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Increasing understanding of the genetics behind Usher syndrome suggests that treatment may become possible in the very near future.

Landscape of genetic therapies for USH2A-related retinitis pigmentosa

A case series of 13 young patients with Charles Bonnet syndrome, which is characterised by visual hallucinations in individuals who are experiencing sight loss, showed that the patients all had inherited retinal diseases or congenital eye disorders but there was no link with visual dysfunction.

The importance of recognising Charles Bonnet syndrome in children

Over the last 15 years, biosimilars have become a major feature of the health care landscape. Physicians in many disciplines, particularly oncology and immunology, have embraced biosimilars. However, access to educational resources on these powerful biologics can be inconsistent, and in turn, some ophthalmologists who could benefit from the adoption of biosimilars are left in the dark.

The real-world application of biosimilars was the focus of discussion for Martin Zinkernagel, MD, PhD, chair of the Department of Ophthalmology at the University Hospital of Bern, Switzerland, and Paolo Lanzetta, MD, professor of ophthalmology and chairman of the Department of Medicine-Ophthalmology at the University of Udine in Italy. In their discussion, the experts addressed several common questions, framed around the phase 3 clinical trial for biosimilar SB11 (BYOOVIZ) from Biogen. SB11 is approved in Europe and the United Kingdom. Like the reference product ranibizumab (Lucentis), SB11 is approved for the treatment of retinal disease including neovascular age-related macular degeneration (nAMD).

Addressing physicians’ levels of familiarity with biosimilars, Dr Lanzetta attributed much of the variation to regulatory discrepancies. “The uptake of biosimilars varies throughout Europe by country and by product,” he said. “Obviously, variation in the uptake of biosimilars [is] influenced by government involvement, reimbursement issues and tender procurement policies.” Recent survey data have revealed gaps in awareness across Europe and in the United States on the efficacy and safety of biosimilars for retinal diseases, Dr Lanzetta said, especially in terms of “real-world data.”

In a clinical application, Dr Lanzetta said, biosimilars may exhibit minor differences from the reference products, but they aren’t considered to have significant impact on the efficacy or safety profile. Typically, the biosimilar and reference medicine must have the same posology and route of administration, with few exceptions, he added.

Dr Lanzetta also said that in the last 10 years, the European Medicines Agency (EMA) has approved the highest number of biosimilars worldwide.

 “And this means, to us physicians, having both the possibility to have experience on their use in terms of safety and evaluating the efficacy after that,” he explained.

One common misconception about biosimilars is that these therapeutics are interchangeable with the idea of generic medicines. But there is a key indicator that biosimilars are unique: the cost. “While generic medicines are marketed at a significantly lower price than name brand ones, why do we not see the same level of cost savings with biosimilars?” Dr Zinkernagel asked.

Dr Lanzetta explained that biosimilars are developed via a rigorous, complex and highly regulated manufacturing process. “Generics are simple chemical medicines or agents, which is not the case for biosimilars and biologics,” he said. “Unlike generics, biologics, and therefore biosimilars as well, are very complex; they’re very difficult to copy. And the development processes are patented and proprietary to the originators.” The proprietary nature of biologic development, he added, is why biosimilars may have differences from their originators.

Prof Zinkernagel and Dr Lanzetta used data from the SB11 phase 3 trial to expand upon the capabilities of biosimilars. Prof Zinkernagel detailed the study: over 700 patients were included in the randomised, double-masked, parallel-group multicentre trial. Over 52 weeks, investigators evaluated the efficacy and the safety profile of this biosimilar SB11 in comparison with monthly ranibizumab for the treatment of nAMD.

“Patients with neovascular AMD were included, [with a] visual acuity range between 20/40 and 20/200,” Prof Zinkernagel said. “[Patients] were randomised in a 1:1 ratio to either have the originator or the biosimilar every 4 weeks from baseline up to week 48.”

Primary end-points were change from baseline in best corrected visual acuity at week 8 and change from baseline in central subfield thickness at week 4. The pre-specified secondary efficacy end-points included longer-term assessments of change from baseline in visual acuity, and the proportion of participants who lost fewer than 15 letters or who gained 15 or more letters in visual acuity from baseline at weeks 24 and 52.

“Other secondary end-points included, of course, change from baseline in central subfield thickness and central retinal lesion thickness at week 24, as well as change from baseline in choroidal neovascularisation [CNV] size and proportion of participants with active CNV leakage seen via OCT [optical coherence tomography] at week 24,” Prof Zinkernagel continued. Describing the results, he said, “When you look at the visual acuity improvements, it’s really equivalent. You have equivalence between the originator and the biosimilar, and the same holds true for a decrease in central retinal thickness. So the curves are basically the same, and also the secondary end-points.”

Prof Zinkernagel also spoke about the immunogenicity outcomes of the SB11 trial, as immunogenicity reactions have been a common problem in past assessments of anti–vascular endothelial growth factor (VEGF) agents. Along with detrimental effects to visual acuity, immunogenicity reactions can also lead to vasculitis and vitritis.

“Now, in this trial, the overall cumulative incidence of anti-drug antibodies, antibodies reacting against this specific drug up to week 52, was very low,” Prof Zinkernagel said. “For the SB11 biosimilar, it was 4.2%, and for the originator it was 5.5%. So very, very similar.”

He also noted that most antibodies were non-neutralising, which generally indicates a weak antibody response. “Furthermore, no statistical or clinically relevant differences in the incidence of anti-drug antibodies and neutralising antibodies were observed between treatment groups at any of the time points,” Prof Zinkernagel explained.

Dr Lanzetta highlighted the unique potentialities for anti-VEGF therapies as an area where physicians can consider treating patients with a biosimilar. “You can either switch a patient from the originator, obviously, or you can also consider treating with a biosimilar treatment-naive patients who may benefit…from being treated with that reference agent or originator agent,” he said. When to deploy a biosimilar will depend on many factors, including the locality where a patient is being treated. “Europe has different countries, different health care systems,” Dr Lanzetta said. “You may consider treating with the biosimilar patients who may not be strictly adherent to the cost of therapy and the frequency of treatment because of some cost issues.”

Just as education on biosimilars is vital to practitioners, awareness and education resources for patients are vital, too. “We spend a lot of time with our patients in letting them know that biologics did undergo a very rigorous approval process through studies, efficacy and safety studies,” Dr Lanzetta emphasised. This education is vital to getting patients on board with biosimilars, and it sparks enthusiasm about the potential benefits. “Once they do understand that, I think they will be very prone to receive a biosimilar; [it’s] in their interest and in the interest of the community, the whole community of patients, and in the interest of the health care system,” Dr Lanzetta said.

1. Biosimilars in the EU: information guide for healthcare professionals. European Medicines Agency. Updated December 2, 2019. Accessed October 3, 2023. 

https://www.ema.europa.eu/en/documents/leaflet/biosimilars-eu-information-guide-healthcare-professionals_en.pd

Editor’s note: A prior version of this article contained a misspelling of the product name BYOOVIZ. It has been corrected. We regret the error.

How biosimilars expand treatment options for patients with retinal disease

Corneal cross-linking (CXL) has transformed the disease course of patients with corneal ectasias since its introduction to clinical practice in 2002. But what CXL had not been designed to achieve was improvements in visual outcomes.

The original (and until recently, the undisputed gold standard) CXL protocol for ectasia has, for most of this time, been the Dresden protocol.

 It involves epithelium removal and 20 minutes of riboflavin application, followed by 30 minutes of UV light irradiation at 3 mW/cm² to deliver a total fluence of 5.4 J/cm². Dresden protocol cross-linking might flatten the cornea by a small amount—often in the range of 1.5 D—but this flattening is too small to make a meaningful difference to the vision of patients with corneal ectasias who undergo the procedure.

But CXL has moved on. We know that oxygen diffusion into the stroma is an essential – and rate-limiting – step in the UV-riboflavin photochemical reaction, and that accelerating the delivery of the 5.4 J/cm² fluence results in a reduction in the stiffening effect.

 The essential role of oxygen also explains why many of the older epithelium-on (epi-on) CXL protocols delivered a poorer corneal stiffening effect than epi-off protocols3: the epithelium consumes oxygen and absorbs UV energy.

 Today, modern, higher-fluence (up to 10 J/cm²) protocols are set to close this efficacy gap.

 Learnings made during these developments prompted a re-thinking of how corneal flattening might be achieved.

The evolution of customised cross-linking

The first generation of customised cross-linking employed the following approach: delivering gradients of UV energy fluences over an epi-off cornea with the highest fluence over the tomographically largest bulging of the posterior cornea. This tomography-guided pattern generates more cross-links over the tip of the keratoconus and thus a greater flattening.

 To achieve the effect, surgeons have to use a UV-A delivery device with an integrated eye tracker that can deliver the different UV fluences to different parts of the cornea, rather than using a regular cross-linking device that delivers a uniform fluence across the cornea.

 Even so, the flattening effects were only moderately predictable: approximately 2 D to 4 D in total,

 even when using adjuncts like supplemental oxygen to improve the cross-linking effect.

ELZA-PACE customised CXL: The next generation

The ELZA Institute has developed a second-generation customised cross-linking method, called 

ELZA phototherapeutic keratectomy (PTK)-assisted customised epi-on cross-linking (PACE)

. ELZA-PACE is a mixture of ELZA’s new epi-on CXL (which needs neither iontophoresis nor additional oxygen) and an epi-off area over the centre of the keratoconus. The epi-off area is created using an excimer laser PTK. 

The PTK is tailored to the center of the keratoconus cone, respecting the individual epithelial thickness profile of that area, thus entirely preserving the stromal tissue – and this brings with it a corresponding impact on oxygen and UV energy penetration into the stroma.

Following the epithelial map-driven PTK, a penetration-enhancer is applied, followed by the riboflavin we developed, which establishes a riboflavin concentration gradient that peaks at the cone. In addition, a greater amount of UV irradiation is applied over the cone area and less over the peripheral regions of the cornea during cross-linking (

Taken together, this generates three gradients: UV fluence, riboflavin and oxygen, as opposed to the one gradient (UV fluence) generated by the earlier, first-generation approach.

Initial findings show a flattening effect significantly stronger than that achieved by earlier generations of customised CXL. Most interestingly, we not only observed maximum keratometry (Kmax) reductions of 4 D to 5 D within the first post-procedure month, but we also saw a steepening of the opposing superior area of several diopters, due to a coupling effect. Taking these two effects together, we often see a marked improvement in the symmetry of the astigmatism.

These changes lead to improvements in the wavefront errors and thus an increase in corrected distance visual acuity with glasses. Over six months to a year, PACE often achieves 8 D to 12 D of total asymmetry reduction and, in some cases, a gain of corrected distance visual acuity with glasses of up to 6 lines. This regularisation of the corneal surface is achieved by remodeling only, all without removing stromal tissue.

Can PACE be performed with a manual abrasion?

We tried and we failed to see a similar effect when performing PACE with a manual abrasion. The reason is that the abrasion has to be tailored around the tip of the keratoconus using a specific topographic map. Doing this manually would mean transferring a specific abrasion offset in the range of 20 µm onto the cornea, and performing an abrasion that includes the area of interest within a few micrometerss.

Patients with corneal ectasias with Kmax values in the range of 50 D to 60 D are excellent candidates for ELZA-PACE. The marked flattening over the cone shifts the patient’s refraction towards hypermetropia. The patients should therefore be at least mildly myopic to begin with. Also, the classic bow-tie keratoconus pattern responds better to ELZA-PACE than other topographical forms.

ELZA-PACE can be used not only in progressive keratoconus but also in stable keratoconus: a typical example would be a 35-year-old patient with stable keratoconus who had been using contact lenses for almost 20 years and who started developing contact lens intolerance.

We avoid performing ELZA-PACE in K readings below 50 D, because we might theoretically encounter slow and long-term flattening. So having a starting point that is beyond 50 D will prevent the cornea from flattening intonon-physiological values.

ELZA-PACE can be combined with other treatments such as the use of intracorneal ring segments (such as the all-Femto-CAIRS [corneal allogenic intrastromal ring segments] procedure by Soosan Jacob, DNB, MS, FRCS, and Shady Awwad, MD, that uses allogenic corneal tissue) and corneal wavefront-guided photorefractive keratectomy.

Our method is based on our new epi-on CXL protocol. During epi-on CXL, we pre-treat the cornea with special drops that enhance the penetration of riboflavin. These penetration enhancers are the result of several years of research and are currently awaiting the CE mark. Once the CE mark is given, ELZA-PACE can be performed by any colleague equipped with an MS-39 device for the epithelial maps and generation of the ablation file (CSO Italy), a SCHWIND AMARIS excimer laser for the custom PTK driven by epithelial maps (SCHWIND-eye-tech-solutions GmbH) and the C-eye cross-linking technology for customised CXL (EMAGine Switzerland).

ELZA-PACE represents a significant advancement in keratoconus treatment without the need for corneal tissue removal. By leveraging the combined gradients of riboflavin, oxygen, and UV irradiation, ELZA-PACE achieves outcomes that surpass those of first-generation customised cross-linking. As ophthalmologists, we must consider ELZA-PACE as a first-line visual rehabilitation option for patients with keratoconus, ensuring they receive the most effective and advanced care available.

1. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. 

Am J Ophthalmol. 2003;135(5):620-627. doi:10.1016/s0002-9394(02)02220-1

2. Richoz O, Hammer A, Tabibian D, Gatzioufas Z, Hafezi F. The biomechanical effect of corneal collagen cross-linking (CXL) with riboflavin and UV-A is oxygen dependent. Transl Vis Sci Technol. 2013;2(7):6. doi:10.1167/tvst.2.7.6

3. Hammer A, Richoz O, Arba Mosquera S, Tabibian D, Hoogewoud F, Hafezi F. Corneal biomechanical properties at different corneal cross-linking (CXL) irradiances.

4. Kling S, Richoz O, Hammer A, et al. Increased Biomechanical Efficacy of Corneal Cross-linking in Thin Corneas Due to Higher Oxygen Availability. 

5. Torres-Netto EA, Kling S, Hafezi N, Vinciguerra P, Randleman JB, Hafezi F. Oxygen diffusion may limit the biomechanical effectiveness of iontophoresis-assisted transepithelial corneal cross-linking.

2018;34(11):768-774. doi:10.3928/1081597X-20180830-01.

6. Freeman RD. Oxygen consumption by the component layers of the cornea. 

J Physiol. 1972;225(1):15-32. doi:10.1113/jphysiol.1972.sp009927

7. Harvitt DM, Bonanno JA. Oxygen consumption of the rabbit cornea. 

Invest Ophthalmol Vis Sci. 1998;39(2):444-448

8. Seiler TG, Komninou MA, Nambiar MH, Schuerch K, Frueh BE, Buchler P. Oxygen kinetics during corneal cross-linking with and without supplementary oxygen. 

. 2021;223:368-376. doi:10.1016/j.ajo.2020.11.001

9. Abrishamchi R, Abdshahzadeh H,
Hillen M, et al. High-fluence accelerated epithelium-off corneal cross-linking protocol provides Dresden protocol-like corneal strengthening. Transl Vis Sci Technol. 2021;10(5):10. doi:10.1167/tvst.10.5.10

10. Kanellopoulos AJ, Dupps WJ, Seven I, Asimellis G. Toric topographically customized transepithelial, pulsed, very high-fluence, higher energy and higher riboflavin concentration collagen cross-linking in keratoconus. 

Case Rep Ophthalmol. 2014;5(2):172-180.doi:10.1159/000363371

11. Wu D, Lim DK, Lim BXH, et al. Corneal cross-linking: the evolution of treatment for corneal diseases. Front Pharmacol. 2021;12:686630. doi:10.3389/fphar.2021.686630

12. Seiler TG, Fischinger I, Koller T, Zapp D, Frueh BE, Seiler T. Customized corneal cross-linking: one-year results. Am J Ophthalmol. 2016;166:14-21. doi:10.1016/j.ajo.2016.02.029.

13. Nordstrom M, Schiller M, Fredriksson A, Behndig A. Refractive improvements and safety with topography-guided corneal crosslinking for keratoconus: 1-year results. 

Br J Ophthalmol. 2017;101(7):920-925. doi:10.1136/bjophthalmol-2016-309210

14. Cassagne M, Pierne K, Galiacy SD, Asfaux-Marfaing MP, Fournie P,
Malecaze F. Customized topography-guided corneal collagen cross-linking for keratoconus. J Refract Surg. 2017;33(5):290-297. doi:10.3928/1081597X-20170201-02

15. Mazzotta C, Sgheri A, Bagaglia SA, Rechichi M, Di Maggio A. Customized corneal crosslinking for treatment of progressive keratoconus: Clinical and OCT outcomes using a transepithelial approach with supplemental oxygen. 

2020;46(12):1582-1587. doi:10.1097/j.jcrs.0000000000000347.

Hafezi is a refractive and cataract surgeon based at the ELZA Institute in Zurich, Switzerland. Prof Hafezi is a council member of the European Society of Cataract & Refractive Surgeons and holds academic positions at the University of Geneva, the Keck School of Medicine of USC, the NYU Grossman School of Medicine, and Wenzhou Medical University. Financial disclosures: EMAGine AG (shareholder); PCT patent/application holder (corneal apparatus for CXL)

Stabilising keratoconus and improving vision using ELZA-PACE customised CXL

Going for gold: The new standard for cross-linking

: On 19 September, Andrea Govetto, MD, PhD, received the inaugural Ramin Tadayoni Award during the opening ceremonies of the EURETINA Congress. Dr Govetto was recognised for his efforts in developing a computational model of fluid flow and retinal tissue deformation in macular oedema. He is a vitreoretinal surgeon at the Oftalmico-Fatebenefratelli Hospital, ASST-Fatebenefratelli-Sacco, Milan, Italy.

In April, the retina community was shocked by the sudden loss of Ramin Tadayoni, MD, PhD. Prof Tadayoni was president of the European Society of Retina Specialists (EURETINA). At the time of his passing, Prof Tadayoni had just begun his 2-year term as EURETINA president. 

In the months that followed, Anat Loewenstein, MD, MHA, previously president elect of EURETINA, assumed the title of president. 

, Prof Loewenstein discussed Prof Tadayoni’s legacy, the work she is doing to honour his vision of EURETINA and the inaugural Ramin Tadayoni award, to be presented at this year’s EURETINA congress in Barcelona, Spain, 19-22 September.

In June, EURETINA announced the Ramin Tadayoni Award. Established in memory of Professor Tadayoni, the annual award will grant €30,000 for research support, and an additional €5,000 directly to the candidate.

“This award is specifically intended to be for young retina specialists, to support them in their research. It’s a nice sum of money, and I’m sure that it will make an impact in the world of retina,” Prof Loewenstein said. “Ramin passed away after 4 months of his presidency, and because I was the president-elect, I need to continue right after him, which is not easy. Ramin, over the years, really supported me, and I want to continue his legacy.”

Professor Loewenstein also expressed special gratitude to Oculis Holding AG for supporting the award as a joint venture with EURETINA. In the future, the EURETINA board hopes to widen industry support for the award, to support a full fellowship, or more, on an annual basis, she said. “I’m grateful to the EURETINA board for agreeing and establishing the award, and to Oculis for supporting it this year,” Prof Loewenstein said. “I am hoping this is just the beginning for this award, and all the good it can do in the retina community.”

Prof Loewenstein credits Prof Tadayoni with helping her become president-elect of EURETINA, and remembered him as a steadfast champion of inclusivity. “His legacy was to do more to make our society a real society—one that not only has a meeting, but also has other purposes, such as mentorship programmes, supporting women in retina, providing and establishing various guidelines on controversial topics, and being an accessible educational resource.”

Prof Tadayoni valued continued, significant education for young retina specialists. “Together, we established the mentorship programme of EURETINA, which pairs young retina specialists with a personal mentor to guide them through a research project. He was chairing, with me, all the mentorship meetings,” Prof Loewenstein recalled. “Every time that he needed to support young, rising retina stars, he would do so wholeheartedly.”

Arshad M. Khanani, MD, MA, FASRS, said more than anything, Prof Tadayoni had hope for the future and a steadfast belief in the capabilities of the next generation. 

“Ramin believed in innovation, bringing new treatment options for our patients and training the next generation of retina specialists,” Dr Khanani said. This award combines all those aspects together to continue Ramin’s legacy.”

Bahram Bodaghi, MD, PHD, FEBO, remembered Prof Tadayoni's wide range of interests, within and beyond ophthalmology. "He appreciated all retina subspecialties, but he had a major interest for myopia," Prof Bodaghi remembered. "His surgical skills were unanimously recognised and admired by all. He was also very attentive to general culture, geopolitics, the discovery of new civilizations and poetry." 

The tributes to Prof Tadayoni, he added, contain a laundry list of character traits: his "exceptional personality" was a unique blend of generosity, kindness, openness to all, humility, honesty, friendship and a true passion for academic excellence.

By all accounts, Prof Tadayoni went above and beyond as a friend, in much the same way he did as a leader in retina research. Dr Khanani, who considered Prof Tadayoni a beloved and admired friend, said it was easy to get along with the late retina leader from day one. 

“He always cheered for young retina specialists and greeted everyone with a smile,” Dr Khanani said. “He was always kind and a team player.”

When asked to describe Prof Tadayoni in a one-word catchphrase, Dr Khanani offered up “leader” and “legend” as suitable summaries. Prof Bodaghi agreed with the latter as a fitting tribute. "Ramin Tadayoni was a giant in ophthalmology," Prof Bodaghi said. "He will remain in our memories as a legend."

Prof Loewenstein was torn between two descriptors: “loyal” and “professional.”

“On the one hand, he was extremely professional, he looked only at evidence-based data. And on the other hand, he was loyal to his coworkers and to his friends, and to me,” Prof Loewenstein said. 

“He didn’t look at all for opportunities to benefit himself," she continued. "He really thought about the good of EURETINA, the good of retina specialists, and the good of retina patients.”

Dr Khanani also described Prof Tadayoni as relentlessly positive and selfless. “He was a great teacher, mentor and a motivator who was always available and willing to help,” he said. “Ramin took pride in mentorship and was genuinely happy in seeing his colleagues succeed.”

Prof Tadayoni's wisdom continues to live on in the colleagues he inspired. "His collaborators quote him very often: 'There is no obstacle that we cannot overcome with unfailing strength and determination,'" Prof Bodaghi said.

Prof Loewenstein said that when she began working with Prof Tadayoni as part of the EURETINA board’s executive committee, she noticed that he put a lot of effort, time and personal resources into the group. “I noticed that he was leading a group by working together in friendship,” she said. “And I remember, very fondly, the way that meetings were done under his leadership.” When Prof Tadayoni was elected EURETINA president, Prof Loewenstein wasn’t surprised.

“We knew each other for many years, and it was, to me, so natural that he became the leader,” she said. “But he was a leader for me even before that.”

1. Oculis and EURETINA Announce the Winner of the Inaugural Ramin Tadayoni Award. Oculus Holding AG. Press release. Published 19 September, 2024. Accessed 19 September, 2024. https://www.globenewswire.com/news-release/2024/09/19/2949295/0/en/Oculis-and-EURETINA-Announce-the-Winner-of-the-Inaugural-Ramin-Tadayoni-Award.html

The Ramin Tadayoni Award supports the next generation of retina researchers while paying tribute to a leader in the field

Remembering a legend: EURETINA members speak about the Ramin Tadayoni Award

As 2023 nears its end, the reporters and editors from the Eye Care Network would like to thank you–our readers–for engaging with our print magazine, eNewsletters and video interviews. Throughout the year, we have had the privilege of working alongside industry opinion leaders to showcase what’s new and what’s upcoming in the ophthalmology space. If 2023 has shown us anything, it is how much we have to look forward to in 2024 and beyond. From groundbreaking research to cutting-edge tech, there is plenty of reason for eye care professionals and their patients to be excited.

This week, you will see a series of posts featuring the best content from Eye Care Network brands. We’ll showcase our colleagues at 

, so keep your eyes peeled (and pardon the pun!).

To kick off our “year in review,” here are the 5 most important stories featured in Opthalmology Times Europe throughout 2023.

Is ophthalmology approaching the end of LASIK?


Jod Mehta, PhD, FRCOphth, who is the Distinguished Professor in Clinical Innovation in Ophthalmology at Singapore National Eye Centre, contributed this cover story for our September issue. The article was based on his 2023 British Society of Refractive Surgery Charles McGhee Lecture. Our editorial team was immediately captivated by the lecture title, “Lenticule Extraction: Will LASIK Cease to Exist?”

Prof Mehta explores that provocative question at length in this article, which charts the potential benefits of lenticule extraction for patients–and the shortcomings that providers must be aware of. While LASIK might not disappear anytime soon, it’s clear the laser refractive surgery landscape is very different now than just one year ago.

ESCRS 2023: Presbyopia treatment with microporation therapeutic technology by Ace Vision Group

Much of our most fascinating content this year came from in-depth conversations with industry leaders at conferences. AnnMarie Hipsley, DPT, PhD, Founder and CEO of Ace Vision Group, met with Ophthalmology Times Europe at the 2023 European Society of Cataract and Refractive Surgeons (ESCRS) meeting to discuss Ace Vision Group's microporation therapeutic technology, used to treat presbyopia. Novel treatments are quickly expanding the range of treatments available for patients with presbyopia, and Dr Hipsley indicated the condition will become a focal point for the eye care space in the days to come.

She used microporation therapeutic technology as an example of the accessible, effective treatments that are newly available to patients. “It's a true biomechanical treatment that's attacking this ocular rigidity from cross-linking in the sclera,” she explained. “It restores the natural dynamic range of focus function in the eye that moves the lens. It's so simple that it seems hard to wrap your brain around. But, it's been a really long journey to get here.”

To hear Dr Hipsley explain the research at length, watch the video here.

Restoring vision through retinal ganglion cell repopulation

Cell therapies are among the most fascinating–and complex–treatment modalities gaining popularity in eye care. In our May issue, Thomas V. Johnson III, MD, PhD, of Wilmer Eye Institute at Johns Hopkins Univeristy School of Medicine in Baltimore, Maryland, dove into the topic of retinal ganglion cell (RGC) repopulation.

Ophthalmology is pioneering the field with clinical trials of stem cell-derived retinal pigment epithelium and photoreceptor transplantation, which could potentially restore vision in diseases such as age-related macular degeneration and macular dystrophies. There are staggering implications to consider when researching potential treatments for optic neuropathies. Optic nerve diseases are both prevalent and irreversible; glaucoma alone affects more than 80 million individuals worldwide.

“The list of challenges in making functional RGC replacement a reality is daunting and will require therapeutic manipulation of cellular pathways involving neuronal survival, migration, dendritogenesis and axogenesis, pathfinding, synaptogenesis and myelination,” Dr Johnson wrote. But, there is reason to be hopeful. “Although the concept of optic nerve regeneration has long been the subject of fantasy, recent advances in neuroscience have converged to a point where functional RGC replacement may now be feasible,” he said.

Learn more about the promising breakthroughs in this space by reading the full article here.

SOE 2023: Optic neuropathy versus maculopathy

Advances in imaging technology have been one of the biggest instigators of broad-scale change in the field of ophthalmology. Physicians are now able to answer questions that have challenged ophthalmologists for years. During the European Society of Ophthalmology (SOE) Congress, held in Prague, Czech Republic, Nicholas Volpe, MD, spoke on one such benefit of optical coherence tomography (OCT).

In his presentation, “Optic Neuropathy Versus Maculopathy,” Dr Volpe addressed recent developments in this area. “This has for ages been a very hot topic for ophthalmologists, because there are a group of patients that have unexplained vision loss and relatively normal appearing fundi, that is both the macula and the optic nerve,” he said. “At first glance [they] appear to be healthy. And for decades, we would go back and forth–is this an optic nerve problem? Is it a macular problem?”

But the conversation has been “revolutionised” by the advent of OCT, he said, as the imaging technique has provided “a much finer anatomic view of what's happening in the retina.” Especially when combined with other forms of testing, Dr Volpe said, physicians have more certainty than ever about the best treatment protocol for their patients.

Dr Volpe spoke with David Hutton about his presentation – watch the video here.

Disease activity criteria shapes dosing interval outcomes in clinical trials

Marco Zarbin, MD, PhD, FACS, delivered his talk, “An Assessment of the Impact of Disease Activity Criteria on Dosing Interval Assignment in Clinical Trial Patients with Neovascular AMD,” at this year’s American Society of Retina Specialists (ASRS) meeting. Following the event in Seattle, Washington, we recapped the highlights of his presentation for the November print edition of Ophthalmology Times Europe. In a testament to the relevance of his chosen topic, this article, published in the last few weeks of 2023, quickly became one of our most-read stories of the year.

“The take-home message of this talk is that the definition of active disease in clinical trials affects the estimates of the durability of the agents that are tested in those trials,” Dr Zarbin explained early in his presentation. Referencing a set of clinical studies for neovascular age-related macular degeneration (nAMD), the CANDELA and PULSAR trials, Dr Zarbin noted that differences in active disease criteria were reflected in the study outcomes.

“It may not be surprising that the durability estimates were not the same,” Dr Zarbin said. “In CANDELA, where either a change in vision or a change in anatomy mandated an injection, about 53% of the patients could be maintained with injections every 12 weeks, whereas in the PULSAR trial, where both a change in vision and a change in anatomy were required to mandate an injection, durability increased such that 83% of the patients could be maintained with injections every 12 weeks or longer.”


See the full story here, with key takeaways that are vital for any practice.

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Familial exudative vitreoretinopathy (FEVR) is an inherited retinal disease that disrupts normal blood vessel formation in the retina. Symptoms can range from mild visual deficits to severe visual impairment or even blindness. Accurate diagnosis of FEVR is challenging because its symptoms—such as retinal detachment and abnormal blood vessels—closely resemble those of other retinal diseases, including retinopathy of prematurity (ROP), Coats disease, and persistent fetal vasculature (PFV). Diagnosis often requires widefield angiography or genetic testing. Due to the overlap of symptoms with other conditions, especially in children, FEVR is frequently misdiagnosed, underscoring the critical role of genetic testing in guiding appropriate management.

Recent research highlighted the role of genetic testing in confirming FEVR diagnoses. The retrospective study reviewed cases from 104 paediatric patients referred with suspected FEVR.

 Genetic testing confirmed FEVR in 55 of these cases, revealing that 60% of patients with confirmed FEVR had initially received incorrect diagnoses. The average age at diagnosis was slightly higher in patients with revised diagnoses compared with those initially diagnosed with FEVR, suggesting diagnostic delays may impact disease progression.

Figures

The study identified several conditions commonly misdiagnosed as FEVR. Particularly in cases of late-preterm infants, ROP was the most frequent misdiagnosis, accounting for about 39% of cases.

 Besides genetic testing that can confirm the diagnosis, fluorescein angiography (FA) is valuable imaging technique for differentiating FEVR from ROP, as both conditions share similar clinical presentations, particularly peripheral retinal avascularity and abnormal vessel growth (

). In FEVR, the FA typically shows symmetric or many times asymmetric peripheral avascular retina without the distinct ridge formation and the organised vascular pattern seen in ROP. Also, there may be abrupt termination of blood vessels at the vascular-avascular junction with signs of neovascularisation or straightening of peripheral vessels, pinpoint areas of hyperfluorescence and segmental areas of vascular leakage.

PFV was misdiagnosed in 15% of cases, partly due to the similarities in retinal vascular anomalies between PFV and FEVR

. Key differences help distinguish PFV from FEVR, such as the presence of retinal folds that connect a stalk extending from the optic disc to the posterior lens in PFV—a distinctive structure not found in FEVR. FEVR is a posterior-temporal-anterior retinal fold vs PFV that is from the nerve to the lens. Additionally, PFV lacks a genetic pattern and may show distinct lens abnormalities, such as a thickened or elongated ciliary process and sometimes a shallow anterior chamber, which are not characteristic of FEVR. Recent observations suggest that unilateral PFV may be a bilateral, asymmetric condition, as retinal vascular abnormalities have been detected in most fellow eyes of patients with PFV. FA highlights further distinctions. In PFV, the affected eye may display leakage from persistent vessels, while the fellow eye can exhibit vascular abnormalities and in 67.1% peripheral vessel avascularity, a feature that, while present in both FEVR and PFV, differs in the specific vascular patterns observed.

 OCT adds diagnostic value by revealing a vascularised stalk in the affected eye in PFV and often a Bergmeister papilla in the fellow eye, imaging characteristics that are helpful for accurate differentiation.

Coats disease, which is misdiagnosed as FEVR in about 7% of cases, shares features with FEVR such as abnormal vascular development and retinal exudation.

 However, Coats disease typically affects only one eye, primarily in young boys, and does not follow a hereditary pattern, whereas FEVR often presents in both eyes. A distinguishing feature of Coats disease is the presence of “light bulb” aneurysms and significant leakage seen on fluorescein angiography, which are not usually observed in FEVR.

 On OCT, Coats disease often reveals extensive intraretinal and subretinal fluid, along with hyperreflective exudates caused by severe vessel leakage. Retinal cysts, outer retinal disruptions, retinal schisis formation and retinal thickening due to chronic exudation are also commonly seen in Coats disease.

The study emphasised the value of genetic testing as a diagnostic tool to confirm FEVR, especially in cases with atypical presentation. Genetic testing can identify pathogenic mutations in genes associated with FEVR, allowing clinicians to differentiate it from similar conditions. Key genes in FEVR, including 

, affect vascular development pathways. When mutations in these genes are present, a diagnosis of FEVR becomes more certain.

Genetic testing is recommended for patients with suspected FEVR when patients have ambiguous clinical presentation; when the family history suggests a hereditary condition, even in the absence of obvious symptoms in family members; and in cases in which initial treatments fail or symptoms persist. A confirmed diagnosis of FEVR aids in several aspects of patient management. It enables targeted treatments and family counseling by providing insights valuable for family planning and identifying relatives at potential risk, allowing for early detection and intervention. Additionally, patients with confirmed FEVR require long-term monitoring, even if symptoms are mild initially, as regular imaging and follow-up can detect any progression early on, supporting prompt treatment when necessary.

While genetic testing has clear benefits, there are limitations for its use. First, it can be expensive and may not be accessible, depending on patients' health care coverage. Moreover, not all FEVR cases have identifiable mutations in known genes. In this study, genetic mutations were only found in 53% of phenotypic FEVR cases,

 which is consistent with current literature.

Genetic testing not only prevents misdiagnosis but also helps clinicians tailor treatments, monitor disease progression, and provide valuable family counseling. Given the high rate of initial misdiagnoses, ophthalmologists should consider incorporating genetic testing into their diagnostic workflows for paediatric retinal disorders. This proactive approach can lead to better patient outcomes, especially for those with atypical presentations or a family history suggestive of hereditary eye disease.

1. Hudson JL, da Cruz NFS, Kunkler AL, Carletti P, Negron CI, Berrocal AM. Revision of Initial Referral Diagnosis after Genotypic Confirmation of Familial Exudative Vitreoretinopathy. 

A confirmed diagnosis of familial exudative vitreoretinopathy aids in several aspects of patient management

Prof. Mariya Moosajee

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