EuroTimes February 2022, Volume 27, Issue 1

February 2022 | Vol 27 Issue 1

Research Education Innovation

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

McGrath

Roibeárd O’hÉineacháin

Contributors

Leigh Spielberg

Gearóid Tuohy

Priscilla Lynch

Soosan Jacob

Colour and Print

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Published by the European Society of Cataract and Refractive Surgeons, Temple House, Temple Road, Blackrock, Co Dublin, Ireland. No part of this publication may be reproduced without the permission of the executive editor. Letters to the editor and other unsolicited contributions are assumed intended for this publication and are subject to editorial review and acceptance.

ESCRS EuroTimes is not responsible for statements made by any contributor. These contributions are presented for review and comment and not as a statement on the standard of care. Although all advertising material is expected to conform to ethical medical standards, acceptance does not imply endorsement by ESCRS EuroTimes ISSN 1393-8983

ESCRS PRESIDENT

Remembering Emanuel Rosen

With the passing of Emanuel Rosen, we have lost a unifying force who represented the best values of the international ophthalmic surgery community. We must thank him for the three elements he introduced, the ESCRS, JCRS, and EuroTimes, which together continue to support and encourage the development of cataract and refractive surgery on a global scale.

MEDICAL EDITORS

With incredible drive and determination, he lit the spark that became the ESCRS. He was President of the ESCRS from its founding in 1987 until 1993. Continuing to serve in many capacities until 2017, he was instrumental in transforming the ESCRS into the fully fledged, highly successful, and important European ophthalmological organisation we have today.

In 1996 he launched, with Steve Obstbaum at the ASCRS, the Journal of Cataract and Refractive Surgery (JCRS). This coincided with the publication of the first issue of the Society’s news magazine, EuroTimes. Working with Carol Fitzpatrick and John Henahan, he saw EuroTimes grow from a first issue of only eight pages to the fully fledged multimedia news magazine it is now.

Dr Rosen was a direct link to surgical pioneers who introduced what are now standard ideas, including intraocular lenses, phakic lenses, phacoemulsification, and corneal refractive laser surgery. This included implant pioneers Harold Ridley, Peter Choyce, Cornelius Binkhorst, and early proponents of phacoemulsification Eric Arnott and Charles Kelman.

It is worth remembering that intraocular implants, phacoemulsification, and corneal refractive surgery were all met with hostility and reluctance by the medical/surgical establishment of the time. Dr Rosen looked beyond this resistance, helping assemble a group of young, passionate surgeons from around the world who were eager to develop new methods of helping improve the vision of their patients.

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)

Dr Rosen also maintained a busy surgical practice—first working with the National Health Service and then as head of the Rosen Eye Clinic. The first surgeon to perform LASIK in the United Kingdom, he used his business acumen to develop a national chain of LASIK clinics. He also was an expert on medical-legal disputes, assisting many colleagues in need of advice.

Emanuel Rosen was present and active during a period in history that saw remarkable progress in cataract and refractive surgery. Since the 1980s, refractive surgery has quickly evolved. Radial keratotomy gave way to photorefractive keratectomy, which led to the development of LASIK, and most recently to presbyopic IOLs, SMILE, and other refractive technologies.

It is probably also worth remembering that the ESCRS began before the European Union came about. One of Dr Rosen’s core beliefs was ophthalmology should be global and inclusive. It was a somewhat radical idea in the first days of the ESCRS to include members from across Europe, welcoming to all. Indeed, it went beyond the borders of Europe to include Turkey, Israel, and Egypt. This was part of his philosophy of breaking down barriers to include the exchange of information towards the betterment of all involved.

We have lost a unifying force who represented the best values of the international ophthalmic surgery community

José Güell

Paul Rosen

Thomas Kohnen Chief Medical Editor

Oliver Findl

Stem Cells for Corneal Disease

Early trials highlight promise of stem cells in treating dry eye disease.

Dermot McGrath reports from the 39th Congress of the ESCRS in Amsterdam

The regenerative properties of mesenchymal stem cells (MSCs) may offer a safe and effective treatment for certain types of dry eye disease based on evidence from initial clinical trials, new research suggests.

“The injection of allogeneic adipose-derived MSCs (ASCs) into the lacrimal gland seems to be a safe and well-tolerated treatment for severe aqueous deficient dry eye disease (ADDE),” reported Michael Møller-Hansen MD.

Dr Møller-Hansen gave a broad overview of recent research carried out at the University of Copenhagen, Denmark, using ASCs as a potential treatment for dry eye disease.

During the past decade, there has been an increasing interest in using stem-cell therapy to treat a wide range of different pathologies, including ocular diseases, Dr Møller-Hansen noted.

MSCs offer several advantages in therapeutic use thanks to their regenerative and anti-inflammatory properties.

“We see a lot of patients with dry eyes in the clinic. When I first started in ophthalmology, I was surprised to see the effect dry eye disease had on their quality of life. It would be good to be able to contribute to improving that situation for these patients,” he said.

Dr Møller-Hansen cited two recent studies in canines with keratoconjunctivitis sicca that underscored the potential of MSCs to offer safe and durable treatment.

“One study showed that a single injection of MSCs had an effect on these canines up to 12 months after one treatment, and the other study reported no systemic or local complications related to the treatment,” he said.

Figure 1. (A): Magnetic resonance image of the left orbit in the anterior-posterior projection at baseline in subject no. 3. The dotted line outlines the left lacrimal gland (B): Transconjuncival injection of adipose-derived mesenchymal stem cells in subject no. 3.

M. Møller-Hansen et al., “Safety and feasibility of mesenchymal stem cell therapy in patients with aqueous deficient dry eye disease,” Ocul. Surf., vol. 19, pp. 43–52, Jan. 2021. Copyright Elsevier.

Moving to human studies, Dr Møller-Hansen reported the results of an open-label clinical trial conducted by their research group in Copenhagen in which seven patients with ADDE received one transconjunctival injection of allogeneic ASCs into the lacrimal gland in one eye.

indicators showed a statistically significant improvement in treated eyes as mean tear osmolarity decreased from 312.9 to 291.6, mean TBUT increased from 3.7 to 7.1, and the mean Schirmer’s I test increased from 4.6 to 8.1/5 min.

Based on these positive results, the team at the University of Copenhagen has almost completed enrolment for a randomised placebo-controlled trial (AMASS) aimed at elucidating the therapeutic effect of allogeneic ASCs in 40 patients with dry eyes due to Sjögren’s syndrome.

The primary endpoint of the study was treatment-related adverse events, while secondary measures included Ocular Surface Disease Index (OSDI), tear osmolarity, tear film break-up time (TBUT), corneal staining (Oxford grade), and Schirmer’s I test.

No adverse events related to the study treatment occurred at any of the follow-up visits, Dr Møller-Hansen reported. The most frequent adverse effects were observed immediately after treatment and included a temporary increase in ocular discomfort and temporary periorbital oedema.

In terms of secondary outcomes, the mean OSDI score decreased from 58.9 at baseline to 34.1 four months after treatment. The other objective measurements of dry eye

“We want to test the hypothesis that injection of allogeneic ASCs into the lacrimal gland increases tear production and reduces inflammation resulting in increased ocular comfort compared to placebo. We have enrolled 36 out of the 40 patients so far and hope to have the final results of the 12-month follow-up towards the end of 2022,” Dr Møller-Hansen concluded.

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Michael Møller-Hansen MD is a researcher at the Department of Ophthalmology, Rigshospitalet-Golstrup, University of Copenhagen, Denmark. michael.moellerhansen@regionh.dk

“I was surprised to see the effect dry eye disease had on their quality of life.”

Cyclosporine Intracanalicular Insert Stalls

Asustained-release cyclosporine intracanalicular insert, OTX-CSI (Ocular Therapeutix), demonstrated a favourable tolerability profile and rapid onset of action for improving dry eye disease (DED) signs and symptoms in a phase 1 study. However, a phase 2 study showed no statistically superior improvement from baseline to 12 weeks compared to controls.

In the phase 2 study, two OTX-CSI formulations showed favourable safety profiles and good tolerability as well as an association with early and sustained improvements in corneal fluorescein staining (CFS) and DED symptoms. The study sponsor, Ocular Therapeutix, announced in an October 22, 2021, press release the company will continue to review the study data for additional information that may inform future development of the OTX-CSI program.

week zero after a 14-day washout period. Patients were eligible for enrolment if they had bilateral DED for at least six months, a severity Eye Dryness Score (EDS) ≥30 rated on a visual analogue scale of 0 to 100, total CFS score (NEI scale) ≥6 and <15, and an unanaesthetised Schirmer score >0 to ≤5 mm/5 min.

The trial’s safety data showed no serious adverse events, treatment-related adverse events, or reports of stinging, burning, or dysgeusia. Efficacy data showed improvements from baseline in Schirmer score, CFS score, EDS severity and frequency, and scores on two DED symptom questionnaires.

Improvements in efficacy measures were observed starting at the first follow-up visit at two weeks post-insertion of OTX-CSI and lasted up to 16 weeks for both the Schirmer test and DED symptom assessments. Mean Schirmer test score improved from 4.2 mm/5 min at baseline to 8.2 mm/5 min at week 12 and 8.5 mm/5 min at week 16. Mean total CFS score was 6.7 at baseline and fell to 2.7 at week 12. Mean scores for EDS severity and EDS frequency were 51 at baseline and fell to approximately 23 and 28, respectively, at week 16.

WHAT HAPPENED IN PHASE 2?

Mitchell A Jackson MD is an investigator in the OTX-CSI clinical trial program. Earlier in October, he presented the results from the phase 1 study at the 39th Congress of the ESCRS in Amsterdam, the Netherlands.

“Intolerable side effects and slow onset of action represent some of the biggest complaints that patients have about the commercially available products used for the chronic treatment of DED. The ocular surface side effects—namely, stinging, burning, and irritation—often lead to non-compliance and therapy discontinuation. In addition, the slow onset of action can be frustrating for patients and lead to early drop-out,” Dr Jackson told EuroTimes

“It is worthwhile to continue exploring OTX-CSI not only for its potential to address the unmet need for effective chronic DED treatments but also because of its promise of overcoming the issue of poor compliance with topical medications. In my opinion, poor compliance is one of the biggest culprits explaining why available therapies are not entirely effective in the real world of patient care.”

OTX-CSI incorporates cyclosporine in a preservative-free, fully biodegradable, polyethylene glycol hydrogel rod. Designed to provide prolonged cyclosporine release, the insert also offers a second treatment modality for DED—punctal occlusion, Dr Jackson said.

The phase 1 and phase 2 trials investigating OTX-CSI were US-based. The phase 1 study had an open-label design and enrolled five adults who had the device inserted bilaterally at

The phase 2 study was a double-masked, multicentre trial that randomised 147 patients into one of four groups to receive one of two formulations of OTX-CSI or one of two vehicle inserts. The two OTX-CSI inserts contained the same amount of cyclosporine but differed in their expected release duration (two-to-three months or three-to-four months), and the vehicle inserts had expected durations of three-to-four months and one week.

At the primary efficacy endpoint visit conducted at week 12 post-insertion, change from baseline Schirmer score was 1.98 mm/5 min for the shorter duration OTX-CSI group, 1.91 mm/5 min for the longer duration OTX-CSI group, 2.24 mm/5 min for the longer duration vehicle group, and 3.08 mm/5 min for the shorter duration vehicle group.

Other efficacy analyses showed improvements from baseline in both OTX-CSI groups in both total CFS and EDS as early as two weeks after insertion. At 12 weeks, however, the improvements from baseline in CFS, EDS severity, and EDS frequency were not statistically significant compared with those achieved in the vehicle groups.

OTX-CSI continued to demonstrate favourable safety and tolerability. There were no ocular serious adverse events, and no study participant withdrew because of adverse events. Ocular pruritus was the most common ocular adverse event recorded, affecting 16% of patients treated with OTX-CSI. The reported rate of ocular discomfort or pain was less than 3%.

Phase 2 study fails to meet primary efficacy endpoint after novel product shows encouraging efficacy signals in earlier trial.

Cheryl Guttman Krader reports

Mitchell A Jackson MD operates a private practice in Lake Villa, Illinois, USA. mjlaserdoc@msn.com

“In my opinion, poor compliance is one of the biggest culprits explaining why available therapies are not entirely effective in the real world of patient care.”

Tracking Keratoconus Progression with AI

Dermot McGrath reports from the 39th Congress of the ESCRS in Amsterdam

Artificial intelligence (AI) has the potential to improve on current methods of quantifying keratoconus detection and could help track eventual disease progression, reports

Riccardo Vinciguerra MD.

Speaking at a Clinical Research Symposium, Dr Vinciguerra presented an overview of the current state of play in terms of AI applications in keratoconus diagnosis and progression.

The ideal preoperative assessment for patients with keratoconus should be reliable, easy, fast, and validated.

“It should have high sensitivity, which means you detect all cases at risk, but on the other hand, it should also have high specificity so we avoid excluding patients that would be fit for surgery,” he added.

Artificial intelligence—particularly statistical AI techniques such as logistic regression, random forest, neural network, and support vector machine—can assist in detecting and tracking keratoconus progression.

“The basic idea is we can use the data we derive from our devices to feed AIs to detect keratoconus and predict its progression. The ‘food’ we can provide to AI tools include topography, tomography, epithelial maps, aberrometry, corneal biomechanics, and biomarkers—basically everything that could help in the detection of the disease,” he said.

Another algorithm, the Pentacam Random Forest Index (PRFI) uses more complex AI and has a cut-off range of 0.125.

“It has been shown to be better than BAD-D, particularly to improve the detection of early cases of keratoconus,” Dr Vinciguerra noted.

Another tool, the Corneal Biomechanical Index (CBI) has also been created with logistic regression, has a cut-off of 0.5, and its use has been validated in multiple papers, he added.

Promising results have also been obtained in published studies using a new combined tomographic and biomechanical index (TBI).

“It uses a random forest methodology, has a cut-off of 0.35, and is a significant improvement over CBI and BAD-D— particularly to detect early cases of keratoconus,” he said.

In terms of the future of detection methods, Dr Vinciguerra said while there have been many papers published on various AI algorithms, very few have been validated in external databases.

“Until we have a clear validation of the AI applications, we cannot be sure they are better than the current standard of care,” he said.

For detecting keratoconus progression, the commercially available platforms on the market do not use AI—rather, they depend on progression over noise level methods to flag it. However, a lot of interesting research is ongoing in this field, and new algorithms are sure to find their way into clinical practice in the near future, he concluded.

A common problem of many AI algorithms is while the methodology may have been published, they are still not widely used in clinical practice and their use has not been validated in external databases, Dr Vinciguerra explained.

Focusing on devices that currently use AI algorithms for keratoconus detection, Dr Vinciguerra said the OCULUS platform can use biomechanical data from the Corvis ST device and tomographical data from Pentacam®.

More specifically, the first AI tool on the Pentacam was the Belin Ambrósio Enhanced Ectasia Display (BAD-D) which uses logistic regression, has a cut-off range of 1.4 to 1.6 Standard Deviations (D values) from normal, uses multiple tomographic parameters, and has been widely validated.

Riccardo Vinciguerra MD currently works as an Ophthalmologist and Scientific researcher at the Humanitas San Pio X Hospital, Milan, as well as a research collaborator at Biomechanical Engineering Group, University of Liverpool, UK. vinciguerra.riccardo@gmail.com

“Until we have a clear validation of the AI applications, we cannot be sure they are better than the current standard of care.”

DALK and PK Key Ingredients for Herpetic Keratitis

Italian doctors describe ways to optimise surgery.

Howard Larkin reports from the 39th Congress of the ESCRS in Amsterdam

Both large diameter, 9.0 mm deep anterior lamellar keratoplasty (DALK) and two-piece microkeratomeassisted “mushroom” penetrating keratoplasty (PK) produced excellent long-term visual and survival outcomes for patients with herpetic keratitis, reported Angeli Christy Yu MD on behalf of Prof Massimo Busin MD.

She recounted a case of a 13-year-old patient with corneal scarring associated with neovascularisation that initially improved with antiviral treatment. Afterwards, “mushroom” PK was performed as a definitive surgical procedure. He regained 20/20 vision which sustained over 10 years.

Such outcomes are not always the case in conventional PK for herpetic keratitis.

“We know herpetic keratitis often associated with deep stromal neovascularisation exceeding two quadrants poses a significant risk for immunologic rejection and subsequent graft failure,” Dr Yu said.

Likewise, these patients are at high risk of herpetic disease recurrence. As a result, conventional PK for herpetic keratitis has a five-year success rate of about 60%.

Long-term antiviral prophylaxis improves the odds of survival by reducing the risk of immunologic rejection and herpetic recurrence. Studies have found oral antiviral prophylaxis is effective for herpetic recurrence prevention, with oral doses ranging from 400 mg twice daily to 800 mg three to five times a day. The American Academy of Ophthalmology recommends high-dose antiviral prophylaxis as well. Dr Yu’s centre uses an initial high-dose oral acyclovir, topical ganciclovir and dexamethasone, and extended tapering of antiviral and steroid prophylaxis.

When possible, Prof Busin’s group uses DALK for herpetic scarring. But when there is a significant macroperforation or unsatisfactory clearance within the optical zone because of a fullthickness opacity, PK is performed.

OPTIMISING SURGERY

Two-piece “mushroom” keratoplasty is designed to optimise the outcomes of full-thickness corneal transplantation, Dr Yu said. Studies show smaller-sized grafts lead to a lower rejection rate but higher refractive error, while larger grafts have higher rejection rates and lower refractive error.

The two-piece “mushroom” graft consists of a large 9.0 mm diameter anterior lamella (mushroom “hat”) and a smaller 6.0 mm diameter posterior lamella (mushroom “stem”). This maximises the refractive benefit of a large anterior lamellar graft while minimising the risk of immunologic rejection by reducing the antigenic load, she explained.

The procedure begins with a partial thickness trephination of 9.0 mm, followed by circumferential manual lamellar dissection. The residual bed is then trephined to the full thickness at

“We know herpetic keratitis often associated with deep stromal neovascularisation exceeding two quadrants poses a significant risk for immunologic rejection and subsequent graft failure.”

Figure 1: 9 mm deep anterior lamellar keratoplasty for vascularised herpetic scar.

6.0 mm, usually centred on the pupil. The donor graft is split via microkeratome dissection into two lamellae, with the posterior lamella fitted into the central full-thickness trephination and the anterior graft sutured in place.

In a study published in the American Journal of Ophthalmology last year, the group reported on 10-year outcomes of 52 eyes using standard two-piece microkeratome-assisted “mushroom” keratoplasty and a predefined antiviral prophylaxis protocol. All eyes were defined as high risk for recurrence based on the presence of at least two quadrants of neovascularisation. At 10 years, the graft junctions were imperceptible, with the cornea remodelling to its original form. Mean best-corrected vision was about 20/32, with 55% achieving 20/25 or better. After an initial loss of 40%, annual endothelial cell loss was 3%. The risk of rejection was 9.7% and recurrence 7.8%, with overall survival of 92%.i

Similarly, 38 eyes that underwent DALK at the centre saw a stromal rejection rate of 6.6%, recurrence of 4.4%, and overall cumulative survival of 96%, Dr Yu reported.

“You can always try pneumatic dissection first, which is successful in 70% of DALK cases. If a significant perforation does occur, you can convert to two-piece mushroom keratoplasty and still achieve excellent visual outcomes and, more importantly, survival rates of up to 90%,” she concluded.

i AM J Ophthalmol 2020; 217: 212–223.

Angeli Christy Yu MD is an ophthalmologist and researcher at the University of Ferrara, Italy, and Ospedali Privati Forlì “Villa Igea”. angeliyu@gmail.com

Figure 2: Two-piece microkeratome-assisted mushroom keratoplasty for vascularised herpetic scar.

Better Outcomes for CXL-Treated Patients

Recommendations

Cheryl Guttman Krader reports from the 39th Congress of the ESCRS in Amsterdam

Optimising outcomes for patients undergoing corneal cross-linking (CXL) for progressive keratoconus or postLASIK ectasia involves strategies implemented during and after the CXL procedure, said Theo G Seiler Jr, MD.

“Customisation of the ultraviolet A (UVA) light irradiation pattern and increasing the availability of oxygen during CXL can improve the efficacy of the CXL. Additional wavefront-guided photorefractive keratectomy (WFG PRK) targeting reduction of selected higher-order aberrations (HOAs) is a powerful treatment option when contact lens-intolerant patients seek functional vision improvement,” Dr Seiler said.

Discussing how to improve the results of the CXL procedure, Dr Seiler focused on increasing oxygen availability to the corneal tissue to increase aerobic reaction throughout the intended stromal depth.

“Oxygen is definitely the bottleneck for achieving sufficient CXL. In 2013, Richoz [et al.] showed by measuring Young’s modulus that CXL is insufficient if the procedure is performed without oxygen. Performing the procedure by providing a 100% oxygen environment can optimise the results,” he said.

In a laboratory study published in 2021,i Dr Seiler and colleagues measured oxygen concentrations at corneal depths of 100, 200, and 300 μm during CXL performed under normoxic (21% oxygen) or hyperoxic (100% oxygen) conditions and using UVA irradiances of 3, 9, 18, or 30 mW/cm2. The results showed that when the procedure was done in the normoxic environment and according to the standard Dresden protocol using an irradiance level of 3 mW/cm2, there was sufficient oxygen available to achieve CXL at all measured depths. However, when the irradiance level was raised to just 9 mW/ cm2, sufficient oxygen for achieving CXL was available only down to 200 μm depth and only in the anterior 100 μm for higher irradiances.

“Our study results are congruent with previously reported OCT data evaluating the depth of the CXL corneal stromal demarcation line using different levels of UVA irradiance,” Dr Seiler said. Oxygen measurements taken when CXL was performed in the 100% oxygen environment showed a surplus of oxygen was present at all measured depths using the 9 mW/cm2 UVA irradiance level. With CXL performed at 18 and 30 mW/cm2 of irradiance, there was not enough oxygen available to achieve sufficient CXL posterior than 100 μm, indicating an optimal irradiance between 9 and 18 mW/cm2 when using supplemental oxygen.

CLINICAL TRANSLATION

Dr Seiler said findings from a clinical study submitted for publication indicate performing CXL in a 100% oxygen environment generally results in a threefold greater reduction in keratometric flattening compared to CXL done under normoxic conditions. The change achieved in most patients ranged from 3.0 to 5.0 D, he said.

In a case presentation, Dr Seiler showed that the use of supplemental oxygen during CXL could result in even greater corneal flattening and an extraordinarily deep demarcation line in some eyes. The patient he described benefited with a

6 to 8 D change in keratometry and had a demarcation line at 380 μm. However, Dr Seiler also noted some eyes achieved only a minor change of just 1 or 2 D.

He added that supplementing oxygen might also improve outcomes of transepithelial CXL.

“We know we do not get deep penetration of oxygen when performing epithelial-on CXL, since the corneal epithelium is the main consumer of oxygen in the cornea and acts as a diffusion barrier. Results of a study by Mazzotta et al.ii showed significant flattening of the steep keratometry and a demarcation line deeper than 300 μm performing transepithelial CXL with supplemental oxygen.”

VISUAL REHABILITATION

Visual function is what matters to patients, and when considering an excimer laser procedure for visual rehabilitation in a contact lens-intolerant patient who requires CXL or has undergone CXL, the physician needs to take into account the effect of the ablation on the biomechanical stability of an already weak cornea. Therefore, the goal is to minimise the depth of tissue removal. A WFG PRK procedure targeting the reduction of only selected HOAs represents one approach.

“We do not need to totally correct the lower order aberrations (LOAs) and improve uncorrected visual acuity. Reducing HOAs can improve best spectacle-corrected visual acuity (BSCVA), and we can tell the patient to wear a soft contact lens or spectacles for further visual rehabilitation,” Dr Seiler said.

Performing the ablation with a smaller optical zone diameter or to use a myopic target refraction are also ways to reduce and achieve a tolerable amount of tissue removed in the ectatic region of the cornea. However, the viability of this approach needs to be investigated and simulated in the preoperative examination. Informed consent must always make patients aware of the potential complications, Dr Seiler said.

Underscoring the latter point, he presented a case involving a patient who underwent topography guided PRK with simultaneous CXL with satisfying topographic results. However, because of stromal scarring presence, the patient’s postoperative BSCVA was only 20/100.

“I performed DALK in this patient, and I definitely would have faced a legal issue if I had not provided good information preoperatively about the possible risks of the laser treatment,” Dr Seiler emphasised.

i Am J Ophthalmol. 2021; 223: 368–376.

ii J Cataract Refract Surg. 2020; 46(12): 1582–1587.

Theo G Seiler Jr, MD is senior physician in the Department of Ophthalmology at the University of Düsseldorf, Germany, and at the Institute für Refraktive und Ophthalmo-Chirurgie (IROC), Zurich, Switzerland.

theo@seiler.tv

focus on optimising CXL efficacy and performing safe post-CXL visual rehabilitation.

Diagnosing and Testing for Herpetic Keratitis

Howard Larkin reports from the 39th ESCRS Congress in Amsterdam

Herpetic keratitis is a significant ocular issue around the world, with a lifetime risk of about 1% for any individual, and about 120,000 episodes annually in the US and 90,000 more in each of the UK, Italy, and France. Adding to the concern, herpetic keratitis is often visually disabling, with visual acuity dropping below 20/200 in about 10% of cases after 20 years.

Yet like other types of infectious keratitis, diagnosis can be complicated, Marc Labetoulle MD, PhD told delegates, noting traditional methods of identifying infectious keratitis miss about half of the diagnoses.

“Biomarkers are needed to improve the reliability of diagnosis of all types of infectious agents.” Other tools such as molecular and genetic tests may also help, he added.

SLIT-LAMP FIRST

Currently, herpetic keratitis is mostly diagnosed at the slit-lamp. But this can be difficult due to the diversity of its presentation, Professor Labetoulle said. It can be epithelial, appearing as superficial punctate keratitis, dendritic, geographic, limbal, or as an archipelago. It can be endothelial, appearing as disciform, diffuse, or linear; or stromal, with or without ulceration. The end-stage form is neurotrophic, which appears in three stages.

He noted it is critical to distinguish between certain types of herpetic keratitis at the outset.

One of the main questions is, “Are steroids contraindicated?” Cases that are epithelial and replicative, stromal and necrotizing, or neurotrophic should not be treated with steroids, at least until the antiviral drugs have not improved the situation, he emphasised.

He also differentiated between true dendritic keratitis that is fractal in shape with early fogging (which can be treated with antivirals), pseudodendritic (which has raised edges), and no diffusion of fluorescein (which calls for withdrawal of medications with preservatives, topical antivirals, antibiotics, and steroids). Pseudodendritic cases are better treated with lots

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of saline and eyedrops. Further, necrotising stromal keratitis is characterised by white and opaque lesions versus opalescent and translucent for non-necrotising.

THEN TESTING

Since these variations require different treatments, a correct diagnosis is critical, Prof Labetoulle said. So, after the slit-lamp evaluation comes testing.

Serum and tear levels of herpes simplex virus (HSV) antibodies are not reliable, he noted. Nor are virus cultures, immunofluorescence, immunochemistry, or hybridisation.

PCR testing is much more efficient than these conventional tests, which Prof Labetoulle does not recommend because they waste resources. Tests of corneal scraping are much more reliable than tear samples in severe cases, but tear sampling is painless and easy to perform. However, quantitative PCR correlates to the expected rate of HSV replication on the ocular surface. Combining PCR with antibodies in tears significantly raises the sensitivity and specificity over the individual tests, raising the positive predictive value to up to 98%, he said. Pitfalls of PCR testing include inhibition of the polymerase chain reaction by eyedrops, including fluorescein, lissamine green, and Bengal rose stains.

Sampling should be considered in cases with unusual presentation and when drug resistance is suspected (this is, however, very infrequent), which can help identify treatments that may be successful. Prof Labetoulle sees the future of diagnosis as a lab on a chip, detecting multiple biomarkers from a single tear.

“A good sampling is an early sampling,” he said. He also anticipates continuing collaboration with microbiologists to investigate cases.

Marc Labetoulle MD, PhD is professor and chair, Ophthalmology Department, Université Paris-Saclay, Paris, France. marc.labetoulle@aphp.fr

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Forecasting the Future for Suprachoroidal Shunts

One surgeon tells why they will be a niche procedure for select surgeons and patients.

Cheryl

Guttman Krader

reports from the 39th Congress of the ESCRS in Amsterdam

Increasing aqueous outflow through the suprachoroidal pathway is a potentially powerful method for lowering IOP. However, available evidence from studies with ab-interno suprachoroidal implants indicates they have limitations in terms of both safety and efficacy, according to Luís Abegão Pinto MD, PhD.

EVIDENCE ON EFFICACY

Outcomes data for ab-interno suprachoroidal shunt surgery are limited. Results from clinical trials following patients for six months to two years after implantation with the MINIject (iStar Medical) show there is less than a 50% chance patients will be drop-free and achieve an IOP in the low teens.

Data from two years of follow-up in the randomised COMPASS trial showed the percentage of patients who were medication-free with an IOP <18 mmHg was significantly higher in the group that had combined CyPass Micro-Stent (Alcon) and cataract surgery versus cataract surgery alone. Dr Pinto noted the mean baseline IOP for this study’s subjects was relatively high (>21 mmHg) because the protocol involved preoperative glaucoma medication washout. Data from a realworld study show lower IOP-lowering efficacy among eyes with a baseline IOP <21 mmHg, he said.

Addressing the question of whether suprachoroidal shunts will survive long-term, Dr Pinto suggested a segment of glaucoma surgeons will likely adopt these devices. A wider uptake might be limited by multiple issues, including efficacy dependent on baseline IOP, non-negligible adverse events, and the technically challenging nature of the surgery itself.

“The main reasons to perform surgery in patients with low baseline IOP is to reduce IOP to the low teens or give a better quality of life by making patients drop-free. The question is whether these devices can meet those goals. Perhaps they are useful for patients with a very high IOP,” Dr Pinto speculated.

Suprachoroidal shunts: how safe are they?

Recommendation1: MIGS trials should NOT induce: > 10% acute loss AND <2% loss/year Should allow >1.000 at age 72

Cypass study (COMPASS XT)2: correct placement of device stays within acceptable range (1.39%) incorrect placement of device magni es (>4x) the acceptable ECL.

“Surgeons have to be really good with the implantation to get the efficacy desired without compromising safety.”

SAFETY AND SURGERY OBSTACLES

Suprachoroidal shunt surgery is challenging. Available data show the device is misplaced in almost 10% of eyes, even when experienced surgeons conduct the procedure. Data from the three-year safety extension of the CyPass randomised trial showed poor placement increases the risk for significant endothelial cell loss.

“Surgeons have to be really good with the implantation to get the efficacy desired without compromising safety,” Dr Pinto said.

As another consideration—the cleft is not silent. Fibrosis in the suprachoroidal space can lead to occlusion of the device or surrounding iatrogenic cleft, resulting in severe IOP spikes in a significant number of patients.

“Unlike with a bleb, surgeons cannot monitor what is happening with fibrosis in the suprachoroidal space,” Dr Pinto said.

TARGET POPULATIONS

Considering current suprachoroidal shunt surgery knowledge, Dr Pinto suggested this technology would likely be adopted by surgeons who: have skill with intraoperative gonioscopy, are comfortable handling the potential anterior chamber complications, and accept the need for long-term, frequent patient monitoring. He proposed that the best candidates for a suprachoroidal shunt include patients with mild to moderate glaucoma not requiring surgery that will eliminate topical treatment, as well as individuals for whom a bleb-less procedure is indicated because of the state of the conjunctival tissue.

Alcon announced a global voluntary recall of the CyPass Micro-Stent in August 2018 over concerns about long-term endothelial cell loss.

The MINIject (iStar Medical) recently received an investigational device exemption (IDE) from the US FDA that allows it to begin a clinical trial.

Luís Abegão Pinto MD, PhD is an assistant professor of pharmacology and ophthalmology, Lisbon University, Portugal. abegaopinto@gmail.com

iStar MINIject

Improving MIGS Outcomes with Aqueous Outflow Imaging

Multiple approaches described, all still evolving.

Cheryl

Guttman Krader reports from the 39th ESCRS Congress in Amsterdam

Minimally invasive glaucoma surgery (MIGS) procedures that aim to increase conventional aqueous outflow have benefits because of their ease and safety but can fall short in their IOP lowering effect.

While various imaging approaches have been successfully used to improve aqueous humour outflow understanding, none of the techniques tried so far has all the characteristics that describe a clinically practical and effective approach that can improve surgical methods and outcomes, according to Alex A Huang MD, PhD.

“An ideal imaging method would be one used pre- or perioperatively so that it gives knowledge just prior to the actual surgery. It should be non-invasive and physiologic, meaning it is done without creating wounds or needing any visualisation agents. And it should be based on positive imaging [so] the user is looking to identify a signal rather than for something lacking or disappearing,” Dr Huang said.

“In addition, the method should be informative to guide the surgery performance and predict success and easy in terms of technical feasibility, the number of steps required, and time intensiveness. Together, these criteria make the ideal aqueous humour outflow imaging methods for improving patient care.”

TRIED BUT CARRYING LIMITATIONS

Describing his group’s work to evaluate OCT imaging and automated segmentation of Schlemm’s canal and collector channels, Dr Huang said drawbacks include very time-intensive imaging acquisition and processing. Furthermore, the clinical meaning of the information it provides is unclear.

“If we see a dilated pathway, does that mean there is more flow or a trapped pocket of fluid that can’t get out?” he asked.

Fluorescein channelographic/canalographic examination is an approach used during viscocanalostomy or canaloplasty to visualise outflow pathways. This approach, however, is performed after trabecular MIGS and suffers from being invasive and nonphysiologic, Dr Huang said.

Imaging of the episcleral venous fluid wave created by a surge of BSS has been used to evaluate trabecular outflow after trabectome surgery and suggested as a possible predictor of surgical outcomes. However, this is a nonphysiologic measure and relies on a negative imaging technique to look for loss of signal after the surgery.

Haemoglobin video imaging of aqueous outflow into the vascular system using a monochromatic camera is preoperative, non-invasive, and physiologic. However, it is not yet a real-time assessment owing to custom analyses and loses the big picture because it is magnified on a small field with examination of individual veins.

Addressing the latter limitation, Dr Huang and colleagues worked on developing aqueous angiography to evaluate aqueous humour outflow and designed a two-tracer method using indocyanine green followed by fluorescein to show outflow improvement after trabecular MIDS. On the plus side, this technique can be done before and after the surgery, has positive imaging, and is “sort of” physiologic, Dr Huang said. But their method has limitations as well as invasive and particularly complex in terms of steps and personnel needed.

“What would be nice is if we could image something that is endogenous and in a positive way,” he said.

He proposed vitamin C imaging as one possibility, but this presents a technical challenge.

“The concentration of vitamin C is 100-fold higher in the aqueous than in the serum. However, vitamin C is a very bland molecule, so it is hard to image,” he explained.

Alex A Huang MD, PhD recently joined the Shiley Eye Institute at the University of California, San Diego, USA, as Alfred Vogt Chair in Ophthalmology. ahuang@doheny. org or alhuanga@yahoo.com

“An ideal imaging method would be one used pre- or perioperatively so that it gives knowledge just prior to the actual surgery.”

New Glaucoma Medications

Pharmacological advances may reduce patients’ need for multiple eyedrops. Roibeárd O’hÉineacháin reports from the 39th Congress of the ESCRS in Amsterdam

New IOP-lowering topical medications with complementary modes of action and new drug delivery systems may help reduce or eliminate the need for multiple eyedrops in glaucoma treatment, reports Simonetta Morselli MD.

Dr Morselli noted that research shows most glaucoma patients will need multiple eyedrops over time. For example, in the Collaborative Initial Glaucoma Treatment Study (CIGTS), 75% of patients required two or more eyedrops to achieve their target pressure in the first two years. Similarly, in the Ocular Hypertension Treatment Study (OHTS), 49% of patients needed two or more eyedrops to have a 20% reduction of IOP after five years.

The inconvenience and discomfort of having to use multiple eyedrops a day can have a considerable impact on a patient’s quality of life and may cause long-term harm to the conjunctiva, Dr Morselli said. Many glaucoma patients may therefore adhere poorly to their eyedrop regimens. In addition, some patients have ocular or systemic diseases that make eyedrops difficult and sometimes impossible to use. She noted that in a survey she and her associates conducted in Italy, 80% of patients were not able to apply drops correctly.

NEW IOP-LOWERING MEDICATIONS

Several new IOP-lowering medications with alternative modes of action have entered the market that may reduce the need for multiple drops eyedrop, Dr Morselli said. They include nitric oxide (N0)-donating prostaglandin analogues, such as Latanoprostene bunod (Vyzulta™, Bausch and Lomb), and Rho-Kinase (ROCK) inhibitors such as netarsudil (Rhopressa, Aerie Pharmaceuticals).

Latanoprostene bunod has two modes of action. It metabolises into latanoprost acid, which increases aqueous humour outflow through the uveoscleral pathway. Butanediol mononitrate releases N0 and increases outflow through the trabecular meshwork and Schlemm’s canal.

In the international multicentre APOLLO study, openangle glaucoma and ocular hypertension patients receiving latonoprostene bunod had IOP reductions from 8.0 mmHg to 9.0 mmHg, compared to reductions of only 6.5 mmHg to 7.5 mmHg among patients receiving timolol.

ROCK inhibitors like netarsudil lower IOP by relaxing the trabecular meshwork, increasing trabecular outflow. In a study involving nearly 900 patients, almost twice as many patients who received a fixed combination of netarsudil and latanoprost (Rocklatan, Aerie Pharmaceuticals) achieved a 30% reduction in IOP compared to those receiving latanoprost alone. Three times as many patients in the Rocklatan group achieved an IOP reduction of 40% as in the latanoprost monotherapy group.

ALTERNATIVES TO DROPS

Dr Morselli noted that new sustained-release drug delivery systems for IOP lowering medications are showing promising results in clinical trials and preclinical testing. They include topical bimatoprost inserts designed for placement in the upper fornix, Travaprost and latanoprost punctal plugs, implants placed in the anterior chamber, and drug-eluting IOLs.

In addition, evidence continues to confirm the efficacy of selective laser trabeculoplasty (SLT) in reducing the glaucoma patients’ need for IOP-lowering medication. For example, in the LIGHT trial 74 2% of treatment-naive patients with primary open-angle glaucoma or OHT randomised to SLT required no eyedrops and none required glaucoma surgery to maintain target intraocular pressure at three years follow-up.i

i Gazzard G. et al, The Lancet 2019, 393; 10180: 1505–1516.

Simonetta Morselli MD is Head of the Ophthalmology Department, S. Bassiano Hospital, Bassano del Grappa, Italy. simonetta.morselli@gmail.com

Ocular Tumours

Alarge-scale epidemiological study of retinoblastoma in Cuba suggests that high survival rates can be achieved despite limited resources in treatment, a new study concludes.

“The incidence rate of retinoblastoma in Cuba has been stable over the past nine years, with Cuban retinoblastoma patients achieving five-year survival estimates similar to the United States, despite limited resources,” Liudmira González Rodriguez MD said.

She added, however, that lower ocular survival is related to the high number of unilateral and advanced retinoblastoma cases and the limited resources of treatment.

“Future studies are necessary to determine whether the Cuban model can be replicated to improve retinoblastoma outcomes in other similar resource-limited settings,” she said.

Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child’s life and vision, Dr González Rodriguez noted. However, patients from lower-income settings often present with late disease, many with extraocular extension and some already with metastasis, and their prognosis is poorer than patients living in higher-income settings.

“About 80% to 90% of children with retinoblastoma live in developing countries, and there is a disparity in overall and ocular survival between higher and lower income countries. However, the epidemiology of retinoblastoma is not well understood nor clearly reported in Cuba, which was one of our main motivations for conducting this study. Furthermore, because Cuba represents a well-defined and enumerated population, it is a unique setting in which to study the epidemiology of this disease,” she said.

The retrospective study included 76 patients in Cuba diagnosed with retinoblastoma between 2010 and 2018. The fiveyear overall survival rates were calculated for cases diagnosed

during the 2010 to 2012 period. The mean age at diagnosis was 1.2 years (range 0.6 to 2.3 years), 40 were males (52%), and 48 patients (62.3%) were unilateral cases.

Of the 106 eyes included in the study, 38 (36%) had exophytic tumour type and 76 (70%) had class D tumours or higher according to the Intraocular Classification of Retinoblastoma (ICRB). The ICRB divides intraocular retinoblastomas into five groups, A (lowest risk) through E, based on the extent of the cancer and the chances of saving the eye using current treatment options.

Leukocoria was the chief complaint in 53 patients (50%) and strabismus in 22 (21%). A total of 78 eyes (74%) were enucleated. The incidence rate was 1.39 cases per 20,000 live births over the study period.

“The overlapping confidence intervals show the retinoblastoma incidence rates did not differ by year during the study period, which is in line with the theory there are no clear demographic or environmental risk factors associated with retinoblastoma, thereby explaining the stable worldwide incidence rates,” Dr González Rodriguez said.

The overall survival in retinoblastoma cases over a five-year period was 94.6%, compared to the estimated figure of 95.2% for the United States based on the scientific literature, she said.

Cuban study may provide template for other resource-limited settings. Dermot McGrath reports from the EURETINA 2021 Virtual Meeting

Liudmira González Rodriguez MD is an ophthalmologist at the Cuban Institute of Ophthalmology in Havana, Cuba. liudmilagr@infomed.sld.cu

Brolucizumab for DME

Brolucizumab-dbll 6 mg (Beovu®, Novartis) may prove useful in diabetic macular oedema (DME) treatment, according to study data presented by Dilsher Dhoot MD during the Retina Subspecialty Day.

Presenting the 52-week results from the KESTREL and KITE studies, Dr Dhoot reported brolucizumab 6 mg was non-inferior to aflibercept in the primary endpoint analysis of mean change in BCVA from baseline at week 52. Patients in the brolucizumab arms received fewer injections compared to the aflibercepttreated patients.

“In both KESTREL and KITE, more than half of patients treated with brolucizumab 6 mg were maintained on a quarterly dosing schedule through week 52 after completing the loading phase. During the first year, brolucizumab-treated patients received a median of seven injections versus nine injections for the aflibercept groups,” Dr Dhoot said.

Treatment with brolucizumab 6 mg was associated with early and durable robust improvements in central subfield thickness (CST) from baseline. Compared to aflibercept, higher proportions of patients treated with brolucizumab 6 mg achieved overall fluid resolution (intraretinal and/or subretinal) and intraretinal fluid resolution.

Importantly, the adverse event data from the two studies showed no evidence that underlying diabetes had a negative impact on a brolucizumab-related incidence of intraocular inflammation.

“The sample size [in KESTREL and KITE] is too small to conclude diabetes is somehow protective against intraocular inflammation. However, we can potentially conclude diabetes is not deleterious as we compare the DME patients to the population in the nAMD trials,” said Dr Dhoot, commenting on the safety profile of brolucizumab in the DME studies relative to that observed in the neovascular age-related macular degeneration clinical trials.

STUDY DESIGN

KESTREL and KITE have a planned follow-up of 100 weeks. Enrolling a total of 926 patients across 36 countries, the studies are comparing brolucizumab with aflibercept administered according to its labelled directions (five monthly injections, then every eight weeks). KITE investigated only the 6 mg dose of brolucizumab. KESTREL included 3 mg and 6 mg brolucizumab arms—but the 3 mg dose did not meet the non-inferiority margin in the primary endpoint analysis of mean change in BCVA from baseline at week 52.

All brolucizumab groups received five loading doses given at six-week intervals and then entered a maintenance phase with injections given every 12 weeks. Based on findings at prespecified disease activity assessment visits (weeks 32, 36, and 48 in the first year), the brolucizumab injection frequency could decrease to every eight weeks per the masked investigator’s discretion.

ANATOMIC DATA DETAILS

Dr Dhoot noted data from the week 32 and week 52 visits give a unique opportunity to evaluate brolucizumab and aflibercept in a head-to-head fashion concerning anatomic timepoints.

“At week 32, patients are eight weeks out after receiving their last doses in all treatment arms, and at 52 weeks, the aflibercept patients and half of the brolucizumab patients are four weeks postdosing while the remaining brolucizumab patients on the q12w interval are eight weeks postdosing. Therefore, the week 52 assessments actually favour aflibercept.”

Against that background, Dr Dhoot reported that in KITE, the mean change in CST from baseline averaged from visits at weeks 40 to 52 was significantly greater in the brolucizumab 6 mg group compared to aflibercept (-187.1 vs -157.7 microns). In addition, the proportion of eyes reaching a CST ≤280 microns were significantly greater with brolucizumab 6 mg at week 32 and week 52 versus aflibercept.

Furthermore, smaller proportions of patients in the brolucizumab 6 mg groups had intraretinal and/or subretinal fluid present at weeks 32 and 52 compared to the aflibercept groups. Looking only at intraretinal fluid showed it was present in fewer patients in the brolucizumab 6 mg groups than the aflibercept groups at weeks 4, 16, 32, and 52.

Brolucizumab was also associated with clinically relevant improvements in diabetic retinopathy. In both KESTREL and KITE, 29% of patients treated with brolucizumab achieved a ≥2-step improvement in DRSS score from baseline at week 52. For this endpoint, pooled results from the two studies showed non-inferiority of brolucizumab 6 mg to aflibercept.

ADVERSE EVENTS

Overall rates of ocular and nonocular adverse events were similar among treatment groups in each study. Across all five study arms, there were five cases of endophthalmitis, including one with brolucizumab 6 mg and two with aflibercept. Three cases of endophthalmitis were culture positive.

Brolucizumab was associated with higher intraocular inflammation rates than aflibercept only in KESTREL, and the rate was higher with brolucizumab 3 mg versus 6 mg (4.7% vs 3.7%). The seven cases recorded in the 6 mg arm included one case of retinal vasculitis in a patient who also had a retinal vascular occlusion.

“Both the retinal vasculitis and retinal vascular occlusion resolved without treatment, and the patient had a 14-letter gain from baseline BCVA at week 52,” Dr Dhoot reported.

In KITE, the intraocular inflammation rate was 1.7% in both the brolucizumab 6 mg and aflibercept arms. There was a single case of retinal vascular occlusion in each arm that was not related to intraocular inflammation.

Pivotal trial data show robust efficacy with reduced injection burden and favourable safety.

Cheryl Guttman Krader reports from AAO 2021 in New Orleans, USA

Dilsher Dhoot MD practices at California Retina Consultants, Santa Barbara, California, USA. ddhoot@yahoo.com

Intraretinal Gene Therapy with ADVM-022

Treatment for DME halted because of worrisome adverse events. Cheryl Guttman Krader reports from AAO 2021 in New Orleans, USA

The INFINITY phase 2 clinical trial—investigating ADVM022 treatment for diabetic macular oedema (DME)— launched after the novel intraretinal gene therapy product showed durable efficacy and acceptable safety in the OPTIC study evaluating its use for treating neovascular age-related macular degeneration.

The adverse events emerging in INFINITY indicated ADVM022 had a very different safety profile in eyes with DME. The results from INFINITY highlight the need to consider the severe comorbid nature of patients with DME and prompted the industry sponsor (Adverum Biotechnologies) to focus on nAMD treatment using low doses of ADVM-022.

Reviewing the results from the two clinical trials, David Boyer MD said, “Much to our surprise (because it was not seen in OPTIC), ADVM-022 treatment in patients with DME caused a marked increase in both anterior segment and posterior segment intraocular inflammation (IOI). There were iris-related events, including transillumination defects, synechiae, and pigmentary changes. More importantly, three patients (25%) in the high dose ADVM-022 group developed severe hypotony (IOP ≤5 mmHg), necessitating surgery with silicone oil and an intravitreal corticosteroid implant.”

The difference in safety between the OPTIC and INFINITY trials is being studied and is unknown, he told delegates.

INFINITY DESIGN AND DATA

ADVM-022 is designed to provide continuous delivery of aflibercept. INFINITY randomised patients into one of three arms to receive ADVM-022 2x1011 vg (vector genome)/eye, ADVM-022 6x1011 vg/eye, or aflibercept 2 mg. Patients in the ADVM-022 groups were further randomised to an initial aflibercept or sham injection.

The primary endpoint assessed time to worsening of DME disease activity in the study eye necessitating supplemental

aflibercept injection. Over 24 weeks of follow-up, very few patients in either ADVM-022 treatment arm needed rescue. BCVA and central subfield thickness remained stable during follow-up to week 34, Dr Boyer reported.

“We also saw tremendous improvement in diabetic retinopathy severity after a single ADVM-022 injection. At 24 weeks, 46% of patients in each of the ADVM-022 groups had a two-step or greater improvement from baseline in the Diabetic Retinopathy Severity Scale score. Rates of a three-step or greater improvement were 36% and 18% in the low dose and high dose groups, respectively,” he said.

The safety data showed intraocular inflammation with ADVM022 was dose-dependent. Significant inflammation based on the presence of anterior chamber and vitreous cells was seen in the 6x1011 vg/eye group. There were very few patients with anterior chamber cells and vitreous cells in the low dose gene therapy. The rate of iris-related events was also higher in the high dose group, and clinically relevant reductions in IOP were observed only in the high dose group, Dr Boyer said.

OPTIC SAFETY REVIEW

In OPTIC, ocular adverse events related to ADVM-022 were mostly mild (83%), and none were severe. Ocular inflammation in eyes treated with ADVM-022 2x1011 vg/eye was minimal and responded to topical steroid treatment. The higher dose of ADVM022 was associated with a little more inflammation, but there was no clinical or fluorescein evidence of posterior inflammation with either dose or any cases of clinically relevant low IOP.

David Boyer MD is Senior Partner at Retina-Vitreous Associates Medical Group, Los Angeles, USA. vitdoc@aol.com

Refractive Lenticule Extraction

Early results of newer lasers suggest competition for SMILE. Howard Larkin reports from the 39th Congress of the ESCRS in Amsterdam

Over the past decade, small incision lenticule extraction (SMILE) using the VisuMax® femtosecond laser (Carl Zeiss Meditec, Germany) has established itself as a viable alternative to LASIK and PRK for corneal refractive surgery.

Now two more options are emerging in the refractive lenticule extraction market: corneal lenticule extraction for advanced refractive correction (CLEAR) using the FEMTO LDV Z8 and Z8 NEO femtosecond laser platforms (Ziemer), and SmartSight, using the ATOS femtosecond laser

(SCHWIND eye-tech-solutions). Both are CE marked for the procedures. Maja Bohač MD, PhD presented the first European results of SmartSight at the Congress.

LOWER LASER POWER

Potential improvements the ATOS system brings include lower laser power levels at higher repetition rates, which may result in a more accurate treatment, and cyclotorsion control during surgery, which may improve astigmatism correction and decrease vertical coma, Dr Bohač said.

Concept of eye tracker guided centration at SCHWIND ATOS. Eye-tracker-guided centration accomplishes centration and docking of the eye to the system. A camera provides the operator with a coaxial view through the cone of the patient interface, including static overlays of the target pupil position (yellow crosshair) surrounded by two concentric hot zones (target hot zone of 200 µm radius, marked as a yellow circle; maximum permissible hot zone of 700 µm radius marked as a red circle). Instructed to move the patient table, the operator brings the pupil (detected by a video-based Eye-Tracker, green crosshair) coincident with the target pupil position, or as close as possible, i.e., within the yellow circle. Then suction is applied, and it is confirmed that the pupil remains within the yellow circle (target hot zone), or at least within the red circle (maximum permissible hot zone); otherwise a new docking is attempted. Further, the last valid laser eye-tracker video frame is used for cyclotorsion control, and the torsional misalignment from the diagnostic image is determined and accounted for (torsional deviation displayed by the rotated green crosshar.

The device also adds a refractive transition zone at the edge of the lenticule, possibly improving quality of vision. Because the lenticule has a zero-thickness edge, it is easier to extract without leaving lenticule fragments behind and requires no minimum lenticule thickness, she added.

In a non-randomised prospective cases series enrolling 60 eyes of 31 patients, 97% achieved uncorrected distance visual acuity (UDVA) of 20/20 or better three months after surgery, Dr Bohač reported. All achieved a spherical equivalent (SEQ) refraction within 0.5 dioptres of the target, and UDVA postoperative was within 1 Snellen line of preoperative corrected vision for 97% of patients. She expects unaided vision will continue to improve.

All patients underwent uneventful SmartSight lenticule extraction, Dr Bohač said. Preoperatively, mean spherical manifest refraction (MRSE) was -4.9±1.7 D (-3.25 to -7.5), and astigmatism was -0.62±0.33 D (-2.00 to -0.25).

“An excellent refractive outcome was observed in terms of manifest refraction, but this was only partly confirmed by the objective refraction and topographical changes. This suggests manifest refraction may be more forgiving in [precisely] determining accuracy of the treatments. At the same time, UDVA is the main driver for patient satisfaction,” Dr Bohač said.

Safety was also satisfactory. One eye lost two Snellen lines of CDVA, though this reversed after a few months, caused by severe dry eye and interface haze due to use of cyclosporine

during recovery, Dr Bohač said. Higher-order aberrations were induced, but not at levels that rose to clinical significance, she added. The three-month results of this cohort have been submitted for publication.

Samuel Arba-Mosquera PhD, of SCHWIND, reported similar 12-month results for SmartSight lenticule extraction from a study conducted by Kishore Raj Pradhan MD, Head of Refractive Surgery at the Tilganga Institute of Ophthalmology and Director of Matrika Eye Center, Kathmandu, Nepal.

The observational study included 221 eyes of 114 patients consecutively treated with SmartSight. The mean age of patients was 28 years with a mean spherical equivalent manifest refraction of -6.26 D and astigmatism of 0.92 D before surgery. These values lowered to an SEQ of +0.48 D and astigmatism of 0.13 D one year after surgery. Mean postoperative uncorrected distance vision was 20/21, with 96% reaching 20/20. Most, 95%, had uncorrected postoperative vision within one line of best-corrected preoperative vision, Dr Arba-Mosquera reported. Just 1% of eyes lost one line, and no eyes lost two lines of corrected vision.

In terms of objective refractive outcomes, R2 for attempted versus actual change in K readings for SEQ was 0.886. There was a trend towards less accuracy at higher corrections, with 70% of eyes within 1.0 D of the ideal average K for the intended target, Dr Arba-Mosquera said.

The figure shows the difference in central epithelial thickness at 12 months postoperatively versus the preoperative baseline. This difference has plotted against the refractive power of the correction, and it shows little to no correlation. On average, the central epithelium thickened by ~3 µm, with maximum changes of 12 µm thicker to 6 µm thinner compared to the preoperative baseline. The vast majority of the data points suggest a minimum change in central epithelial thickness between zero and 5 µm.

-2-4-6-8-10-12

Difference between UDVA and CDVA.

Postoperative changes in central corneal thickness and central stromal thickness were minimal over the 12 months, suggesting about 3.0 μm of corneal (epithelial) remodelling, he noted. Correction of spherical error was more predictable than for astigmatism, but both were substantially improved. The three-month results of part of this cohort have been publishedi, and these 12-month reported results are accepted for publication.

ANOTHER OPTION

There were also reports of successful corneal lenticule extraction using the FEMTO LDV Z8, which also features lower pulse power and the ability to recentre the laser after docking. These studies include a series of five eyes where a complete lenticule dissection and extraction were performed through two 3.0 mm tunnel incisions, one leading to the posterior and one to the anterior planes. Clear corneas were observed on the first day post-surgery.ii

Similarly, a prospective study involving 24 eyes in 24 patients operated with the FEMTO LDV Z8 for moderate to high myopia reported a median value of uncorrected visual acuity one week after surgery of decimal 0.9 (0.7–1.0), and after one month of 1.0 (1.0–1.0). The research did not observe any intraor postoperative complications, and 79.2% of patients had no loss of maximum corrected visual acuity. The mean corneal thickness before surgery was 555.9±28.2 μm, which decreased significantly to an average value of 464.8±26.9 μm one week after surgery (p<0.05).iii

i J Refract Surg., 2021 May; 37(5): 304–311.

ii Izquierdo L et al., J Cataract Refract Surg., 2020 Sep; 46(9): 1217–1221.

iii Doga AV et al., Vestn Oftalmol., 2020; 136(6. Vyp. 2): 214–218.

Samuel Arba-Mosquera PhD is an optical and vision researcher at SCHWIND eye-tech-solutions. samuel.arba.mosquera@eye-tech.net

Maja Bohač is Head of Refractive Surgery at the Svjetlost Eye Clinic, Zagreb, Croatia. maja.bohac@svjetlost.hr

Ametropia after Refractive Lens Exchange

Treat the patient, not the refractive error. Cheryl Guttman Krader reports from the 39th Congress of the ESCRS in Amsterdam

Surgeons need to be aware that a refractive surprise can occur in an appreciable percentage of cases of refractive lens exchange and residual refractive error is the primary reason for patient dissatisfaction after premium IOL surgery.

As good news, a refractive surprise can be managed with excellent results in most patients, said Nic J Reus MD, PhD.

Speaking at the ESCRS Congress about managing ametropia after refractive lens exchange, Dr Reus discussed identifying the cause and corrective options. He said avoiding patient dissatisfaction because of a refractive surprise, however, begins with appropriate preoperative counselling.

“How many refractive surprises you encounter in practice depends on how you managed patient expectations before surgery. Suggesting to patients with high ametropia the surgery will reduce the refractive error is very different from saying they will be completely spectacle independent,” Dr Reus emphasised.

“We also have to recognise and take into account in our preoperative counselling that the refractive outcome will not be within 1 D of target in perhaps 5% of patients, and we cannot achieve perfect reduction in astigmatism with toric IOLs in all patients.”

REVIEWING MANAGEMENT OPTIONS

Correcting residual ametropia with spectacles or contact lenses is always a viable option, even though most patients do not hope for this outcome when choosing refractive lens exchange.

In eyes with a toric IOL and residual astigmatism, rotating the lens may correct the problem. Surgeons can plan the procedure using online tools such as www.astigmatismfix.com or with the Barrett Rx formula at www.apacrs.org.

Surgeons can also consider excimer laser enhancement, but an ASCRS paper advised using this approach only to correct spherical errors ≤1.0 D. IOL exchange can be done in cases with larger refractive errors and hyperopic errors, but carries risks of posterior capsule rupture, corneal oedema, and surgically induced astigmatism because of its larger incision. Options for power calculations in IOL exchange include refractive vergence formula, Holladay R formula, or Barret Rx formula.

Sulcus placement of an add-on IOL is another option that is technically relatively easy, very predictable, and done through a smaller incision. With this approach or any surgical correction, patients need to be informed the procedure may exacerbate ocular surface disease and bothersome dry eye symptoms, Dr Reus said.

If performing the bilateral refractive lens exchange sequentially rather than simultaneously and a refractive surprise appears in the first eye, the error can be taken into account by adjusting the IOL power when treating the fellow eye. In this situation, the second IOL power should be between 30% and 50% of the prediction error, he explained.

PEARLS FOR PATIENT COUNSELLING

ANALYSING THE CAUSE

Before planning any intervention for a refractive surprise, surgeons should wait at least six weeks for the refraction to stabilise after the primary surgery. Then, a meticulously performed complete ophthalmic examination—including manifest refraction, slit-lamp exam, corneal topography, and biometry—is needed to understand the cause.

“I often retake the keratometry measurement myself with a Javal keratometer. [Bear in mind] getting the most plus refraction is especially important in eyes implanted with the newer monofocal plus, extended depth of focus, and trifocal IOLs. Although you probably did a careful slit-lamp examination preoperatively, you may have missed some preexisting pathology, or there may be capsular fibrosis, ophthalmic viscosurgical device behind the IOL, or cystoid macular oedema,” Dr Reus observed.

Check IOL power by comparing the power of the implanted lens with the intended power and by reviewing the biometric data used for the calculations. Dr Reus suggested using optimised and even personalised lens constants and choosing the right formula could minimise power calculation errors.

“Personally, I like to use the Barrett Universal II and Barrett Toric formulas that include the posterior corneal astigmatism,” he said.

A refractive surprise may not be the surgeon’s fault, given the unknowns accompanying the surgery, including effective lens position. Nevertheless, Dr Reus advocated offering patients an apology while explaining the reason for the outcome.

Management discussions should include the various options, the possible complications, and the pros and cons of treating the refractive surprise.

“Please explain any spectacle dependency. For example, patients who had a trifocal IOL and want it exchanged for a monofocal IOL because of bothersome dysphotopsia may not realise they will no longer be able to read without glasses,” Dr Reus said.

“Or, if patients have halos at night because of residual myopia after monofocal IOL surgery, they need to know they might lose their ability to read without correction after a refractive enhancement.”

Dr Reus concluded his presentation with sound advice: “Treat the patient, not the refractive error. It can be that you are more unhappy than the patient.”

Photo copyright: LINK Photography

Nic J Reus MD, PhD is in the Department of Ophthalmology, Amphia Hospital, Breda, the Netherlands. nreus@amphia.nl

“How many refractive surprises you encounter in practice depends on how you managed patient expectations before surgery.”

High Levels of Safety and Efficacy for New Aspheric Monofocal Lens

Dermot McGrath reports from the 39th Congress of the ESCRS in Amsterdam

The Clareon® aspheric monofocal lens delivered excellent visual outcomes and stable refractive results with very low rates of posterior capsule opacification (PCO) for up to two years after implantation, according to Rudy MMA Nuijts MD, PhD, who presented the two-year interim results of the IOL study.

“The two-year visual outcomes were excellent, with stable refractive results. There were no unanticipated adverse events, and very low rates of PCO and Nd:YAG capsulotomies were observed,” he said.

Conducted at 16 different study centres in Europe and three in Australia, the ongoing prospective, multinational, single-arm trial is assessing the long-term safety and effectiveness of the Clareon (Alcon Vision LLC) lens implanted in patients who required bilateral cataract extraction.

Discussing the properties of the lens, Professor Nuijts described it as a novel monofocal aspheric hydrophobic lens composed of flexible acrylic material with a high refractive index. Based on the AcrySof® platform, the foldable, singlepiece IOL is designed for implantation in the capsular bag through a 2.2 mm incision using the dedicated AutonoMe™ preloaded injector system.

“The Clareon has been developed with an improved manufacturing process yielding a smoother surface, patented edge profile, and improved water distribution, leading to reduced glistening formation,” he said.

Inclusion criteria for the study were adults more than 22 years of age with bilaterally visually significant cataract and a preoperative best-corrected distance visual acuity (BCVA) worse than 0.2 logMAR in the better-seeing eye. The IOL power was calculated to achieve a postoperative spherical equivalent within 0.50 D of emmetropia using the available IOL range of +15.00 D to +25.00 D.

Of 245 patients initially enrolled, 215 were implanted, 209 of which were bilateral cases. At two years postoperatively, a total

of 190 first eyes (88.4%) and 189 second eyes were available for analysis, Prof Nuijts reported.

At two years, the postoperative monocular mean corrected distance visual acuity (CDVA) was 0.03 logMAR in first and second eyes, and more than 96% of eyes had CDVA of 20/25 or better.

The mean manifest refractive spherical equivalent was also within target by one week postoperatively and maintained at 0.06 D in first and second eyes at two years. There were no unanticipated adverse events.

Clinically significant posterior capsule opacification (PCO) was reported for 3 first (1.4%) and 5 second (2.4%) eyes. Clinically significant PCO requiring Nd:YAG laser capsulotomy was reported for 3 first (1.4%) and 5 second (2.4%) eyes. Grade 0 glistenings were reported in 386 out of 387 eyes.

The efficacy and safety of the Clareon lens was confirmed by a 12-month multicentre clinical trial at 16 sites carried out in the United States and presented by David Lubeck MD.

Of 342 patients who completed the study, more than 99% achieved monocular CDVA of 0.3 logMAR or better, and 87% achieved monocular CDVA of 0.04 logMAR or better. The most common non-serious adverse event was posterior capsule opacification in 5.4%, with an Nd:YAG laser rate of 4.6% at 12 months.

Rudy MMA Nuijts MD, PhD, is Professor of Ophthalmology, Vice Chairman, and Director of the Cornea Clinic and the Center for Refractive Surgery at the University Eye Clinic Maastricht, Maastricht University Medical Center (MUMC), the Netherlands. rudy.nuijts@mumc.nl

Refractive

The TECNIS Eyhance (Johnson & Johnson Vision) refractive extended depth of focus lens (EDOF) provides similar distance vision and quality of vision to an aspheric monofocal lens while enhancing intermediate vision both monocularly and binocularly, according to a study presented by Dr Mayank A Nanavaty.

Monofocals, he said, are the most commonly used intraocular lenses due to factors including low cost, excellent distance vision, fewer dysphotopsias than diffractive lenses, and their ability to be used in eyes with retinal and other pathologies.

However, the Eyhance uses a refractive design that continuously changes power from the periphery to the centre of the lens. This means it doesn’t have any rings in it so there is no glare and halos. The result is similar distance vision and aberrations with enhanced intermediate vision at a price typically covered by national insurance plans, he reported.

PROSPECTIVE, RANDOMISED STUDY

In a prospective randomised study involving 47 patients, Dr Nanavaty and colleagues compared uniocular and binocular uncorrected and corrected distance and intermediate visual acuity, wavefront aberrations, and defocus curves of the Eyhance and the RayOne (Rayner) monofocal lens at one and threeto-nine months after surgery. They also interviewed patients regarding glare and halos and administered the Catquest-9SF questionnaire. The follow-up time was initially planned for three months but was extended up to nine months due to the COVID19 pandemic, Dr Nanavaty said.

At follow-up conclusion, there was no significant difference in logMAR measures of corrected distance visual acuity. However, the Eyhance group showed significantly better distance corrected intermediate vision measured at 66 cm and a broader defocus curve (Figure 1). The Eyhance IOL also provided better mean uncorrected distance and intermediate VA, though slightly higher astigmatism in the RayOne IOL group may have accounted for the difference.

There was some difference in spherical aberration, with the Eyhance more negative results, but this was not clinically significant, Dr Nanavaty said.

Neither group had patients report glare or halos. Similarly, both groups saw improvement in Catquest-9SF Rasch scores from preoperative levels, ending with nearly identical scores of 2.91±0.81 for Eyhance and 2.97±0.16 for RayOne.

“In my private practice, I changed my monofocal option to Eyhance because it is a monofocal-plus lens, and it works very well without any glare and halos,” Dr Nanavaty said.

Mayank A Nanavaty MBBS, DO, FRCOphth, PhD is a Consultant Ophthalmic Surgeon at Brighton and Sussex University Hospitals, Brighton, UK. mayank_nanavaty@hotmail.com

IOL enhances intermediate vision, rivals monofocal at distance and quality. Howard Larkin reports from the 39th Congress of the ESCRS in Amsterdam

Figure 1:

A) Uniocular defocus curve at one month. B) Uniocular defocus curve at three-to-nine months.

C) Binocular defocus curve at one month. D) Binocular defocus curve at three-to-nine months.

Selecting Advanced Technology IOLs

Innovations in objective visual behaviour testing help match patients with optimum advanced technology IOLs.

Roibeárd O’hÉineacháin reports from the 39th Congress of the ESCRS in Amsterdam

Subjective and objective preoperative assessment of patients’ day-to-day visual behaviour helps tailor the selection of advanced technology intraocular lenses (AT-IOLs) to their individual visual needs, according to Arthur B Cummings MD, FRCSEd, PCEO.

Dr Cummings noted the COVID-19 pandemic has brought about dramatic changes in consumer behaviour, with greater spending on personal healthcare and well-being. In addition, masks and the resultant fogged glasses have increased the demand for refractive cataract surgery. These trends have coincided with an explosion in the development of advanced technology IOLs, with a wide range of focal properties, including new non-diffractive extended range or EDOF IOLs, monofocalplus IOLs, and trifocal IOLs.

“To keep this momentum going we need to ensure a safe and seamless patient experience with efficacious outcomes and high patient satisfaction,” he said.

Achieving that aim requires the optimisation of every aspect of eye care delivery, with special consideration given to the changes society has adopted in response to the pandemic. For example, booking an appointment online should be as easy as booking a restaurant, flight, or hotel. In addition, the medical history form should be easy to submit from a phone, tablet, or laptop, and the initial consultation should be conducted on a virtual basis wherever possible. This is not only to navigate COVID-19 but in fact provides a better patient experience.

OBJECTIVE VS SUBJECTIVE ASSESSMENT

The subjective assessment of patients’ visual needs, whether in lengthy interviews or questionnaires, has several shortcomings, Dr Cummings noted. Interviews are time-consuming and depend on the patient’s ability to express themselves and the surgeon’s ability to understand them. Questionnaires can provide important information regarding work, lifestyle, and personality type, but they do not show the whole picture and they remain completely subjective.

A new device called the Vivior Vision Behaviour Monitor can objectively obtain a truer assessment of patients’ visual needs. The device uses time-of-flight distance sensors, ambient light, RGB sensors, and inertial and magnetometer sensors to measure patients’ daily visual behaviour.

The Vivior monitor is roughly the size of a USB drive and designed to clip on the side of spectacles. After gathering 36 hours of visual data during the testing period, patients return the device, and the recorded data is uploaded to a cloud site. Artificial intelligence algorithms then provide a profile of the patient’s visual priorities, which can then be compared to the optical performance properties of every IOL with a published defocus curve. In essence, the software determines the most appropriate IOL defocus curve that best matches the patient’s defocus curve.

PREPARING FOR SUCCESS

For surgeons considering the Vivior monitor, Dr Cummings advised patients should be free of all ocular surface morbidity at the time of surgery. In addition, patients should be excluded if they have irregular topography or tomographic signs of disease in the macula or outer retina when considering diffractive AT-IOLs.

In terms of an IOL power calculation, artificial intelligencebased formulas are providing the best refractive outcomes at present, he noted. He also emphasised that, when obtaining informed consent, the surgeon should be sure the patient understands the IOL choices and refractive targets regarding the procedure.

“We are at a turning point in the uptake of advanced technology IOLs. We can increase the odds of success with meticulous planning and execution of procedures with appropriate patient selection and appropriate selection of IOL power and IOL design,” Dr Cummings concluded.

Arthur B Cummings MD, FRCSEd, PCEO is a Consultant Ophthalmologist, Wellington Eye Clinic and Beacon Hospital, Dublin, Ireland. abc@ wellingtoneyeclinic.com

Disclosures: Dr Cummings is MAB of Vivior and Alcon and on Alcon’s Board of Directors.

Demystifying AI in IOL Power Calculations

Does AI disguise more than it explains?

Dermot McGrath reports from the 39th Congress of the ESCRS in Amsterdam

Although there is considerable hype around the potential of artificial intelligence (AI) as a means to improve IOL power calculation accuracy, the reality is a big data approach is less accurate than a physical method such as raytracing, according to Paul-Rolf Preussner MD, PhD.

“A big data approach can be more accurate than classical IOL formulas but not more accurate than a physical approach such as raytracing—particularly so in complex eyes that fall outside the ‘normal’ range of measurements,” Dr Preussner told the conference.

Big data also typically need adjustment for different IOL models and are not appropriate for post-LASIK eyes.

“You cannot take the results from one IOL model and try to apply it to another lens model without losing accuracy. A big data approach is also not applicable to post-LASIK eyes where a full corneal tomography is needed,” he said.

Creator of the OKULIX raytracing software, Preussner said he considers the term “artificial intelligence” a bit of a misnomer when it comes to discussing algorithms for IOL power calculation.

“To be frank, I do not really like the term ‘artificial intelligence’ for software algorithms because I think it disguises more than it explains. Things mostly appear much simpler once you have cracked the mystifying shell.”

In IOL power calculation, the key is to understand the mathematical structure of the impact of the input variables (corneal and axial data) on the output (IOL power and refraction), he explained. The predicted refraction differences can be represented graphically using pseudo-colours for axial eye length and corneal radius function as input valuables.

“These functions are smooth, steady, and monotonic, which means the problem is actually mathematically simple,” he said.

Dr Preussner conducted a study comparing the predicted refraction differences between the SRK/T, Hoffer Q, Holladay I, and Haigis formulas, as well as the Hill RBF algorithm (the “big data” approach) and OKULIX raytracing software in 6,004 eyes implanted with an Alcon SN60WF lens. The Hill RBF algorithm and raytracing method were also compared to a simple two-dimension linear interpolation algorithm (LINEAR) using the same approach.

In terms of the results, Dr Preussner said that comparing the accuracy of the different methods is a “bit like comparing apples with pears” because of the different number of used input variables.

In the study of 6,004 eyes, the Hill RBF using three variables performed better than OKULIX with two input variables, which was better than LINEAR. However, in a subset of 908 eyes and using four input variables for OKULIX (axial length, corneal radius, anterior chamber depth, and lens thickness), OKULIX performed better than Hill RBF and LINEAR.

“All of these methods—Hill RBF, OKULIX, and LINEAR— were better than standard formulas. The differences were statistically significant but are not very relevant clinically,” Dr Preussner said.

Allsubimagesshowthepredictiondifferences(sphericalequivalent)ofthe indicatedmethodsinpseudocolors,asfunctionofaxialeyelengthandmean cornealradius.Thepseudocolordefinitions(look-up-tables)andthehistogram distributionsofthedifferencesareshownintheupperleftcorners.Differencesofmorethan ±0.5Dareindicatedinblack.Suchhigherdifferencesare mostlyfoundinthemarginsofthedistributioninthecomparisonswiththe

Preussner MD, PhD, University Eye Hospital, Mainz, Germany. pr.preussner@uni-mainz.de

Paul-Rolf

Figure1: SystematicDifferencesin6004Eyes

Figure 1: Systematic Differences in 6,004 eyes. All subimages show the prediction differences (spherical equivalent) of the indicated methods in pseudocolors, as function of axial eye length and mean corneal radius. The pseudocolor definitions (look-up-tables) and the histogram distributions of the differences are shown in the upper left corners. Differences of more than ±0.5 D are indicated in black. Such higher differences are mostly found in the margins of the distribution in the comparisons with the formulas.

Optimising IOL Power Calculations

New approaches to improve prediction of effective lens position.

Dermot McGrath reports from the 39th Congress of the ESCRS in Amsterdam

New approaches for assessing estimated lens position (ELP) with better intraocular lens (IOL) position prediction and axial length changes in cataract surgery should be considered to optimise IOL power calculations, a new study suggests.

“With the introduction of highly precise optical biometers, the main limiting factor for IOL power calculations is [estimating] the effective lens position, which is key in minimising residual refractive errors,” David Pablo Piñero Llorens PhD said. Significant discrepancies between predicted and actual ELP often result in refractive surprise, he noted.

“Something that has been suggested but never studied in detail is the potential anatomical changes occurring after cataract surgery and the possible changes in axial length due to the volumetric changes related to the surgery. Several studies have looked at this, but one of the main criticisms is there are potential artifacts with optical biometers, which [do] not allow [for] a precise measurement of the axial length in pseudophakic eyes,” he said.

Dr Piñero Llorens’s prospective study set out to optimise the ELP calculation of two different monofocal IOLs using measurements obtained with an optical biometer in terms of the position of the IOL and potential ocular globe changes after cataract surgery. The team assessed post-surgery anatomical changes using an optical low-coherence interferometry system (OLCI) previously validated in pseudophakic eyes.

A total of 472 eyes from 280 patients with a mean age of 73.5 years undergoing cataract surgery were divided into two groups according to the IOL implanted: one group of 330 eyes with AcrySof® IQ SN60WF (Alcon), and the other group of 142 eyes with Akreos® MI60L (Bausch & Lomb). Refractive and biometric changes were evaluated during a six-month followup period with an optical biometer taking account of potential measurement artifacts.

The team also made a comparison between the ELP estimated with the SRK-T formula (ELP SRK-T) and ELP calculated considering clinical real data (ELP AXL-corrected clinical).

As well as significant changes in refraction, they detected a significant increase in anterior chamber depth (ACD) and a significant reduction in the axial length (AXL). The mean difference between ELP SRK-T and ELP AXL-corrected clinical was 0.17 (±0.39) and -0.23 (±0.43 mm) in groups one and two, respectively.

Mean differences between the IOL power implanted and IOL power calculated using the SRK-T formula and ELP AXLcorrected clinical were -0.39±0.90 D (p<0.001) and 0.39 D±0.87 D (p<0.001) in groups one and two, respectively. “A strong and statistically significant correlation of these differences with the difference between predicted and clinically obtained spherical equivalent was found in both groups,” Dr Piñero Llorens said.

Summing up the results, Dr Piñero Llorens said potential anatomical changes occurring after cataract surgery could explain the level of refractive predictability obtained using the vergence formula SRK-T.

“This supports the hypothesis that these anatomical changes are real and not only due to an artifact from optical biometers. New approaches for estimating ELP with better predictions of the position of the IOL and AXL changes with surgery should be considered to optimise IOL power calculations. These calculations could also be implemented for other types of monofocal and multifocal IOLs,” he concluded.

“With the introduction of highly precise optical biometers, the main limiting factor for IOL power calculations is [estimating] the effective lens position, which is key in minimising residual refractive errors.”

Dr Piñero Llorens is a researcher at the Department of Optics, Pharmacology, and Anatomy at the University of Alicante, Spain. david.pinyero@ua.es

Dr Hideki Fukumitsu is a PhD student at the Department of Optics, Pharmacology, and Anatomy at the University of Alicante, Spain.

THOMAS KOHNEN European Editor of JCRS

JCRS HIGHLIGHTS

DYSPHOTOPSIA AND IOL DESIGN

A new IOL design with a 7.0 mm optic and plate haptics appears to produce less positive and negative dysphotopsia while providing good visual outcomes. A prospective randomised patient-masked comparative clinical study including 120 eyes of 86 patients compared the 7.0 mm and plate-haptics (ASPIRA-aXA, HumanOptics) with the 6.0 mm and C-loop haptics (ASPIRA-aA, HumanOptics). Both are single-piece, aspheric IOLs manufactured from the same hydrophilic acrylic material with a refractive index of 1.46. The study found a statistically significant difference between both groups in positive dysphotopsia at 1 month postoperatively—31.6% in the 7.0 mm IOL group versus 52.4% in the 6.0 mm group. The number of cases progressively decreased in both groups throughout the clinical follow-up, and the difference was no longer statistically significant at months 3 and 12. There was also a statistically significant difference in the incidence of negative dysphotopsia at 1 month postoperatively, with a lower incidence in the 7.0 group (5.4%) versus 20.6% in the 6.0 mm group. The new design also provided good visual performance in terms of stable visual acuity and refraction, contrast sensitivity, mesopic vision, and glare sensitivity. The study also suggested that longer axial length and greater pupil dynamics might serve as predictive risk factors for positive dysphotopsia. MK Bonsemeyer et al., “Dysphotopsia and functional quality of vision after implantation of an intraocular lens with a 7.0 mm optic and plate haptic design”, 48(1): 75–82, January 2022.

7.0 MM IOL NEGATIVE DYSPHOTOPSIA LABORATORY STUDY

In a related laboratory study, investigators used optical modelling to compare 6.0 mm and 7.0 mm intraocular lens (IOL) optic diameters on peripheral retinal illumination with implications for negative dysphotopsia. They used ray-tracing software to simulate retinal illumination from an extended light source for pseudophakic eyes with different IOLs to verify their effect on negative dysphotopsia. The simulations involved biconvex IOLs with optic diameters of 6.0 mm and 7.0 mm, refractive indices of 1.46 and 1.55, and a 2.5 mm pupil. For the lower refractive index (1.46), the 6.0 mm IOL was modelled with a 5.5 mm optic surrounded by a 0.25 mm rim. The 7.0 mm IOL was modelled with a 6.0 mm optic surrounded by a 0.5 mm rim. The team found similar results for IOLs with both refractive indices. The 7.0 mm optic expanded the image field. Furthermore, high-angle input light was found to miss a 7.0 mm optic at a larger visual angle than a 6.0 mm optic, shifting illumination of the peripheral retina by this light anteriorly. Consequently, investigators created an extended and more peripheral dark nasal region. The narrow retinal shadow using a 6.0 mm optic is converted to a broader, more peripheral shadow when using a 7.0 mm optic. This could explain the lower negative dysphotopsia rates associated with a larger 7.0 mm optic, the authors note. JC Erie et al., “Effect of a 7.0 mm intraocular lens optic on peripheral retinal illumination with implications for negative dysphotopsia”, 48(1): 95–99, January 2022.

Artificial Intelligence in Ophthalmology

Andrzej Grzybowski Editor

BOOK Reviews

PUBLICATION

ARTIFICIAL INTELLIGENCE IN OPHTHALMOLOGY

EDITOR

ANDRZEJ GRZYBOWSKI

PUBLISHED BY SPRINGER 123

Conjuring up all sorts of associations, from self-driving cars to the Wachowskis’ bloodthirsty robot overlords of The Matrix, Artificial Intelligence as a topic is at once fascinating and intimidating. But AI is not a nebulous concept. As you go about your day, AI is targeting advertising, filtering emails, and labelling pictures on the phone in your pocket, whether you are aware of its activities or not. It is difficult to know where to start when trying to understand how AI is likely to change clinical practice in ophthalmology, now and into the future. This vast and increasingly important topic is tackled in Artificial Intelligence in Ophthalmology, (Springer) edited by Andrzej

Grzybowski MD, PhD.

The text, available in book and digital form, is aimed at a general audience and is accessible for ophthalmologists with no need for a background in computer programming. Beginning with an introduction that discusses the “Promises, Hazards, and Challenges” of AI in ophthalmology, the reader is brought right back to the first descriptions of the central components of AI in the 1940s, through to the exponential growth in research and applications of AI in the current COVID-19 era. Further chapters move on to the basic systems of AI, their various applications in eyes, and major topics of safety and trust, as we increasingly move from assistive to autonomous AI.

The book also introduces technical aspects of deep learning (DL)—an important type of machine learning and itself a field of AI. It highlights the performance of DL tools, which are at a sufficiently high standard to bring AI into the clinic. IDxDR, a deep learning-based software that identifies referable diabetic retinopathy from fundus photographs, is the first FDAapproved AI application in ophthalmology. The Convolutional Neural Network (CNN) is described, among other forms of DL. The architecture of the CNN is intriguingly likened to the structure of the visual cortex, as both are composed of layers of nodes (or neurons) which feedforward from input to eventual classifying output; simple cells respond to lines, and complex cells respond to location-invariant patterns.

Further chapters focus on a wide range of applications of AI across different sub-specialties, from cornea to retina. They include problems such as age-related macular degeneration, glaucoma, retinopathy of prematurity, diabetic retinopathy, and keratoconus. Diabetic retinopathy screening emerges as an important success story in AI. The book also covers diagnostic applications in ocular oncology and neuro-ophthalmology.

Cataract and refractive surgery get special attention, including AI applications such as screening for keratectasia prior to laser refractive surgery, improving accuracy in IOL biometry calculations, and incorporating AI into cataract surgery training.

In the context of increasing desire and need for telemedicine, the promises of AI are balanced throughout the text by potential challenges such as medicolegal and ethical issues. Elon Musk tweeted in 2021, “There is also the existential threat of AI, which we should aspire to mitigate.” For ophthalmologists, it seems we do not face an existential threat yet; Grzybowski’s text reveals the myriad benefits that AI tools may add to our practice.

If you have a book you would like to have reviewed, please contact: seanh@eurotimes.org

Ophthalmic YAG and SLT Laser System

Right on the Mark

“Precision treatments with the YAG/SLT laser”

NIDEK, a leading manufacturer of modern YAG lasers, introduces the advanced YAG and SLT combination laser, YC-200 S plus, and the enhanced YAG laser, YC-200.

A suite of technologies has been incorporated in these lasers to achieve seamless function and greater precision. Features for targeting pathology, accurate energy delivery, and operative assist functions allow the surgeon to deliver treatments “Right on the Mark”.

DR EMANUEL ROSEN FRCS, FRCOPHTH

Looking Back on Emanuel Rosen’s Contribution to Ophthalmology

By Philippe Sourdille MD, past president of

The ESCRS is Emanuel’s lifetime achievement. From the very beginning up to current times, he created, managed, and increased the influence of our society.

I first met him in 1969 at a congress in Jerusalem organised by Professor Michaelson. We both had just completed our residency, and his special interest at that time was to illustrate clinical situations of the eye through an innovative photographic approach. To be in Jerusalem months after the Six-Day War was a very emotional time for all participants. We were staying in the King David Hotel, where colleagues from 15 nations presented their work on the anterior and posterior segments of the eye. Emanuel’s work, despite his young age, was one of the meeting’s highlights.

The late 1960s and early 1970s were a hard time for intraocular implants. Some painful first-generation results had created a most difficult situation for our field. Two great Dutch colleagues, Cornelius Binkhorst and Jan Worst, were the forefront in defence of iris fixation as a safe approach for implants. Their innovative creativity and dedication paved the way to the gradual acceptance of implants.

Emanuel was one of the few surgeons to follow the new trail. At that time, microsurgery was not routine, phacoemulsification was far from general acceptance, and some famous names in ophthalmology were campaigning against all types of intraocular implants. Emanuel displayed a vision for the long term and a strong character to get us through these times.

In 1981, Cornelius Binkhorst created the European Implant Club, and international meetings were organised every year in different countries. Emanuel was named president in 1989.

In 1991, the meeting was held in Paris, Dan Lebuisson and myself in charge. English was the official language at the Paris meeting, with simultaneous translation in French. This was the first time when an ophthalmological meeting in France was not held in French. Some of my French colleagues considered that as a relighting of Joan of Arc’s bûcher, and we had to face some harsh criticisms!

Despite these difficulties, the Congress in La Defense was a great success, with more than 400 participants from all over Europe and America. This was a very large audience in a still pioneering and struggling field. Manual extracapsular cataract extraction competed with phacoemulsification. Implants were made of PMMA and needed a large incision. Intracapsular fixation had just been described. Refractive surgery was mostly radial keratotomy, with mentions of the first LASIK and laser surgery procedures.

After the meeting, we had a debriefing session with Emanuel, Ulf Stenevi, and Paddy Condon. The results were positive by all means: scientific value, audience participation and interest, industry support, financial success. But the general feeling was that we had to improve and stabilise the organisation. The historical words of Emanuel then were: «Should we reinvent the wheel every year, should we not have a permanent office and a board?». A unanimous yes was the answer and Paddy

the ESCRS

proposed working with Agenda Communications, a company based in Dublin. This started a decades-long effective and fruitful collaboration with Mary d’Ardis, Carol Fitzpatrick, Susan Little, and their staff.

The official language for the next meeting was then expected to be controversial, especially in France. Emanuel raised the point and turned to me, asking for my advice. The answer was: «Whether you like it or not, English is not a foreign language, it’s a survival language!». Emanuel added: «Coming from a French man, we can take that» and this was the end of the discussion. Emanuel was acclaimed first president of the newly named European Society of Cataract and Refractive Surgery, ESCRS.

In 1996, merging the European and the American journals of cataract and refractive surgery was another strategic change, initiated and realised by Emanuel and Steve Obstbaum. To date, this is still one of the few successful mergings of American and European journals. Confidence and friendship were the leading forces in this amazing adventure, where the two initiators’ charisma played a major role in bringing together colleagues of different cultures.

In 1996, during an ASCRS meeting in Seattle, Emanuel, Michael Blumenthal, and myself decided to hold an ESCRS winter session dedicated to refractive surgery. At that time, no official European society held a scientific and educational comprehensive program in the winter months. Our first meeting took place in Spain. Despite great presentations, it was close to disaster, with only 87 pioneers participating. We survived this failure, and the winter meeting has become very successful from thereon.

Creating the ESCRS, merging the journals, and creating a cataract and refractive educational programme are three milestones of our society where Emanuel Rosen played a leading role. Up until the end of his life as journal editor, officer of the society, and active participant in all our meetings, he was our companion. Our debt to him is huge.

The first four ESCRS presidents, from right to left: Emanuel Rosen, Philippe Sourdille, Michael Blumenthal, Thomas Neuhann.

Consultant Ophthalmologist Manchester UK, Co-founder and co-editor Journal Cataract & Refractive Surgery, Chairman of ESCRS EuroTimes, Founder and chief medical editor of ESCRS EuroTimes, Founder and past president of the ESCRS, Past president of UKISCRS and IIIC, Lifetime Achievement Award from International Society of Refractive Surgery

Thoughts on the Passing of Emanuel Rosen

By Prof Noel Alpins AM

Emanuel (Manny) Rosen was my friend and colleague for more than two decades. As saddened as I was by his passing, I hold many fond memories of my experiences with him in numerous countries and on several continents. I often saw him as only a few degrees of separation between me and his countryman, Harold Ridley, who implanted the first intraocular lens in 1949. Ridley went on to co-found (with Peter Choyce) the Intra-Ocular Implant Club in 1966, which became the International Intraocular Implant Club (IIIC) in 1975. Manny served as president of the IIIC from 2000 to 2002.

Manny’s twin passions for photography and ophthalmology were evident in his Jan Worst Medal Lecture given in 2007 to the IIIC, with spectacular photography of both scenery and fluorescein angiography, the latter published in a book in 1969.

Manny and I travelled together on several occasions to IIIC meetings—memorably through South Africa and Botswana, where we went on safari, and other times to Aruba, Cambodia, Japan, and New Zealand. We also served together on several editorial boards on which he presided, such as the Journal of Cataract and Refractive Surgery (JCRS) and EuroTimes. We enjoyed one another’s company at international meetings as far distant as Australia and USA and made a point to meet regularly at the annual meeting of the European Society of Cataract and Refractive Surgery, wherever it happened to be. He was President of the ESCRS from 1987 to 1993.

The legacy Manny left for future generations of ophthalmologists is immense. His dedicated work as a skilful editor provided an exemplary standard to guide members of the editorial boards he led, to elevate the quality of manuscripts and the publications they comprised. Manny’s dry wit and sense of humour together with his tireless efforts were instrumental in EuroTimes’ increasing success as an effective medium to communicate the diverse subjects it encompassed in clinical ophthalmic practice. It has granted this publication the widest of readership looking for concise information on topics encountered in modern-day practice.

Manny wrote many splendid editorials for the JCRS in his time as European Editor. Many of these have had practical relevance and been useful for reviewers to reference, to help guide authors in their revisions of their submissions, to clarify detail and achieve consistent terminology while following established conventions. Accuracy in scientific presentation was a high priority for him.

Manny was always ready to offer sage advice when asked. He had a broad knowledge of many relevant subjects and shared his wisdom in a genuine manner. Manny had profound influence on ophthalmology through his work, his publications, and the organisations he was instrumental in establishing with his enthusiasm and energy such as ESCRS, JCRS, and EuroTimes. He had a generous spirit and will be dearly missed by all who knew him—in countless countries and on most continents. My sincerest sympathies go to Barbara and all his family.

TRIBUTES TO EMANUEL ROSEN FROM AROUND THE WORLD

Emanuel Rosen was a true friend. Emanuel had many good sides. One was he was an excellent teacher. We worked together in the late 1970s, running courses in cataract surgery. We were both at the first meeting of the European Intraocular Implant Club (the predecessor to the ESCRS) in 1982, which had 160 participants in one room. He had the vision, that without a Society as a backbone, things would go nowhere in our field. He had the ability to communicate to colleagues that were, like himself, not only interested in the surgery itself, but what it meant for society. He was the leader in the early days and the person that knew where we should go. Carefully and calmly, he made sure we got there. He is the founding father of the ESCRS. Without him, there would be no ESCRS.

— Ulf Stenevi

I remember Emanuel very vividly as a passionate refractive surgeon, one of the founding fathers of ESCRS, and a long-time editor of the JCRS and EuroTimes. Dealing with publications—whether peer-reviewed or not—appeared to be of greatest interest to him and for me was his most significant and valuable contribution to our field.

— Oliver Findl

I think he was the end of an era, as one of the few surviving surgeons of the 1980s, which saw the transformation of cataract surgery from ECCE to phaco, and IOLS from anterior chamber to iris clip, and on to sulcus and bag fixation. It was a very dynamic time.

I think, however, his greatest contribution was as a superb committee person. Getting surgeons from different continents and countries to agree on anything is like herding cats, but with his affable non-confrontational Lancastrian personality, he could achieve the impossible—as seen in the founding of the ESCRS and JCRS.

— David Spalton

Emanuel will be remembered for his enthusiasm and energy, which led to an innovative and visionary career. He was one of the giants in ESCRS and modern ophthalmology history.

— Rudy Nuijts

So sorry to hear that Emanuel Rosen, one of the greatest ophthalmologists in the world, founder of the ESCRS, and one of my mentors, has passed away. It is a great loss to eye surgeons the world over. His heart and vision will remain unparalleled. I will always be thankful for his help! But above all, I will miss his kind presence, his encouraging words, and the goodness of his heart which he gave freely. “If we have seen further,” to paraphrase Isaac Newton, “it is by standing on the shoulders of giants.” Giants like Emanuel.

— Cyrus Mehta

Emanuel has been a leading light in the life of the ESCRS. Through the years, there are few ESCRS initiatives that have not been enlightened by his insight or touched by his skilful management. Indeed, he was a steady and constant influence in the ongoing success of ESCRS.

— Stephen Obstbaum

Biodegradable Eyedrops

Santen unveiled plans to launch the first bio-based plastic eyedrop bottle in Europe, the Middle East, and Africa in early 2023. The company says this is part of its global commitment to create a zero-carbon world and a sustainable future. The bottle is made from a sugar cane-derived material that uses natural resources while maintaining the structural integrity of traditional plastic, so the medication is kept stable.

“To achieve Santen’s Vision for the Earth 2050, we have three environmental targets for 2030—which consist of contribution to a carbon-free society, conservation of limited resources including water, and reduction of plastic use. The introduction of the biomass plastic bottle is part of our efforts to achieve our Vision. Santen is committed to strengthening the business foundation for its sustainable growth with full recognition that conserving the global environment is one of the most important challenges,” said Takahiro Morita, Corporate Officer, Core Principle and Corporate Social Responsibility, Santen. www.santen.com/en/sustainability/eco/#note002

NEWS IN BRIEF

IC-8 MOVES AHEAD

AcuFocus received an Approvable Letter from the FDA for its IC-8 small aperture IOL for cataract patients. The aspheric monofocal lens has an embedded filter with a small central aperture. The IC-8 lens is based on the same pinhole lens optical principle as the Kamra (AcuFocus) corneal inlay and is designed to provide an increased depth of focus compared to a standard spherical IOL. Initial studies and case reports relating to corneal pinhole inlays for the correction of presbyopia in patients with previous LASIK are promising.

“We are thrilled to receive the approvable letter from the FDA ahead of our MDUFA date. And we look forward to working with the FDA to successfully complete these customary pre-approval inspections,” Al Waterhouse, president and chief executive officer of AcuFocus, said in a statement. www.acufocus.com

ACCOMMODATIVE IOL MAKES PROGRESS

MASTERING MYOPIA WITH THE OCULUS

OCULUS announced the launch of the new GRAS (Gullstrand Refractive Analysis System) software module of the Myopia Master®. The company says the innovation will simplify keratometry, axial length, and refraction measurements. The company has adapted the Gullstrand eye model for use with very young patients as well, extending the application field of the Myopia Master to include children. The company notes the availability of products and features may vary by country. www.myopia-master.com

The Juvene™ IOL (LensGen) moved one step closer to US approval, receiving Investigational Device Exemption (IDE) from the US Food and Drug Administration (FDA). This allows the company to begin a pivotal study of the company’s device for patients with cataracts. The Juvene IOL is a single-piece IOL with two fluid reservoir haptics, two optics attached by a flexible actuator, and active and passive fluid chambers. The capsular forces exerted on the haptics during accommodation cause the fluid to be pumped centrally into the optic resulting in a shape change and increased refractive power without splitting the light like multifocal IOLs. The lens is designed for implantation in the capsular bag through a sub-4 mm incision. www.lensgen.com

Cost Effectiveness

In an era of rising demand for limited resources, cost-effective care is becoming an increasingly important concept for both clinicians and patients. But bridging the gap between how it can be applied to improve clinical practice and how to use it to guide macro- and meso-level health policy decisions is essential to optimise overall resource use and individual patient outcomes says Carmen D Dirksen MD, PhD.

Cost effectiveness is all about value, said Dr Dirksen, noting that there are many different ways to conceive it in healthcare.

Typically, in ophthalmology, the focus is on reducing symptoms and complaints, vision improvement, preventing blindness, minimising side effects, preventing complications, improving patients’ functioning, and increasing patients’ quality of life.

“These are the ‘usual suspects’ in evidence-based practice [that] focus on the clinical and health benefits. But maximising health comes at a price—literally.”

On the one hand, most health systems must deal with ever-increasing costs driven by a variety of factors, including technological and pharmaceutical advancements and an ageing population with multiple morbidities that complicate clinical management.

On the other hand, resources are limited in time, money, and personnel.

“To capture this side of the coin, we need a broader conceptualisation of value than only patient health,” Dr Dirksen said.

VBHC VS EE

One such concept currently receiving much attention is valuebased healthcare (VBHC). Introduced by Michael Porter in 2006 and described in a famous paper in the New England Journal of Medicine in 2010, VBHC is designed to increase patient value while creating awareness and minimising cost. Patient value is central and defined as patient-relevant outcomes related to the costs associated with the outcome, Dr Dirksen explained. As such, VBHC can be used to continuously improve healthcare quality and guide individual practice decisions based on general and patient-specific preferences.

By contrast, economic evaluation (EE) is a concept that deals with the relative value of treatments, in which option costs are compared.

“The main question of economics is how to allocate scarce resources in an optimal way,” Dr Dirksen said.

EE includes cost-effectiveness analysis, in which money spent is evaluated against clinical endpoints. However, cost-utility analysis—money evaluated against generic quality-of-life years (QALY) gained or preference-based quality-of-life indicators gained—is generally preferred.

“The universal nature of the QALY makes it possible to compare healthcare technologies over populations, but also over disease areas.”

EE creates a framework for evaluating new versus existing health technologies and informing allocation decisions. Consideration of opportunity costs and displacement effects (the reductions in one activity due to increases in another) is essential.

“Doctors want the best for every individual patient, but in a budget-constrained system, each euro you spend on one patient you cannot spend on another patient, so choose wisely,” Dr Dirksen said.

EE considers the costs and health benefits of multiple interventions against one another to determine the incremental cost of a benefit unit for each intervention, also known as an incremental cost-effectiveness ratio (ICER).

ICERs are evaluated against threshold values that distinguish high-value from low-value care, with treatments having an ICER over the threshold—for example €50,000 per QALY gained, deemed lower value. This kind of EE is often used to inform coverage and reimbursement decisions—for example, covering the cost of manual but not femtosecond laser-assisted cataract surgery.

EE also may guide investment decisions by insurers in health systems and can be used at the department and practice levels for allocating resources. It can guide decisions to adopt specific technologies and treatments, reduce practice variation, and identify the most cost-effective options for sub-groups of patients. However, EE is not effective for guiding treatment decisions on the individual patient level because individual patients vary in what they value in outcomes.

BRIDGING THE GAP

“Can we bridge the gap between EE and VBHC? Both address ‘bang for the healthcare buck,’” Dr Dirksen asked. They could be better aligned by using VBHC patient-relevant outcomes, such as core outcomes sets and patient-reported outcomes, as measures of effectiveness for EE cost effectiveness and cost consequence analyses. Integrating patient-centred outcomes into QALYs also has been recently proposed.i

“Although EEs generally guide policy decisions at the macro and meso levels, adopting high-value care and abandoning lowvalue care based on EE will contribute to developing VBHC systems. The results of EE or cost information may also enter clinical practice guidelines and decision-making,” she said.

“I think we should at least try to bridge the gaps. Connecting EE with evidence-based medicine and evidencebased practice and VBHC both at the professional community level and methods level will serve patients, healthcare, and society,” she concluded.

i. Walraven J et al., Value in Health, 2021; 24(7): 1038–1044.

Carmen Dirksen MD, PhD is professor of health technology assessment, Maastricht University, Netherlands, and CEO of the Clinical Trial Centre, Maastricht. c.dirksen@mumc.nl

Bridging the gap between economic analysis and value-base care is essential. Howard Larkin reports from the 39th Congress of the ESCRS in Amsterdam

Posterior Capsular Opacification (PCO)

Dr Soosan Jacob MS, FRCS, DNB

Posterior capsular opacification (PCO), also called aftercataract or secondary cataract, is the most common postoperative complication of cataract surgery. The previously reported incidence ranges between a quarter to half of patients developing PCO within a few months to five years of surgery. A better understanding of risk factors and better techniques and technology have helped decrease PCO formation in recent times. Newer thinking attributes some advantage to limited capsular fibrosis in helping stabilise the IOL within the bag.

MECHANISM

Extra-capsular cataract surgery retains anterior and equatorial capsular areas harbouring the lens epithelial cells (LEC) as well as the posterior capsule. LECs undergo proliferation to form monolayers, and some undergo abnormal differentiation and migration onto the posterior capsule to result in PCO. Various growth factors and cytokines such as transforming growth factor-β and fibroblast growth factor-2 stimulate myofibroblastic differentiation and cell-mediated capsular contraction. These and others such as hepatocyte growth factor and matrix metalloproteinases contribute to cell proliferation, migration, and cell-mediated contraction and thereby PCO formation.

CLINICAL FEATURES

PCO causes decreased vision, decreased contrast sensitivity ranging from mild to severe, and glare and halos. Broad opacities may be visually insignificant, but fine opacities and wrinkles can cause significant visual degradation. Patients with multifocal IOLs may have earlier onset of PCO and may also present visual dissatisfaction earlier.

IOL exchange after YAG laser posterior capsulotomy is difficult, so it’s therefore before IOL explantation. It is important to verify dissatisfaction is due to PCO and not the multifocal optics. PCO can also cause loss of effect of accommodative IOLs, Z-syndrome with Crystalens, and visual dysphotopsia. A small rhexis can cause anterior capsular contracture or phimosis and IOL dislocation.

PCO is easily identified on slit-lamp examination as opacification of varying degrees of the anterior and posterior capsules. Using retro-illumination alone can underestimate PCO and should be combined with reflected light examination. Fibrotic and proliferative forms of PCO exist and Scheimpflug image densitometry-based grading, slit-lamp photographs in reflected light and retro-illumination, OCT analysis, computerised analysis, and subjective grading can be used to grade PCO based on area as well as density.

PCO can also be seen as Elschnig’s pearls. These are round pearls seen on retro-illumination. They are graded as none, trace, mild, moderate, and severe based on appearance ranging from none to thick sheets of epithelial pearls.

PCO may also present with Soemmering rings—a peripherally placed ring of cortical fibres proliferates from equatorial LECs retained between the posterior capsule and the edges of the anterior capsular remnant. Soemmering rings are usually asymptomatic, but they can cause tilt or IOL dislocation and glare if thick. They can get dislodged during secondary surgeries and drop into the vitreous, where they may incite inflammation. They may be removed using glued IOL scaffold technique to decrease chances of fragment drop from the ring.

RISK FACTORS

A knowledge of risk factors is important, as PCO can result in patient dissatisfaction, more postoperative visits, increased costs, and risks from additional procedures. Senile mature cataracts have a lower risk than immature cataracts. Paediatric cataracts have almost a 100% rate of PCO, resulting not only in decreased vision but amblyopia. Diabetes, uveitis, myotonic dystrophy, retinitis pigmentosa, and traumatic cataract are other risk factors.

Certain surgeries such as extracapsular cataract extraction and poor techniques such as incomplete cortical removal, wholly or partially sulcal-fixated IOLs, and incomplete overlap of the rhexis all around the IOL optic also increase risk.

The design of IOL affects the incidence of PCO. Square, sharpedge IOLs create a capsular bend, hindering the migration of LECs when compared to round-edge IOLs. Other design features such as slim haptic-optic junction also help. IOL material, too, has a role in decreasing PCO. Hydrophobic material is superior, but this effect may occur only by creating a sharp capsular bend. No difference has been seen between three-piece and one-piece hydrophobic acrylic IOLs. Certain OVD—e.g., those containing exogenous hyaluronic acid—may induce lenticular migration.

PREVENTIVE MEASURES

Various surgical techniques have been tried to decrease PCO. These include cortical cleaving hydrodissection, thorough cortical wash, capsule polishing, OVD removal, in-the-bag IOL placement, and 0.25 to 0.5 mm circumferential optic coverage by the anterior capsular rim (shrink-wrap effect). Other approaches include using phaco instead of ECCE, primary posterior capsulorhexis (PPCC) with optic capture, or posterior capsulotomy with vitrector in paediatric patients. Other strategies include primary laser capsulotomy with optic capture in adults and special IOLs—such as bag-in-lens IOL or bulky IOLs that keep the anterior and posterior capsules separated and allow aqueous circulation within the bag. Therapeutic agents are also employed, such as antimetabolites, anti-inflammatory agents, hypo-osmolar drugs, and heparin. Others use devices as sealed capsule irrigation devices that temporarily seal the capsule with a suction device and irrigate with a pharmacological agent to prevent PCO. A capsular bending ring that decreased ACO and PCO is in clinical trials. Dodick phacolysis can remove the laminin layer of posterior capsule. Newer approaches include Zepto capsulotomy and gene therapy.

Everything you always wanted to know about…

Though anterior capsular polishing removes LECs, a study by Liu et al did not see a decrease in residual cell growth but rather an increase in cell proliferation in capsular bag cultures. It decreases anterior capsular opacification (ACO) but also delays the fusion of anterior and posterior capsules, allowing LECs to go past the square edge of the IOL. Since some capsular fibrosis helps stabilise the bag and thereby the IOL, complete removal of all LECs by any means results in a “dead bag syndrome”, causing excessive bag floppiness, subluxation, etc. A fine balance is therefore required in leaving some LECs behind sufficient to stabilise the bag but not cause PCO. New research aims at modulation and not complete removal of LECs.

MANAGEMENT

Nd:YAG laser capsulotomy is a simple and effective treatment, but it can add to expense and is unavailable in developing countries. Successful YAG capsulotomy is challenging in patients with poor fixation or poor cooperation as well as those with media opacities such as corneal oedema or scarring that degrade the laser beam or make the aiming beam difficult to visualise. Nd:YAG is relatively contraindicated with glass IOLs as they may crack. It also is possibly contraindicated in the presence of inflammation, increased IOP, cystoid macular oedema, or a high risk of retinal detachment. The function of filtering blebs may be compromised post-YAG, and it is therefore a relative contraindication.

In case endothelial keratoplasty, vitreoretinal surgery, or an IOL exchange is required, the surgery should be avoided or at least delayed till the need for maintaining the capsular barrier is over. Cruciate and circular patterns are preferred, and the

capsulotomy opening should be the size of the scotopic pupil but may have to be larger for multifocal optics—though there are no studies to verify this. In addition, the size may increase slightly postoperatively. IOL pitting may occur following YAG and can be avoided using posterior laser offset. Extensive pitting can cause image degradation, even necessitating IOL exchange. It is less seen now with better IOL material, better laser machines, more experience, and better techniques.

YAG anterior capsulotomy in a cruciate spoke like pattern around the edges is used for capsular contraction syndrome. It is preferable to wait about three months and confirm the cause of symptoms before YAG capsulotomy, as IOL exchange is difficult to perform with an open posterior capsule. This also allows stabilisation of IOL within the bag and prevents vitreous prolapse around the optic. Topical steroids and anti-glaucoma medications may be given for a week after YAG. Complications of Nd:YAG capsulotomy include retinal detachment, cystoid macular oedema, rise in IOP, IOL pitting, bleeding from the iris, and corneal oedema.

Dense membranes or media opacities may necessitate surgical capsulotomy with needle or capsulectomy with vitrector. Pharmacological and immunological methods for the prevention of PCO under research include pharmacological agents such as anti-inflammatories, immuno-modulators, antiproliferative, antiadhering, anti-transdifferentiating agents.

Dr Soosan Jacob is Director and Chief of Dr Agarwal’s Refractive and Cornea Foundation at Dr Agarwal’s Eye Hospital, Chennai, India, and can be reached at dr_soosanj@hotmail.com.

LEGEND

A: Anterior capsular opacification; B: Elschnig’s pearls seen on retroillumination; C: Fibrotic type of PCO with striae seen on posterior capsule; D: YAG laser capsulotomy done in a thick fibrotic posterior capsule

The ASCRS Annual Meeting is scheduled to be held in Washington, D.C.

Support, encourage, and fund individuals interested to start clinical research activities in the eld 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 bene t of patients