. Dr Garg first presented data on the rate of IOL exchange after cataract surgery among Medicare beneficiaries in the United States. He reported that in 2019, there were approximately 12,300 claims for IOL exchange procedures out of a total of more than 3.5 million cataract surgeries, translating into an IOL exchange rate of 0.35%. “However, surgeons who do complex cataract surgery or refractive procedures using light splitting IOLs would probably like to do an IOL exchange procedure in more than 0.35% of cases. Yet, we do not do the exchange for a variety of reasons, with risk being one,” he said. “Perhaps we would do exchange more often if we could mitigate risk. Modular IOLs address that issue by preserving the benefits of small-incision cataract surgery and making the exchange procedure easier, safer, and more predictable.” He continued by explaining that modularity also enables future IOL upgrades. Some systems could serve as a platform for drug delivery and biometric sensing technologies. In addition, certain modular designs promote the stability of the IOL in the capsule by maintaining the physiologic integrity of the capsule and reducing fibrosis and posterior capsule opacification.
OPTION OVERVIEW Dr Garg reviewed four modular IOL systems that are either commercially available (Harmoni® Modular IOL [Clarvista/ Alcon]) or in development (Gemini Refractive Capsule™ [Omega Ophthalmics], Atia Vision modular presbyopia-correcting IOL [Shifamed], and Juvene™ [LensGen]). The Harmoni Modular IOL, which has the CE mark, is a two-component hydrophobic acrylic IOL consisting of a 6.5 mm base element and a 6.0 mm exchangeable optic that fits within the base and attaches with peripheral anchoring features. The device is implantable through a 2.2 to 2.4 mm-clear cornea incision with the two parts assembled in the capsular bag. Once inside the eye, the front optic can be rotated to adjust the toric axis if needed. It can also be replaced to change the refraction or add or remove multifocality. The Gemini Refractive Capsule fills the capsular bag and acts as a scaffold, keeping the bag open and able to receive an IOL, biometric sensor, or a drug delivery system. Study data from one month of follow-up support the biocompatibility of the system and its stability, Dr Garg said.
“The assessments indicated the actual lens position was predictable and revealed no issues with capsular fibrosis or PCO. The device, which is small enough to fit through any standard-size cataract incision, appeared to be large enough to maintain capsular volume,” he reported. The Atia Vision modular presbyopia-correcting IOL has a shape-changing, accommodating engine base and an exchangeable front optic to provide refractive predictability and allow for future upgrades as technology develops. The base has a hydraulic multiplier design said to mimic the natural dynamic accommodation mechanism of the eye. By maintaining direct contact with the open capsular bag, the base enables efficient transfer of force from the ciliary muscle to the optic. Discussing the Juvene lens, Dr Garg noted its implantation in more than 120 eyes. The Juvene has a modular base with a fixed optic and an accommodating fluid lens that tabs into the base lens. By filling the capsular bag, the design aims to minimise some of the compromises with traditional IOLs that underlie refractive errors, Dr Garg said. “The Juvene reduces shift in effective lens position, rotational shift, PCO development, and vitreoretinal tension that can also affect lens stability. Although we can have the best biometry and power calculation formulas, we do not know what will happen when the IOL is in the eye. With greater IOL stability in the eye, we might have a better chance of being even better with our IOL power calculations.” An analysis of data from 51 eyes implanted with the Juvene lens showed good refractive stability during follow-up at 12 months with a mean change in MRSE of -0.01D between one and 12 months. Patients who followed up to three months also showed good rotational stability, in which the average rotation from the intraoperative axis was 1.7 degrees. Both toric and non-toric base lens modules for the Juvene IOL are in development. The company may pursue the development of monofocal and monofocal toric lenses for the front optic, as well as opportunities for drug delivery and biometric sensor devices. Sumit Garg MD is Professor of Ophthalmology, Gavin Herbert Eye Institute, University of California, Irvine, USA. He is a scientific advisor for LensGen. Contact him firstname.lastname@example.org EUROTIMES | OCTOBER 2021
CATARACT & REFRACTIVE
More data from new devices and IOL power formulae improve refractive outcomes. Howard Larkin reports from ASCRS in Las Vegas, USA
efore 2000, the ZEISS IOLMaster and Haag-Streit Lenstar revolutionised cataract surgery by introducing laser interferometry technology for more accurately measuring ocular axial length. “It took a lot of the guesswork out of axial length measurement,” Robin R Vann MD told a session at Refractive Surgery Day. But the demands of today’s cataract refractive surgery require even more from biometry devices and IOL power formulae, he said. “We have to go beyond just axial length measures and look at other aspects of the eye to get good outcomes.” Over the past decade or so, that has meant incorporating tomography and topography into axial length measuring devices. Early examples include the Pentacam® AXL, NIDEK AL-Scan, and GALILEI G6. Hybrid designs incorporating a swept-source OCT engine—such as the ZEISS IOLMaster 700, Alcon Argos® Movu, Haag-Streit EyeStar 900, Heidelberg ANTERION, and Tomey OA-2000—are now available.
“We have to go beyond just axial length measures and look at other aspects of the eye to get good outcomes.” IMPROVE WORKFLOW
By combining a range of refractive cataract diagnostics into a single machine, these devices improve workflow, reducing the amount of clinic space and time it takes to work with patients, Dr Vann observed. “The patient doesn’t have to move from machine to machine,” he noted. Tomography and/or topography can help visualise the posterior cornea, measure higher-order aberrations, and assess corneal shape changes—all critical to successfully implanting modern presbyopia-correcting and toric lenses. Incorporation of swept-source OCT has been a crucial step forward, he emphasised, “We’ve seen from the retinal world how it can revolutionise the fidelity and resolution of some of the captures in the retinal field. So too, it can do this for us in cataract surgery planning.” Advantages of swept-source OCT over laser interferometry include longer wavelengths for greater penetration, making it possible for devices such as the ZEISS IOLMaster 700 to image through 97% of mature cataracts and 98% of advanced cataracts, Dr Vann said. Faster engines enable the capture of 2,000 to 3,000 scans per second, enabling better imaging—advantages observed in recent comparative studies. EUROTIMES | OCTOBER 2021
Swept-source OCT devices allow for visualisation of the anterior segment and the macula in the same scan, Dr Vann noted. Individual devices offer features such as segmental axial length, pachymetry, and anterior and posterior corneal topography. Software packages such as the Alcon SMART Suite and ZEISS FORUM/CALLISTO are beginning to integrate these rich data sets with surgical microscopes and other intraoperative devices to support better-informed decisions before and during surgery.
IOL FORMULAE Just as important as better biometry is IOL power formulae capable of transforming the extra data into better lens choices. In the late 1990s, Jack Holladay MD identified nine categories of eyes based on axial length and anterior segment size, Dr Vann said. These different eyes, ranging from nanophthalmia to large eyes with axial myopia, and different formulae may be better for different eye types. Traditional formulae only captured differences in the anterior segment portion of axial length, so new formulae were developed to better model effective lens position based on other variables, Dr Vann noted. Newer IOL formulae fall into three categories: vergence/ray tracing, AI formulae, and hybrids. The Holladay II and Barrett Universal vergence and Olsen C ray tracing fall under vergence/ray tracing, Hill RBF AI and PEARL-DGS under AI formulae, and LADAS Superformula and the Kane formula under hybrids. “Many of these have come out in the last four to five years, and there is not a lot of data to look at the success rates.” That said, studies since 2015 have consistently shown the Barrett Universal as one of the best performing formulae, Dr Vann said. The Kane formula has shown good performance in the last two years, with one review of 958 articles finding it has the best performance across all axial lengths. (Kane J et al. doi: 10.1016/j. ophtha.2020.08.010). Another 2020 study found the Kane was best for eyes with axial lengths under 22 mm (Wendelstein J et al. doi: 10.1136/bjophthalmol-2020-318272) and eyes over 30 mm (Cheng H et al. Am J Opthalmol. 2021; 223: 100–107). Given the lack of articles on newer formulae outcomes, Dr Vann advised surgeons look to meetings and new publications to validate accuracy. Newer generation formulae are improving accuracy on extreme axial lengths, with the Barrett Universal II still excellent for eyes over 22 mm, and the Kane excellent at all lengths, he said. New formulae are constantly being released, such as the Hill RBF III, which has more data for smaller and larger eyes that should improve its accuracy. But good biometry is critical, Dr Vann said. “Please, please keep in mind that formulas are only as good as the data captured.” He recommended surgeons review their own outcomes to determine the best method to proceed. Robin Vann MD is an associate professor of ophthalmology at Duke University School of Medicine, Durham, North Carolina, USA, and can be reached at email@example.com.
CATARACT & REFRACTIVE
Adjusting IOL Power in the Eye Femtosecond laser technology moves toward human trials. Howard Larkin reports from ASCRS in Las Vegas, USA
OS 4TM THE NEXT GENERATION
femtosecond laser treatment capable of altering the power and other optical characteristics of commercial intraocular lenses after implantation is on the brink of human trials, reports Liliana Werner MD, PhD. The investigational treatment uses laser refractive index shaping to alter the IOL refraction in the eye. The femtosecond laser uses green light at 520 nm and operates at energy levels below the threshold for ablation or cuts. It induces a chemical reaction in the targeted area of the IOL optic material that locally increases hydrophilicity, which decreases the refractive index. An inscribed phase wrapping pattern creates a thin lens of different refractive power within the IOL, Dr Werner explained. This process can produce changes such as increasing or decreasing sphere power and adding, subtracting, or cancelling cylinder, asphericity, or multifocality.
The new OS 4 marks the beginning of the next generation of retina, glaucoma and cataract surgery. The all-in-one platform has received numerous exciting features that provide even more comfort, precision and safety.
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Liliana Werner MD, PhD, is a professor of ophthalmology and visual sciences at the Moran Eye Center, University of Utah, Salt Lake City, USA, reached at firstname.lastname@example.org
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Extensive safety studies show the laser treatment does not create any toxic substances or leaching from the lens, does not promote glistenings or other lens defects, and maintains stable refractive changes over time that are unaffected by YAG capsulotomy. The process does decrease light transmission slightly, from 83.2±1.4% before adjustment to 81.8±1.8% afterward (as observed in an in vitro study with a specific commercially available IOL), and increases backlight scatter, but at levels not thought to be clinically significant, Dr Werner said. Modulation transfer function curves are virtually unaffected by the adjustment of -2.0D on the same IOL. In a short-term in vivo rabbit study, commercially available monofocal hydrophobic IOLs were implanted in both eyes of six New Zealand rabbits and adjusted using the laser to target adding 3.6 dioptres sphere, a treatment that took 23 seconds. The only side effect was gas bubbles behind the lens that disappeared within a few hours. There were no inflammatory reactions or damage to the IOLs observed. Four weeks after implantation, clinical outcomes were similar between treated and untreated controls implanted with the same IOLs. Refractive outcomes for treated lenses were close to target with a mean of +3.7±0.03D, Dr Werner reported. A sixmonth study involving seven rabbits also found no significant differences between treated and untreated animals. The laser also can be used to customise the lens before implantation, allowing more changes than can be made in vivo, Dr Werner said. “The advantage is the laser can turn a monofocal IOL into a custom multifocal IOL in an affordable manner.” It eliminates the need for highly trained technicians and large capital and inventory investments to manufacture premium lenses, she added. Trials were set to begin last year in Panama were postponed due to COVID-19, but should resume soon.
EYE SURGERY. SWISS MADE.
EUROTIMES | OCTOBER 2021 Anzeige_OS4-The next generation_93x266mm_print_ESCRS.indd 1
A New Era for CXL Changing mindsets on treatment timing and technique expected to improve outcomes for keratoconus patients. Cheryl Guttman Krader reports from ASCRS Cornea Day 2021, Las Vegas, USA
he first published paper describing corneal crosslinking (CXL) as an effective treatment for progressive keratoconus appeared in 2003. The procedure has been commercially available in Europe for more than a decade and five years in the United States. Now, Parag A Majmudar MD says, the time has come for two major paradigm shifts in the use of CXL for keratoconus. “We should be thinking about treating keratoconus at the earliest possible stage. I don’t think there is any other way to tackle the problem. And while we are challenging this status quo, the second paradigm shift will be to adopt the epi-on approach. In 10 years, I foresee we will not be doing epi-off CXL,” Dr Majmudar reported.
EPI-ON VS EPI-OFF Dr Majmudar observed the controversy over which is the better technique for CXL, epi-on or epi-off, has been raging for years. Proponents of epi-off CXL argue it is the more effective of the two, but Dr Majmudar contended that conclusion is debatable considering recent data for the epi-on procedure. “What is not debatable is the epi-on technique is better for the patient and the surgeon because it reduces the risk of infection and scarring and is associated with faster recovery, allowing patients an earlier return to normal life,” he added. Dr Majmudar proposed that even if one accepts the idea that epi-off CXL is 100% effective and the epi-on technique is only 80% effective, the difference between treatments is likely inconsequential if the paradigm shifts to very early keratoconus treatment. “With aggressive screening done by primary eye care providers, we can be catching keratoconus when it is just beginning. And with early diagnosis, we can treat keratoconus when the cone is minimal,” he said. “Then, even if epi-on is a slightly weaker procedure, it will probably have enough effect to provide adequate stability and maintain the good vision present with early keratoconus.”
IMPROVING EPI-ON OUTCOMES WITH NEW TECHNIQUES Research in recent years has revealed that one key to achieving better efficacy with epi-on CXL is to ensure adequate oxygen in the cornea. Thus, a treatment protocol was designed for the commercially available iLink system (Glaukos) that uses supplemental oxygen. Recently reported results from a phase three randomised, placebo-controlled clinical trial investigating this approach showed the study met its primary endpoint comparing treatment groups for change from baseline to six months in maximum corneal curvature (Kmax). EUROTIMES | OCTOBER 2021
Dr Majmudar told attendees of his experience performing epi-on CXL with the investigational EpiSmart system (CXL Ophthalmics). It improves oxygen availability in the cornea through pulsed delivery of the UVA light, which, compared to continuous irradiation, allows time for oxygen to replenish in the corneal stroma. As another feature, the proprietary riboflavin formulation used in the procedure contains sodium iodide that results in oxygen formation, which may enhance the effectiveness of the cross-linking procedure. Phase three studies to support registration of the epi-on EpiSmart system in the United States are in progress. A 2018 paper observed two years of follow-up for 512 eyes treated for keratoconus, forme fruste keratoconus, or post-LASIK ectasia. The published results reported the EpiSmart procedure was associated with significant improvements in mean Kmax, total higher order aberrations, and coma (Stulting RD, et al, J Cataract Refract Surg. 2019; 44 (11): 1363–1370). “Kmax decreased more than 1D in three times as many eyes as it increased more than 1D, and that difference was highly statistically significant. Furthermore, no eyes treated with the epi-on system progressed in two years, and there was no loss of effect comparing results from evaluations at one and two years.”
MORE CHANGES COMING Dr Majmudar proposed that in the future, CXL may be performed using drops alone without UVA light. IVMED-80™ (iVeena Delivery Systems), a topical drop that induces CXL by enhancing lysyl oxidase activity in the cornea, is under investigation in clinical trials that have generated some promising early results. Accelerated CXL protocols that improve patient flow while possibly also reducing risk of haze and allowing faster visual rehabilitation may also be coming. Reflecting on the current and future developments, Dr Majmudar concluded his talk by stating that CXL is at the dawn of a new era. Addressing his audience of American ophthalmologists, Dr Majmudar noted many international colleagues are already moving towards implementing the new techniques. “I think we will start seeing significant improvements in our paediatric patients who will be uniformly screened earlier for keratoconus and treated at its earliest onset. The repercussions for these patients in terms of improved quality of life will be immense. So, let’s start thinking about changing how we think about keratoconus and CXL.” Parag A Majmudar MD is Associate Professor of Ophthalmology, Rush University, Chicago, Illinois, USA email@example.com
Viewing Cosmetic Eye Colour Change with a Different Lens
Dermot McGrath reports from the French Implant and Refractive Surgery Association (SAFIR) Annual Meeting
lthough several techniques exist to permanently change eye colour, not all of them offer the same safety profile. Patients need to be made aware of the serious risks to their ocular health involved in some of the procedures currently being offered, warns Marc Muraine MD. “There is a growing demand for procedures of this kind and a lot of media coverage about them. So while our natural reaction might be to simply say ‘no’ to all forms of cosmetic surgery, I believe it merits a response from the scientific community to inform our patients [objectively] and avoid some of the more dangerous options being promoted,” he said. Dr Muraine identified four principal techniques to change eye colour: artificial iris implants, laser photocoagulation of the iris, corneal tattooing, and cosmetic contact lenses. Although not approved in the European Union or the United States, artificial iris implants are widely advertised and promoted on the internet and are sometimes offered as part of package holiday deals, Dr Muraine said. He recounted the experience of one patient who went to Tunisia and received the BrightOcular® (Stellar Devices) artificial iris. “It was pretty tragic but shows the risk with these implants— the patient was operated subsequently for bilateral corneal decompensation, which required a double transplant,” he said. The case was not an isolated incident, Dr Muraine pointed out, citing a recent study by Corinne Dot MD et al, which reported that of 65 eyes of 33 patients who received artificial iris implants, only five eyes (7.7%) did not experience complications (JCRS, 46; 34–39). More than 92% of patients experienced at least one complication, with corneal decompensation in 78.5% of patients, glaucoma in 52.3%, and explantation in 81.5%. “These implants are clearly best avoided—the only merit they have is they are reversible if we manage to take them out in time,” he said. Techniques that use Nd:YAG laser photocoagulation to depigment the stromal iris are the most recent to effect permanent eye colour change, Dr Muraine said. He cited a recent prospective study by Pedro Ruiz MD in Barcelona, Spain, which included a series of 1,176 eyes that underwent photoablative cosmetic iridoplasty with up to nine years of follow up (Int Ophthalmol. 41, 1381–1393 ). “The procedure was shown to be safe and effective with no impact on intraocular pressure and a high level of patient satisfaction. The only notable complication was delayed and brief iritis, which was self-limited with routine topical treatment. Because the procedure depigments the iris, it is only possible to change the colour from dark to lighter shades, which might be a limitation for some patients,” Dr Muraine said.
Key advantages of the Nd:YAG laser procedure are that it does not involve any masking of the iris, and the pupil remains reactive. “It could potentially be offered to patients, but only under close medical surveillance and with appropriate preoperative psychological counselling, as the procedure is irreversible,” he added. A better-known technique in France is the use of corneal tattooing or keratopigmentation, Dr Muraine said, who has himself successfully used it for therapeutic reconstruction of iris defects. Surgeons such as Francis Ferrari MD in Strasbourg and Jorge Alio MD, PhD in Alicante, Spain, have recently used femtosecond lasers to create a lamellar tunnel and inject biomedical pigments using a 27-gauge cannula to effect eye-colour change.
“These implants are clearly best avoided—the only merit they have is they are reversible if we manage to take them out in time.” “Dr Alio published a study of the technique in seven patients and reported no complications and a high level of patient satisfaction with up to six months of follow up,” Dr Muraine explained. Although the evidence to date seems encouraging, Dr Muraine said further study was needed, and additional long-term complications could not be ruled out. “One potential problem with this technique is that the iridocorneal angle will be more difficult to analyse in the event of suspected glaucoma, or if there is a cataract to be operated, or another pathology of the anterior segment is present. The procedure is also not easily reversible, so the same rules apply in terms of psychological counselling for the patient before surgery,” he said. In terms of cosmetic contact lenses, Dr Muraine said they have a very poor track record in scientific literature. He cited a prospective multicentre study at 12 French university hospitals by Arnaud Sauer MD that found of 256 patients included for contact lens-related microbial keratitis, 32 (12.5%) were cosmetic lens wearers (Acta Ophthalmol. 2011 Aug; 89(5): e439–42). “The conclusion was that patients with cosmetic lenses are less likely to be instructed on appropriate lens use and basic hygiene rules. Consequently, they tend to experience more acute vision-threatening infection, with six times greater risk of infection,” he said. Marc Muraine MD is Professor and Head of the Ophthalmology Department, Charles Nicolle Hospital, Rouen, France firstname.lastname@example.org EUROTIMES | OCTOBER 2021
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Meditation and Glaucoma Roibeárd Ó hÉineacháin reports from the 9th World Glaucoma E-Congress
reathing exercises based on yogic principles can reduce IOP and improve perfusion of the optic disc in patients with primary open-angle glaucoma (POAG), according to a study presented by Brajesh Lahri MD. “Mindfulness-based meditation can be used as an adjunct therapy in the management of primary open-angle glaucoma,” Dr Lahri said. The study involved 60 early to moderate POAG patients with mean age of 51.7 years. All had an IOP of 21mmHg or less on one or two glaucoma medications. None of the patients had ocular comorbidities, and none already practised yoga, meditation, or aerobics in any form, he noted. Dr Lahri and his associates randomised the patients into two equal groups. All the baseline parameters were comparable in both groups. One group practised 45 minutes of mindfulness-based stress reduction (MBSR) breathing exercises under the guidance of a trained yoga teacher. The other group served as controls. Both groups continued their routine glaucoma medications. “The MBSR technique mainly involves taking long and deep breaths and focusing attention on the natural, relaxed flow of air going in and out of the body. The exhalation should last longer than inhalation with a pause between each breath,” Dr Lahri explained.
IOP DECREASED, OPTIC DISC PERFUSION INCREASED
At the six-week follow-up, patients in the MBSR group had a statistically significant reduction in IOP, from a baseline value of 18.46mmHg to 15.34mmHg. They also had improvements in all of the optic head perfusion parameters measured with OCT angiography. The improvements included an increase in circumpapillary vessel density from 15.8% to 17.4% in the superior quadrant and 14.2% to 16.5%, in the nasal quadrant. Furthermore , the patients’ circumpapillary vascular perfusion increased from 38.9% to 41.1% in the superior quadrant, 42.2% to 44.5% in the inferior quadrant, 40.1% to 43.8% in the temporal quadrant, and 40.6% to 42.8% in the nasal quadrant. All of these changes were statistically significant. There was a statistically significant increase in flux index (0.38 to 0.40). In contrast, the control group had no statistically significant change in IOP—which was 18.1mmHg at baseline and 17.65mmHg at six weeks. The control group also did not have significant changes in IOP circumpapillary vessel density and circumpapillary vascular perfusion. Dr Lahri suggested MBSR may reduce IOP by a parasympathetic-driven relaxation response, an upregulation of nitric oxide production, a reduction of serum cortisol levels, and an increase in serum melatonin levels. It’s the first study documenting an increase in the Optic Nerve Head Perfusion following a short course of MBSR. He added MBSR may increase optic disc perfusion through a reversal of autonomic dysfunction, an increase in parasympathetic activity, and increased nitric oxide levels in the aqueous and plasma. Brajesh Lahri MD practices at Dr RP Centre for Ophthalmic Sciences, All India Institute of Medica Sciences, New Delhi, India and can be contacted at email@example.com EUROTIMES | OCTOBER 2021
ESCRS Pioneer Awards • Support, encourage, and fund individuals interested to start clinical research activities in the field of cataract and refractive surgery • Introduce and develop a body of clinical research work, addressing a challenging “problem” in order to devise a practical “solution” • Facilitate and support an independent culture of study for the ultimate benefit of patients
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The Vulnerable Balance Between Glaucoma and CSFP
Pressure imbalance on lamina cribrosa lies at the heart of glaucomatous optic neuropathy. Roibeárd Ó hÉineacháin reports from the 9th World Glaucoma E-Congress
he difference in pressure exerted on the lamina cribrosa by IOP and cerebrospinal fluid pressure (CSFP) could be a potential additional key to the vulnerability of the optic nerve in glaucomatous optic neuropathy may be, according to Prof Jost Jonas MD, FARVO. The optic neuropathy that characterises glaucoma is unlikely to be primarily vascular because glaucomatous optic neuropathies share many features absent in vascular optic neuropathies. Such features include neuroretinal rim loss and optic cup deepening. Both high and normal pressure glaucoma show parapapillary beta zone atrophy. A loss of equilibrium between the IOP, the CSFP, and blood pressure may more likely be at fault. “The CSFP is the counterpressure against IOP. The theory could be that glaucoma patients with normal IOP have a low orbital CSFP leading to an increased translaminar cribrosa pressure difference,” Dr Jonas said. There are several peer-reviewed studies in the published literature showing lower CSFP and a higher translaminar-cribrosa pressure (TLCP) difference (the difference between IOP and CSFP) in glaucoma patients compared with controls. For example, in a retrospective study, mean CSFP was significantly lower in 28 open-angle glaucoma patients than in a control group of 49 non-glaucomatous patients (Berdahl et al, Ophthalmology 2008;115:763¬–768). In addition, linear regression analysis showed that the cup-todisc ratio correlated independently with the intraocular pressure, CSFP, and TLCP difference.
In another study, lumbar CSFP was significantly lower in normal-pressure glaucoma patients than in the high-pressure glaucoma group or the control group. The TLCP difference was also significantly higher in the normal-IOP glaucoma group and the high-IOP glaucoma group than in the control group (Ren et al, Ophthalmology 2010;117:259–66). Glaucomatous optic nerve damage correlated with IOP, CSFP, and TLCP difference. However, in a multivariate analysis, visual field loss only had a significant association with the TLCP difference and had no significant association with IOP or CSFP. In the control group, CSFP significantly correlated with both systolic blood pressure and IOP. The TLCP difference was not significantly associated with blood pressure. Higher CSFP also correlated with younger age and body mass index. Using the data from the controls, Dr Jonas created a formula for deriving CSFP from BMI and diastolic blood pressure and then subtracting the result from IOP as the TLCP difference. When they applied the formula to the populations of the Beijing Eye Study and the Central India and Medical Study, they found open-angle glaucoma, but not angle-closure glaucoma, was significantly associated with a higher TLCP difference but not with IOP in both studies. Jost B Jonas MD is a comprehensive ophthalmologist, clinical scientist, and Chairman of the Department of Ophthalmology of the Medical Faculty Mannheim of Heidelberg University. Jost.Jonas@medma.uni-heidelberg.de
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EUROTIMES | OCTOBER 2021
Preventing Glaucoma Blindness We can do it, so why don’t we? Howard Larkin reports from ASCRS in Las Vegas, USA
arly detection and going beyond IOP lowering will be the keys to reducing progression rates to blindness in glaucoma, which have been stubbornly steady for 20 years, Richard A Lewis MD said during his Binkhorst Medal Lecture. Hippocrates was the first to describe glaucoma in 375 BC—and for more than 2,000 years, if someone received that diagnosis, they went blind, Dr Lewis said. It wasn’t until the mid to late 19th century that the first effective treatments, such as iridectomy and pilocarpine, were invented. It was another century before several types of glaucoma and causes were defined and more effective treatments, including medications to lower IOP and surgical trabeculectomies and tubes, finally reduced the probability of going blind—from 25.8% in the 15 years before 1980 to 13.1% in the 15 years after, he observed. But the rate of progression to blindness remains about 13% to this day. “Which is a lot higher than other ocular diseases. It’s a bit frustrating that we’re having a tough time breaking that barrier,” Dr Lewis noted.
MEDICINES, LASERS, AND MIGS So, what’s happened over the last 20 years? There’s been a lot of seeming progress. More than $130 million in funding from the US National Eye Institute has helped identify risk factors for early diagnosis, including corneal thickness, cupping, and elevated intraocular pressure (IOP), Dr Lewis said. And the introduction of prostaglandins and ROCK inhibitors have made it possible to meaningfully control IOP, though eye drop side effects remain challenging. Selective laser trabeculoplasty (SLT) has proven a cost-effective, medium-term IOP control technique. Even more exciting has been the advent of MIGS, including the iStent inject® (Glaukos), Hydrus® (Ivantis), and XEN® (Alcon) devices, Dr Lewis said. “But here we are in 2021, and we still have this high degree of blindness,” he observed.
WHY PATIENTS STILL GO BLIND Noting that the more advanced glaucoma is at diagnosis, the lower IOP must be to prevent further vision loss, Dr Lewis identified several factors that may be contributing to progression. First is underdiagnosis. “We don’t determine [when] their pressures are elevated; we don’t determine they have cupping until it is far advanced. They are coming in for presbyopia or cataracts and by then they have lost a fair amount of vision,” Dr Lewis said. Second is adherence with topical treatment. “They are either unable to take their medications or won’t get those medications renewed,” Dr Lewis said. Third is inadequate treatment. MIGs devices don’t lower IOP enough, and trabs and tubes have about a 50% failure rate at five years. “Invariably, they are back on medications and having multiple procedures,” Dr Lewis lamented.
WHAT CAN BE DONE Dr Lewis offered three ways to meet the currently unmet need to prevent visual loss in glaucoma. First is earlier detection of at-risk patients. Instead of relying on occasional pressure checks and visual field measurements, EUROTIMES | OCTOBER 2021
genetic tests may help identify high-risk patients. While this is challenging since glaucoma is multifactorial, a test is close to approval, Dr Lewis said. Technologies that enable home or even continuous IOP monitoring also are in development, which should improve diagnosis. Second is more effective IOP-lowering therapies, especially at night when eye drops can be ineffective, and much of the damage may occur. One option in development by John Berdahl MD and Equinox is a pair of goggles that lower pressure on the eyes during sleep, which have been shown to reduce IOP significantly. “You can literally dial in the IOP you want,” Dr Lewis said. New medications that target episcleral as well as conventional outflow might do a better job than current drugs of lowering IOP, he added. Interventional glaucoma is another approach in which sustained release and injectable delivery might help solve the compliance issue. Directly applying drugs to the trabecular meshwork, as does the DURYSTA® (Allergan) bimatoprost implant, the optic nerve, or other affected area also could improve efficacy, Dr Lewis added. “The current challenge is to find the appropriate medications.” Third is broadening treatment options beyond lowering IOP. Since glaucoma results from damage to the retinal ganglion cells, therapies that bypass IOP and directly affect this mechanism are promising, Dr Lewis said. Neuroprotective medications delivered earlier in the disease before major damage has occurred have potential. One delivered as an intravitreal injection is in clinical trials. High-dose vitamin B3 also has been shown to improve visual fields in about 24% of glaucoma patients, he stated. Genetic technology may also help restore vision eventually, Dr Lewis said. A mouse model has already shown results. “It’s on the horizon.” Richard Lewis MD pioneered minimally invasive glaucoma surgery (MIGS). He maintains a glaucoma practice in Sacramento, California, USA. Dr Lewis is a past president of both ASCRS and the American Glaucoma Society. firstname.lastname@example.org
Differentiating NTG vs POAG NTG and POAG belong to the same spectrum of progressive IOP-sensitive optic neuropathies. Roibeárd Ó hÉineacháin reports from the 9th World Glaucoma E-Congress
hile there are at present no sets of clinical parameters or risk factors for differentiating normaltension glaucoma (NTG) from primary open-angle glaucoma (POAG), advances in imaging technology and genetic analysis may provide a more clinically useful classification of glaucoma subtypes, according to Jeffrey Liebmann MD. “Normal-tension glaucoma and primary open-angle glaucoma are part of the same clinical spectrum of optic neuropathies, characterised by progressive structural and functional damage to the optic nerve with pressure-dependent and pressure-independent risk factors,” Dr Liebmann said. He noted the classical definition for NTG is open-angle glaucoma with an IOP of 21mmHg or below. However, IOP measurements can be unreliable due to factors such as variations in corneal thickness and hysteresis, as well as human and instrument error. Furthermore, tonometers only measure transcorneal pressure. True IOP can only be obtained via intracameral cannulation. “Goldmann tonometry is our reference standard, but not a ‘gold standard’ and certainly not ground truth. We all know that there is no perfect tonometer, and an inaccurate measurement cannot define different diseases,” Dr Liebmann said. Research has identified many IOP-independent risk factors for NTG and POAG, including age, myopia, and factors related to perfusion and retinal ganglion cell health. But no sets of risk factors yet identified are specific to either NTG or POAG, he noted.
Research has also revealed many subtypes of glaucomatous degeneration of the optic nerve, such as focal ischaemic, senile sclerotic, and myopic with generalised enlargement. But none are exclusive to either NTG or POAG. NTG is also indistinguishable from POAG by the appearance of the visual field. However, new imaging technologies may allow a finer distinction between different glaucoma subtypes. Clinicians can now examine the microvasculature of a patient’s retina and the optic nerve and intracellular organelles, such as the mitochondria. Research is also providing an improved understanding of tissue metabolism and oxygenation and the role that it plays in POAG’s pathophysiology. The greatest advances in glaucoma diagnostics may come from human genetics. Already, research conducted at centres around the world has identified links between different glaucoma subtypes and genetic variants. The discoveries include links between variants of the myocilin gene and juvenile glaucoma and between variants in the optineurin gene and some types of NTG. Research has also identified many other genes and groups of genes associated with POAG. Jeffrey Liebmann MD is Professor of Ophthalmology, Glaucoma Service Director, and Vice Chair for the Department of Ophthalmology at Columbia University Medical Center, New York, USA email@example.com
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EUROTIMES | OCTOBER 2021
New Testing Paradigms Glaucoma neuroprotection clinical trials achievable with reasonable numbers and cost. Roibeárd Ó hÉineacháin reports from the 9th World Glaucoma E-Congress
espite glaucoma’s slow rate of progression, clinical trials of neuroprotection do not require large study populations or lengthy follow-up to detect clinically relevant and IOP-independent improvements in the survival and function of the neurons of the visual system, according to Professor Robert Weinreb MD. “With an appropriate drug and new testing paradigms, a trial of neuroprotection now has a high likelihood of achieving clinical endpoints within a reasonable time period and at a reasonable cost,” said Dr Weinreb.
CLUSTERED TESTING The key endpoint in neuroprotection trials, and the regulatory gold standard, is the improvement or stabilisation of the visual field. One way to optimise the sensitivity of visual field testing in a trial setting is to cluster the testing at baseline and the end of the trial, he explained. The clustering approach to visual field testing can help overcome the insensitivity of testing in the early stages of glaucoma and its variability at the later stages of the disease. In addition, it allows for a shorter trial duration and a lower number of participants to show a result. He cited the UKGTS trial as an example of the effective use of clustered testing in assessing visual function changes. The trial involved 516 open-angle glaucoma patients. With the time to visual field progression within two years as the clinical endpoint, visual field testing performed on a clustered basis showed patients who received latanoprost had significantly better visual field preservation than those who received a placebo. He added the findings of the cohort study he and his associates conducted indicate that by using rate of progression and frequent testing, glaucoma therapy clinical trials could be completed within 18 months of follow-up and with fewer than 300 participants. The study’s authors have named this approach to testing the Short-Term Assessment of Glaucoma progrEssion (STAGE) model.
SLO/OCT model ・ SLO model
STRUCTURAL ENDPOINTS Changes in the optic disc and the retinal nerve fibre layer could also be of great value as clinical endpoints, as the changes can occur before detectable changes in visual function. The measurements are also easy to perform, allowing rapid acquisition of a large number of tests, reducing the sample size, trial duration, and expense required to reach a clinical endpoint. The challenge for the future is to determine the features of glaucomatous degeneration of the optic nerve that predict visual field loss, he stressed. “The FDA is open to using structural endpoints in clinical trials of new glaucoma drugs provided, the structural measures predict clinically meaningful functional change,” he added.
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Robert N Weinreb MD is Chair and Distinguished Professor of Ophthalmology at the University of California, San Diego, USA; Director of the Shiley Eye Institute; and Director of the Hamilton Glaucoma Center firstname.lastname@example.org EUROTIMES | OCTOBER 2021
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New EP2 antagonist eye drop provides IOP reduction similar to prostaglandin-analogues. Roibeárd Ó hÉineacháin reports from the 9th World Glaucoma E-Congress
new non-prostaglandin eye drop formulation called omidenepag isopropyl (EYBELIS®, Santen) has an IOP-lowering effect comparable to that of latanoprost for primary open-angle glaucoma (POAG) and ocular hypertensive patients, but without the cosmetic side effects, said Makoto Aihara MD, PhD. “Omidenepag isopropyl could be the new first-line drug for glaucoma,” he continued. Dr Aihara noted that omidenepag isopropyl (OMDI) is a prodrug hydrolysed in the eye to its active form, omidenepag—a selective, non-prostaglandin, prostanoid EP2 agonist. Omidenepag has a novel mechanism of action that lowers IOP by increasing aqueous humour outflow through both uveoscleral and trabecular pathways. Unlike prostaglandin F2α analogues currently in clinical use, omidenepag has no measurable effect on the FP receptor in the eye, eliminating the risk of FP-mediated adverse events such as eyelash growth and prostaglandin-associated periorbitopathy (PAP). OMDI has been approved for POAG treatment in Japan, Korea, and Taiwan, he noted. Several trials have confirmed OMDI’s safety and efficacy. For example, in phases one and two of the multicentre randomised controlled trial, IOP decreased from 23.78mmHg to 17.81mmHg after four weeks of treatment with OMDI 0.002% in 94 POAG patients, and 23.40mmHg to 16.96 mmHg after the same length of treatment in 96 patients randomised to latanoprost. Dr Aihara noted that OMDI’s side effect profile is different from latanoprost. The more common adverse events among patients receiving OMDI were conjunctival hyperaemia (24.5% versus 10.4%) and corneal thickening (11.7% versus 1.0%), whereas punctuate keratitis was less common (0% versus 7.3%) than in eyes treated with latanoprost. A phase three study evaluating long-term IOP reduction achieved with OMDI in patients with POAG or OHT supported the study findings. It showed that after 52 weeks of treatment with OMDI 0.002%, mean IOP decreased by 2.4mmHg (19.5%) in 48 patients with a baseline IOP of 16mmHg to 22mmHg and 5.64mmHg (23%) in patients with baseline IOP of 22mmHg to 34mmHg. There were no reports of cosmetic adverse events like PAP syndrome or increased pigmentation of the iris, eyelid, and eyelashes throughout the study. Moreover, in an ongoing study involving 12 POAG patients with PAP syndrome who were switched to OMDI 0.002% from a prostaglandin analogue, deepening of the upper eyelid sulcus improved in six patients, and a flattening of the lower eyelid bags improved in three after 12 months. Makoto Aihara MD, PhD is Chair and Professor of Ophthalmology, University of Tokyo, Japan email@example.com; firstname.lastname@example.org
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Posterior Capulsar Rent Glued IOL Scaffold: A—PCR with retained nuclear fragments in eye with inadequate capsular and iris support; B, C—Fragments are brought to AC and emulsified over a glued IOL scaffold; D—A surgeon performs pupilloplasty, and scleral flaps and conjunctiva are closed using fibrin glue.
posterior capsular rent (PCR) should be recognized immediately since continuation of surgery can lead to various complications such as enlargement of tear, vitreous prolapse, nucleus drop, loss of capsular support (including the rhexis), and an increase in the risk of posterior segment complications such as retinal tears, detachment, and cystoid macular oedema. Signs a PCR has occurred include sudden deepening of the anterior chamber (AC), transient pupil dilation, challenging nuclear rotation, and decreased nuclear fragment followability. Other signs include an area of clear red reflex, visible PCR margins, striae on the posterior capsule, difficult cortex aspiration, and pupillary peaking. Surgeons should be on the lookout for the presence of material such as ophthalmic viscosurgical device (OVD), cortical material or nuclear fragments within the vitreous. The pupillary snap sign described by Ronald Yeoh refers to a sudden pupil constriction during hydrodissection and signifies a blown-out posterior capsule. Some common principles of PCR management include maintaining AC depth by injecting viscodispersive OVD before withdrawing instruments; using viscodispersive OVD as a shield or scaffold below nuclear fragments to prevent nucleus drop as well as vitreous aspiration. Other management practices include supplementing topical anaesthesia with sub-Tenon block and/or intracamEUROTIMES | OCTOBER 2021
eral, preservative-free Xylocaine; using slow motion phacoemulsification and irrigation/ aspiration (I/A) with low flow, low vacuum, and lowered bottle height; using bimanual I/A and appropriately directing irrigation to avoid vitreous hydration and fragment drop. Proper vitreous management is critical and includes identifying vitreous using preservative-free intravitreal triamcinolone acetonide (IVTA) and bimanual vitrectomy. The surgeon should avoid vitreous traction at all times. Management also includes using a high cut rate and low vacuum; using the vitrector in the appropriate mode (irrigation-cut aspiration) to always cut vitreous before aspirating; using 23- or 25-gauge pars plana vitrector to alternately cut vitreous and aspirate cortex by shifting modes using the footswitch. A pars plana approach to vitrectomy is thought to have advantages as it pulls prolapsed vitreous back into the posterior segment instead of pulling more vitreous forwards as an anterior vitrectomy might. Continuing from part one of this multipart series where we discussed management of PCR without vitreous loss, a posterior continuous curvilinear capsulorhexis (PCCC) is a useful manoeuvre to know in cases of small, central rent without vitreous loss as it prevents any further extension of the PCR and allows in-the-bag IOL implantation. The PC is flattened using OVD, and micro forceps are used to carefully convert the tear into a PCCC.
This is the second part of a series by Dr Soosan Jacob MS, FRCS, DNB
PCR WITH RETAINED NUCLEAR FRAGMENTS AND VITREOUS LOSS It is important to avoid vitreous traction and rent enlargement. After injecting dispersive OVD over the rent, the phaco or I/A probe is gently withdrawn. Any residual nuclear fragments are assessed and dispersive OVD is instilled behind the fragments to keep them from descending. If none have dropped into the vitreous, the priority is localising them safely in the AC over the iris to avoid nucleus drop. IVTA-assisted anterior vitrectomy is then done to remove prolapsed, entangled vitreous before proceeding with either nucleus or cortex removal. Bimanual vitrectomy is preferred as it has advantages of 360-degree access between opposite ports and the ability to direct irrigating flow away from the rent and fragments, thus preventing vitreous hydration and increasing vitreous prolapse and fragment drop into the vitreous cavity. Once prolapsed vitreous is removed, the nuclear fragments are emulsified using slow motion phaco. Surgeons should use either viscodispersive OVD as scaffold or, more preferably, a pre-placed IOL as scaffold. Whole nuclei or large pieces, especially if hard, may be managed by conversion to extracapsular cataract surgery. For this, suture the phaco incision and make a separate corneo-scleral or scleral incision. Pieces are brought into the AC using a Sinskey
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hook. After suitably protecting the endothelium using viscodispersive OVD, use a vectis to bring them out through the new incision. Extract the pieces, then suture all large incisions before proceeding to operate under closed chamber conditions. Complete cortex aspiration with bimanual I/A, always stripping towards the rent to avoid extension of the PCR. Constantly look for accidental vitreous aspiration and, if present, immediately stop I/A to avoid vitreous pull and risk of retinal traction and detachment. Continue I/A again only after vitrectomy. Finishing dry aspiration of the cortex is also possible using a bent cannula. Surgeons can access the capsular bag and the cortex from the posterior aspect via pars plana ports or sclerotomies created for a glued IOL. Use a pars plana vitrector in irrigation aspiration-cut mode. An anterior chamber maintainer (ACM) or a trocarACM (TACM; as described by Agarwal et al) may be used for infusion if desiring a second instrument in the other hand.
Dmitrii Samsonov, Irkutsk Branch of the S. Fyodorov Eye Microsurgery Federal State Institution, Russia
If the nucleus or fragments descend into the anterior vitreous, a few described manoeuvres can bring them into the AC. Posterior-Assisted Levitation (PAL) may be used to levitate a nucleus or fragment which is lying just posterior to the PC through
a pars plana approach. However, this can potentially cause vitreous and retinal traction, so perform with care. PAL used with Viscata can stabilize and elevate a descending nucleus. It’s possible to use sleeveless phacotip-assisted levitation (SPAL) for an entire nucleus or fragments that dropped into the posterior segment. Finish the core vitrectomy and release the fragment completely before attempting to lift it with the sleeveless phaco probe. Brought into the AC, the nucleus is then emulsified using IOL scaffold technique or extracted after enlarging the incision. Unless well experienced, all situations with a descended nucleus are best managed by a vitreoretinal surgeon.
THE IOL SCAFFOLD TECHNIQUE As described by Agarwal et al, a foldable IOL is pre-placed within the AC, over the iris, and under the nuclear fragments so the haptic of the IOL occludes the pupil and compartmentalises the anterior and posterior segments. Importantly, it also prevents fragment drop, vitreous prolapse, and PCR enlargement. The surgeon may remove the cortex before placing the IOL or afterwards by introducing the bimanual I/A probe under the IOL. Another approach to strip the cortext includes a posterior approach with a vitrector. The IOL is finally translocated into the sulcus or as per the surgeon’s choice of IOL fixation.
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In the absence of iris support, the IOL may be pre-placed into the sulcus. If there is not adequate iris and capsular support, consider the glued IOL scaffold technique. In that case, the nucleus is brought anteriorly into the AC, and a glued IOL is fixed below the iris plane to act as a scaffold during phacoemulsification.
Dr Soosan Jacob is Director and Chief of Dr Agarwal’s Refractive and Cornea Foundation at Dr Agarwal’s Eye Hospital, Chennai, India, and can be reached at email@example.com.
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09.09.2021 13:42:23 2021 EUROTIMES | OCTOBER
Novel Gene Therapy for Stargardt Disease
team at Radboud University Medical Centre, Nijmegen, the Netherlands, reported a novel antisense oligonucleotide strategy for the treatment of Stargardt disease. The research team developed an RNA therapy to rescue splice defects within a particular gene, ABCA4, with a corrective strategy to remove aberrant transcripts that aim to restore normal biological function. Stargardt disease (STGD1) develops through mutations in the photoreceptor-specific ABCA4 gene which encodes the adenosine triphosphate-binding cassette, subfamily A, member 4. The ABCA4 gene encodes a transporter protein within retinal photoreceptor cells facilitating the active transport of potentially toxic retinoid compounds removing toxic by-products from the visual cycle. A number of pathogenic variants within specific introns of the ABCA4 gene may result in aberrant splicing of the gene—including pseudogenes—essentially non-functional segments of DNA. Splicing defects within pseudogenes of ABCA4 can insert aberrant “pseudoexons” (PEs) into the ABCA4 pre-mRNA.These PEs can result in the disruption of the reading frame and also lead to nonsense-mediated decay (NMD). One way to address this problem is through the use of antisense oligonucleotides (AON), which aim to block pseudoexon insertion and develop therapeutic possibilities to overcome the splicing defects. Patients studied from derived cultured cells use these AON agents to block the PEs from splicing into the ABCA4 mRNA and restore normal splicing. A recent publication on these patient-derived cells, including 3D retinal organoids, reported that several AONs, “appear to be a promising tool to correct splicing defects associated with the pathogenic variants identified in this study, warranting further development of these molecules toward clinical trials in order to halt the progression of this disease.” (doi.org/10.1016/j.omtn.2020.06.007) Stargardt disease, also referenced as fundus flavimaculatus, was first discovered by German ophthalmologist Karl Stargardt in 1909. His report described juvenile macular dystrophy in seven patients from two separate families, presenting in the first or second decade of life with a reduction in central visual acuity. Today, it is the most common form of inherited macular dystrophy, affecting 1 in 10,000 individuals worldwide. Not dissimilar to retinitis pigmentosa with a high degree of clinical heterogeneity, Stargardt patients may develop severe visual impairment or even complete blindness due to photoreceptor death and the retinal pigment epithelium (RPE) cells. ABCA4-associated retinopathy develops through biallelic variants in ABCA4 identifying the transmembrane protein of 2,273 amino acids. Allelic heterogeneity presents with more than 1,000 pathogenic mutations to date, and there is a strong correlation between the clinical phenotype with the severity of the ABCA4 genotype. Over recent decades, ABCA4 variants have been identified outside the protein-coding exons. A majority of deepintronic pathogenic variants result in the activation of a splice site within an intron. Insertion of an aberrant pseudoexon into the ABCA4 pre-mRNA leads to disruption of the normal protein. One mechanical way to correct this challenge is to use relatively small RNA molecules of 18–25 nucleotides binding complementarily to their target pre-mRNA, preventing the inclusion of the PE into the final mRNA transcript upon splicing. AONs represent a new class of genetic therapies that exert their action by modulating target gene expression, a potentially viable therapeutic approach for the treatment of numerous inherited retinal diseases. EUROTIMES | OCTOBER 2021
cryptic splice donor site
Exon 3 Exon 4
Exon 1 Exon 2
Exon 1 Exon 2 Exon 3 Exon 4 normal splicing
cryptic exon containing stop codon or frameshift nonsense-mediated decay Mutation
Exon 1 Exon 2 Exon 4
Exon 1 Exon 2 Premature termination nonsensemediated decay or truncated protein
In-frame skipping of exon 3 (3n nucleotides) partially functional protein
Toxic gain-of-function mutation or triplet repeat expansion Pre-mRNA
Exon 1 Exon 3 Exon 4 Blockage of ribosome binding Out-of-frame skipping of exon 2 (3n+l or 3n+2 reduced translation nucleotides frameshift protein knockdown
RNA-DNA hybrid RNase H-mediated degradation
Kanmin Xue & Robert E. MacLaren (2020) Antisense oligonucleotide therapeutics in clinical trials for the treatment of inherited retinal diseases, Expert Opinion on Investigational Drugs, 29:10, 1163–1170, DOI: 10.1080/13543784.2020.1804853
Single-stranded oligodeoxynucleotides can be readily designed to hybridize with a target pre-mRNA. While poor stability has hampered the clinical viability of such oligos, significant advances have been enormously improved on the modified chemistry of these AONs.
EARLY CLINICAL TRIALS Clinical trial reports from phases one and two of an intravitreally administered AON to correct a splicing defect with the common deep-intronic mutation in CEP290-Leber congenital amaurosis (LCA10) have demonstrated safety and early efficacy in improved visual function. Moreover, AON-based therapies are also in early trials for common mutations found in RHO-associated autosomal dominant retinitis pigmentosa (ADRP) and Usher syndrome type 2. Beyond the AON approach, a virus-based design could use AAV with engineered nucleotide sequence to target the relevant splice sites, avoiding continual repeat injection administrations. The research group has announced a start-up company, “Astherna”1, to advance their work and develop proposed clinical trial studies. The group’s main objective is overcoming the current unmet treatment of Stargardt disease. Astherna is the first biotech company founded by the Radboud University Medical Centre for eye diseases. One founder of the research team, Professor Carrel Hong commented, “I am delighted and proud that Astherna has been founded. We can now really mean something for the many patients with Stargardt disease. [At] the Radboud medical centre, we see people with this condition [the most], so we can make our research directly applicable to patients. I see young patients in my outpatient clinic who know that they are going to lose their sight at some point. It has a huge impact on the life choices they need to make: what education can they do, what kind of job lies ahead for them? The earlier we can help them, the less sight they will lose. These are the people we do it for.” Gearóid Tuohy BSc, PhD, MSc 1. Astherna, https://astherna.com
NEWS IN BRIEF ALDEYRA RP DRUG APPROVED The US FDA granted orphan drug status to Aldeyra Therapeutics’ ADX-2191 treatment for retinitis pigmentosa. ADX-2191 (methotrexate for intravitreal injection) is the first drug approved by the FDA for the treatment of retinitis pigmentosa. The drug has also been granted orphan drug status for treatment of primary vitreoretinal lymphoma and received both orphan drug and fast track status for the prevention of proliferative vitreoretinopathy.
MAKING IOLS A WORK OF ART Medical device company Voptica will announces the first and only inverted meniscus intraocular lens (ArtIOLs®) to improve peripheral vision at 2021 ESCRS Satellite Symposium in Amsterdam. “Current intraocular lenses are designed to optimise image quality at the eye’s central retina, with not much attention to their off-axis performance,” Pablo Artal, PhD, CEO, and Co-founder of Voptica, said. “IOLs are very thin in comparison with our natural lens. The reason is obvious, because we favour surgery through a small incision, but from the point of view of the optics in the periphery, the impact can be important since standard lenses provide a wrong field curvature and elevated astigmatism.”
TREATMENT FOR PROGRESSIVE CHILDHOOD MYOPIA Santen announced an exclusive licensing agreement for SYD101, Sydnexis’ investigational proprietary low-dose atropine formulation, for Europe, Middle East, and Africa (EMEA). SYD101 is currently undergoing a large multicentre phase three clinical trial, the STAAR study, in Europe and the US. SYD-101 is a low-dose atropine sulphate ophthalmic solution—0.01% and 0.03%. The low-dose atropine formulation is designed to be pharmacologically stable without needing to lower the pH in order to achieve a shelf life of up to three years at room temperature, according to the developer.
SANTEN AND IAPB PARTNER Santen EMEA announced it would work with the International Agency for the Prevention of Blindness to help implement the United Nations General Assembly resolution encouraging an international approach to improve access to basic eye services around the world. “The adoption of UN resolution on eye health represents a major leap towards the realisation of our world vision, Happiness with Vision,” said Shigeo Taniuchi, President & CEO of Santen.
SLOW-RELEASE DELIVERY SYSTEM FOR RANIBIZUMAB Genentech’s Port Delivery System with ranibizumab (PDS) moved closer to US FDA approval with the acceptance of its Biologics License Application (BLA), which is under Priority Review. The PDS is designed for the long-term treatment of neovascular, age-related macular degeneration. It would free patients from the need for frequent intravitreal injections. The company also recently announced its BLA for faricimab treating wet age-related macular degeneration and diabetic macular oedema was accepted. The FDA also accepted the company’s application for diabetic retinopathy.
TREATMENT FOR MACULAR OEDEMA The US FDA accepted Bausch + Lomb and Clearside Biomedical’s resubmitted New Drug Application for triamcinolone acetonide suprachoroidal injectable suspension (Xipere). The companies are investigating the potential of the triamcinolone acetonide suprachoroidal injectable suspension for the treatment of macular oedema associated with uveitis. This would be Clearside’s first commercial product and the first approved drug delivered into the suprachoroidal space (SCS).
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AAO 2021: Re/Create 12 – 15 November New Orleans, Louisiana, USA
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39TH CONGRESS OF THE ESCRS OCTOBER 8-11, 2021 AMSTERDAM
Friday October 8th | 15:45 - 16:30 CEST The Power of Patient Outcome Data for Sustainable Cataract Care Moderator: Joaquim Murta Making Value Based Healthcare in Cataract a Reality: Insights from VBHCAT Project in Portugal Joaquim Murta, Portugal
Transforming Healthcare on Outcomes Insights - the Experience and Learnings from NHS Wales Gareth Roberts, United Kingdom
Real World Data on Nd YAG Laser Capsulotomies and their Complications in French Patients Antoine Brezin, France
Saturday October 9th | 15:30 - 16:15 CEST Embrace the Power of Digital Visualization & Fluid Control in Phaco Procedures
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Moderator: Saleh Al Messabi The importance of remaining in focus with stability at every step of the surgery Khalid Al Sabti, Kuwait
The impact of color and enhanced eﬃciency in Cataract surgery Saleh Al Messabi, United Arab Emirates
Redeﬁne eﬃciency and safety with digital cockpit piloting and advanced ﬂuidics Kjell Gunnar Gundersen, Norway
The power of immersion and procedural protection in educating fellows Robert Rejdack, Poland
Sunday October 10th | 11:45 - 12:45 CEST Advancing Cataract Refractive Surgery and Presbyopia Correction Better outcomes for more patients Moderator: Gerd Auﬀarth AcrySof® IQ Vivity®: An innovative approach to Presbyopia Correction Gerd Auﬀarth, Germany
Advanced Technology IOLs: Choose the right lens for the right patient Rudy Nuijts, Netherlands · Edoardo Ligabue, Italy · Ertan Sunay, Turkey
From Biometry to Smart Planning Solution for PC-IOLs correction Norbert Pesztenlehrer, Hungary
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