Dr. Michael Mbagwu, of the VA Palo Alto Health Care System; Byers Ophthalmic Innovations Fellow, Byers Eye Institute, Stanford University Medical School, speaks on the highlights of his virtual 2021 ARVO presentation regarding the development of an algorithm tool that links patient imaging to their clinical data, specifically within the American Academy of Ophthalmology's (AAO) IRIS Registry. 

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Dr. Michael Mbagwu speaks on the highlights of his virtual 2021 ARVO presentation regarding the development of an algorithm tool that links patient imaging to their clinical data, specifically within the AAO IRIS Registry.  

Linking patient imaging to AAO IRIS Registry clinical data

Dr Theodore Leng medical advisor at Verana Health and director of clinical translational research, Byers Eye Institute, Stanford University School of Medicine, discusses the highlights from his presentation on "AAO IRIS Registry Data Replicates VIEW 1 and VIEW 2 Clinical Trial Outcome Data," in which the first replications using real-world data of a phase 3 trial was utilized, during the virtual 2021 ARVO meeting. 

Dr Theodore Leng discusses the highlights from his presentation on "AAO IRIS Registry Data Replicates VIEW 1 and VIEW 2 Clinical Trial Outcome Data," during the virtual 2021 ARVO meeting. 

Looking at real-world trial data replication outcomes of AAO IRIS Registry data 

Dr. Daniel F. Kiernan, a vitreoretinal surgeon at The Eye Associates, Sarasota, Florida, discusses the highlights of his 2021 ARVO virtual presentation on the effect of dexamethasone intracameral drug-delivery suspension on macular thickness based on optical coherence tomography (OCT) testing following vitreoretinal surgery.

Dr. Daniel F. Kiernan discusses key findings of a clinical study analyzing the effect of dexamethasone intracameral drug-delivery suspension on macular thickness based on OCT testing following vitreoretinal surgery.

Clinical results analyze dexamethasone implant effect on macular thickness

The understanding of the epidemiology, natural history, causal mechanisms, and treatments for diabetic retinopathy (DR) has evolved dramatically over recent decades. 

The staggering statistics underscore the importance of this progress considering that by 2040, an estimated 642 million patients will be affected by diabetes globally. Importantly, 7.3 million are undiagnosed and a third of the population is pre-diabetic, which, as Lloyd Paul Aiello, MD, PhD, noted, is a less recognized problem.

Aiello is a professor in the Department of Ophthalmology at Harvard Medical School, and director, Beetham Eye Institute, Joslin Diabetes Center, Boston.


“The percentages of diagnosed, undiagnosed, and total diabetes among adults increase dramatically with age, in some cases more than 7-fold between ages 18-44 and 65 and older,” Aiello said. “The incidence of diagnosed diabetes increases about 2-fold after age 40.”

Aiello explained further that about 20% of the US population over 65 years are projected to have diabetes by 2035. Diabetes currently is the seventh leading cause of death in the US.”

Black, non-Hispanic, and Hispanic populations have higher prevalence rates of diabetes than white, non-Hispanics. While diabetes about 20 years ago was far more prevalent in the southern US, it is now highly prevalent nationwide, with the rates having increased from 1.5%-6.9% in 2004 to 12.2%-33.0% currently.

High A1c, blood pressure, and cholesterol, are well-known risks.

“A concern is that less than 20% of diabetic adults control these risk factors adequately and more than 75% do not adhere to minimal activity guidelines,” he said.


DR is one of the most common complication, with a prevalence of 49%; however, there is hope, because the cases of global blindness actually decreased slightly in Western Europe and high-income areas of North America possibly because of nationwide diabetic retinopathy screening programs in the UK, improved glycemic control, and better therapies,

Decreases in diabetic macular edema (DME),

 proliferative diabetic retinopathy (PDR), retinopathy progression, clinically significant ME, and visual impairment have occurred.

 Evaluation of about 15,000 patients at the Joslin Clinic showed a median best-corrected visual acuity (VA) of 20/20 and 92% had 20/40 or better.

In addition to improved diabetes care, treatment rates and better therapies also are credited for improved outcomes. Treatment with panretinal photocoagulation (PRP), which prevents about 98% of blindness when patients were treated in a timely fashion, increased substantially.

Anti-vascular endothelial growth factor (VEGF) therapy was a huge leap forward4 and is evolving as a viable alternative to PRP for PDR. Ranibizumab (Avastin, Genentech) was non-inferior to PRP, provided better vision during the first 2 years post-treatment and better mean visual field outcomes, and decreased chances of vitrectomy and developing DME.

Anti-VEGF therapy has been extremely effective for DME with study data now over 5 years.

 The major anti-VEGF drugs are all beneficial with somewhat similar efficacy except in certain subpopulations.



Supplementation with deferred/prompt laser treatment helped maintain VA gains, and 56% never needed any laser over the 5-year study.

Interestingly, while a number of anti-VEGF injections are needed in early treatment, far fewer are needed later on to maintain the visual gains.

A new therapeutic option is treatment of non-PDR. The Panorama Study

 showed high percentages of patients with 2 or more steps of improvement, lower rates of worsening in DR severity, and fewer vision-threatening complications from baseline with anti-VEGF therapy compared with sham.

In addition, the development of sophisticated imaging modalities is changing evaluation and treatment modalities and how diabetes-related eye disease is screened in the community.

A major hurdle for DR is the lack of patient awareness, which is a substantial contributor to non-adherence to eye care guidelines and poor outcomes, Aiello emphasized. 

Retinal imaging is the best way to view almost the retinal surface with some devices now showing nearly the entire retina in a single image. Hand-held imaging devices are evolving and will likely help monitoring of patients in underserved areas.

The future of DR care may include several exciting new research areas. One is retinal binding protein 3 that may protect against many aspects of DR.

In addition, there are pathways that do not depend on VEGF, and artificial intelligence and deep learning that are already entering the clinical arena.

This article is adapted from Aiello’s presentation at the Association for Research in Vision and Ophthalmology 2021 virtual annual meeting. He has no financial interest in this subject matter.

1. Liew G, Michaelides M, Bunce C. A comparison of the causes of blindness certifications in England and Wales in working age adults (16-64 years), 1999-2000 with 2009-2010. BMJ Open 2014;4:e004015. Doi: 10.1136/bmjopen-2013-004015.

2. Klein R, Knudtson MD, Lee KE, et al. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXIII: The twenty-five-year incidence of macular edema in persons with type 1 diabetes. Ophthalmology 2009;116:497-503.

3.Klein R, Klein BEK. Are individuals with diabetes seeing better? a long-term epidemiological perspective. Diabetes 2010; 59:1853-60. https://doi.org/10.2337/db09-1904.

4. Writing Committee for the Diabetic Retinopathy Clinical Research Network. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy. A randomized clinical trial. JAMA 2015;314:2137-46.

5. The Diabetic Retinopathy Clinical Research Network, Elman MJ, 

 RW, et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 2010;117:1064-77.

6. The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med 2015;372:1193-203.

7. Wykoff CC. Intravitreal aflibercept for moderately severe to severe non-proliferative diabetic retinopathy (NPDR): 2-year outcomes of the phase 3 PANORAMA Study. Data presented at: Angiogenesis, Exudation and Degeneration Annual Meeting; February 8, 2020; Miami, FL.

8. Yokomizo H, Maeda Y, Park K, et al. Retinol binding protein 3 is increased in the retina of patients with diabetes resistant to diabetic retinopathy. Sci Transl Med 2019;11:eaau6627. doi: 10.1126/scitranslmed.aau6627

Articles

During a presentation at the ARVO virtual meeting, Lloyd Paul Aiello, MD, PhD, explains that a key hurdle for diabetic retinopathy is the lack of patient awareness, which is a substantial contributor to non-adherence to eye care guidelines and poor outcomes.

Diabetes and DR: Making progress in the global epidemic

The 6-month results of a phase 1/2 clinical trial of the subretinal gene therapy drug AGTC-501 for X-linked retinitis pigmentosa (XLRP) indicated that the drug was well tolerated out to month 12 in patients treated in the central retinal area.

Meaningful improvements were achieved in the macular sensitivity and significant changes in the best-corrected visual acuity (BCVA), according to Paul Yang, MD, PhD, assistant professor, Oregon Retinal Degeneration Center, Casey Eye Institute, Oregon Health and Science University, Portland.

This is good news for affected patients, because no other treatment is currently available for patients with XLRP. Luxturna (Spark Therapeutics) is the only FDA-approved treatment for RP due biallelic pathogenic variations in 

, which represents only 1% of cases of RP. In contrast, XLRP accounts for 10% of patients with RP, and 80% of cases of XLRP have a mutation in the 

In the ongoing phase 1/2, open label, dose-escalation clinical trial under discussion, investigators used an adeno-associated viral vector to deliver a normal functioning copy of the 

A total of 29 male patients were assigned sequentially to 1 of 5 dosing groups (lowest to highest, 4.0 x 1010 vg/ml to 3.2 x 1012 vg/ml) and underwent injection of AGTC-501 into the central or peripheral macular region in 1 eye. The primary outcome was safety, and the secondary outcome was the efficacy of the treatment based on assessments that included BCVA and microperimetry from 6 to 12 months after treatment. All patients were age 6 years and older.

The central macula was treated in 21 patients and the peripheral retina in 8 patients.

Yang reported that the treatment was generally well tolerated across all doses. Six serious adverse events have been documented thus far, all of which were unrelated to the study drug; these included retinal detachment, concussion, and uncontrolled secondary glaucoma due to prophylactic corticosteroids. Most adverse events were mild and resolved without sequelae; the most frequent were anterior and/or posterior chamber inflammation, blurred vision, conjunctival hemorrhages and hyperemia, and vitreal cells.

Intraocular pressure elevations were related to coriticosteroid use and were well controlled medications with the exception of the severe adverse event that required an Ahmed valve.

Ocular adverse events that were related to the study drug occurred infrequently; these included anterior chamber cells in 4 eyes, retinal pigment epitheliopathy in 2 eyes, and vitreal cells in 2 eyes, he reported. The untreated eye was reported to be affected by adverse events in 3 cases; xanthopsia in 1 fellow eye, and bilateral iritis and photopsia involving 2 fellow eyes.

Yang reported the results from the 20 patients who were treated centrally. At the 6-month time point, the results showed improved BCVA across all the centrally dosed groups. The results were significant (p≤0.001) when compared to the untreated fellow eyes.

“Eleven patients had improvements in the BCVA of 5 or more letters in the treated eyes compared to the fellow untreated eyes,” he said.

Nine of the centrally treated patients with a complete data set were evaluated at 12 months. Among these patients, there was a significant (p ≤ 0.005) difference in the proportion of treated compared with untreated eyes with a gain of 5 letters or more that started as early as 1 month after treatment that was sustained out to 12 months, Yang described.

Among the centrally treated patients, 18 patients had microperimetry data that could be evaluated. Of these patients, 8 were responders; responders were defined as those with 7 decibels or more improvement in the retinal sensitivity at 5 or more retinal loci in the central 36 loci of the perimetry grid at 6 months. At the 6-month evaluation, the responders had an improvement in mean sensitivity across the central 36 loci in the treated eye that was significantly greater (p ≤ 0.05) than that in the untreated eye.

Eight of the patients had microperimetry data that could be evaluated at 12 months. Of these, 4 patients were responders.

“Among those 4, the change in the mean sensitivity within the centrally treated area was greater in the treated eye compared with the untreated eye at 6 and 12 months, although the difference did not reach significance at 12 months,” he explained.

The doses that resulted in the best responses were the high, higher, and highest doses (respective doses, 3.6 x 1011mg/ml, 1.1 x 1012 vg/ml, and 3.2 x 1012 mg/ml) with respective response rates of 29%, 43%, and 50%.

“Subretinal gene therapy in this cohort of XLRP patients was well tolerated with a favorable safety profile to month 12,” Yang concluded. “There was evidence of responses to the treatment using the criteria of a 7-decibel or more improvement at 5 or more retinal loci in the treated eye. The patients treated peripherally will require long-term follow-up to determine the treatment efficacy. A significant improvement in the BCVA of 5 or more letters was seen through month 12, which is supportive of a biological signal.”

The patients will be followed over the long term. The next study, the Skyline clinical expansion trial, is underway and will enroll another 12 patients and randomized to either a group 2 low dose or a group 5 high dose, and a mobility maze will be added. At 12 months, the fellow eyes will also be dosed. A phase 2/3 study, the Vista trial, also is planned that will enroll 60 patients and randomized to the same high- and low-dose treatment arms and an untreated control arm. All eligible control eyes will receive dosing at 12 months.

This article is adapted from Yang’s presentation at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual meeting. He is a consultant to and receives clinical trial support from AGTC.

During an ARVO presentation, Paul Yang, MD, PhD, explained that in a clinical trial, investigators used an adeno-associated viral vector to deliver a normal functioning copy of the RPGR gene via subretinal injection.

Initial data from AGTC-501 subretinal gene therapy for X-linked RP demonstrates safety, efficacy

Customised myopic LASIK using automated ray tracing optimisation appears to offer improved and predictable results. The procedure is driven by artificial intelligence (AI) and represents a clear step forward in LASIK technology.

The roots of the technology can be traced to topography-guided treatments introduced in Europe in the early 2000s; the treatment approach ultimately led to the introduction of the Athens Protocol, which combines topography-guided and partial transepithelial photo-reactive keratectomy and corneal crosslinking. 

“The topography-guided treatments were used to treat sick or problematic eyes, with enlargement of optical zone and treating irregularities such as those seen in keratoconic eyes,” noted Dr A. John Kanellopoulos from the LaserVision Clinical and Research Eye Institute in Athens, Greece, and New York University Medical School, United States.

The advancements in the technology are demonstrated by the surgeon’s ability to treat, for example, a herpetic scar. The topography-guided procedure can return the cornea to a normal state; in contrast, before the availability of the technology, a corneal transplant might be considered in a patient who was contact lens intolerant.

The technology can also be used to treat normal eyes, Dr Kanellopoulos explained. “Use of TMR [topography-modified refraction] in routine myopic eyes not only achieves emmetropia but also pushes the envelope to achieve significant gains in lines of vision postoperatively,” he said.

This technology was initially theoretical and difficult to perform, Dr Kanellopoulos recounted, because of the extensive team diagnostics required and calculations by the surgical team. The advent of ray tracing first validated the effort to push refractive surgery beyond wavefront-optimised treatments and standard clinical refractions to the next level.


Dr Kanellopoulos and Dr Dylan Stevens evaluated both eyes of 25 cases in a consecutive case series that were treated with femtosecond laser-assisted myopic LASIK. The eyes were evaluated for all refractive parameters. Dr Stevens is also from the LaserVision Clinical and Research Eye Institute in Athens, Greece, and New York University Medical School.

These procedures differ from the standard method by using a novel wavelength outcome AI platform, which calculates the ablation profile based on measurements from a single device, the Sitemap (Alcon). This device performs three types of measurements for each patient: axial length measurements with interferometry, Scheimpflug tomography and Hartmann-Shack wavefront analysis. The investigators evaluated the visual acuity, refractive error, keratometry, topography, high-order aberrations and contrast sensitivity during 3 months of follow-up.

The AI of the InnovEyes software calculates the low and higher-order aberrations for each eye in four steps and performs ray tracing in two opposite directions in a model eye using the axial length measurements obtained previously. The corneal topography measurements are then used to calculate the propagation of 2,000 light rays through the anterior corneal surface, corneal stroma, the posterior corneal surface, through the anterior chamber and onto the anterior lens surface.

The wavefront data are used to calculate the light that travels through the eye, from the retina, through the vitreous cavity, onto the posterior lens surface through the natural lens and onto the anterior lens surface. Finally, tilt is calculated between the lens and cornea.

This process is markedly faster than previously, taking just seconds compared with hours. “This process facilitates viewing the eye as a total visual system; that is, as a system of multiple refractive entities,” Dr Kanellopoulos said.

The results in the 25 eyes showed that in patients with a broad range of myopia up to 8 D and significant astigmatism in some patients at 3 months postoperatively, there were highly relevant changes: mean refractive error decreased from −5.06 ± 2.54 D (range, −8.0 to −0.50 D) to −0.11 ± 0.09 D; refractive astigmatism from −1.07 ± 0.91 D (range, −4.25 to 0 D) to −0.15 ± 0.04 D; and topographic astigmatism from −1.65 ± 0.85 D to −0.26 ± 0.11 D.

According to Dr Kanellopoulos, 65% of eyes gained one line of vision and 38% gained two lines. The root mean square changed from 0.25 to 0.35 μm and the contrast sensitivity improved postoperatively. “The visual outcomes were remarkable,” he said. 

“This technology has the potential to offer improved and more predictable outcomes through total eye aberration data and ray tracing refraction calculation, and the data are compelling,” he concluded. The data from this study have been subsequently published in peer-reviewed literature.


Dr Kanellopoulos has no financial disclosures related to this content.

Kanellopoulos AJ. Topography-modified refraction (TMR): adjustment of treated cylinder amount and axis to the topography versus standard clinical refraction in myopic topography-guided LASIK. Clin Ophthalmol. 2016;10:2213-2221.

Kanellopoulos AJ. Initial outcomes with customized myopic LASIK, guided by automated ray tracing optimization: a novel technique. Clin Ophthalmol. 2020;14:3955-3963.

Customised myopic LASIK using automated ray tracing optimisation has the potential to offer improved and more predictable outcomes, a study shows.

AI enhances customised myopic LASIK with ray tracing optimisation

Reviewed by Elise Orhan, PhD, and Thierry Bordet, PhD

A non-viral gene therapy sustained drug-delivery product (EYS809, Eyevensys) that delivers anti-vascular endothelial growth factor (VEGF) to the eye may replace the need for repeated intravitreal anti-VEGF injections and improve vision in patients diagnosed with wet age-related macular degeneration (AMD).

This real-world approach would both address the tremendous treatment burden imposed on patients with wet AMD by providing an effective longer acting treatment and a non-VEGF-based therapy for patients who need a more convenient treatment approach to control disease progression long term and to achieve improved vision.

This platform is based on the electrotransfection of DNA plasmids that turns the ciliary muscle into a production site for the intraocular expression and secretion of therapeutic proteins, according to Elise Orhan, PhD, the preclinical project leader at Eyevensys.

EYS809 is a dual-gene plasmid designed to deliver sustained concentrations of both the anti-VEGF inhibitor aflibercept (Eylea, Regeneron Pharmaceuticals) and decorin, an endogenous transforming growth factor-beta inhibitor with known anti-angiogenic and anti-fibrotic properties, that has been demonstrated to reduce choroidal neovascularization (CNV) in the rat laser CNV model.

According to Thierry Bordet, PhD, senior author and chief scientific officer of Eyevensys, Decorin has the potential to enhance the efficacy of anti-VEGF therapy by reducing CNV leakage and scarring via non-VEGF dependent pathways.

During the study, aflibercept or decorin-coding plasmids (30 µg/eye) were electrotransfered in the rat ciliary muscle 3 days before laser was applied to induce CNV. Intravitreal injection of a human equivalent dose of aflibercept (15 µg/eye) or recombinant decorin (1 µg/eye) at the CNV induction served as positive controls. Fluorescein angiography (FA) was performed on day 14 to assess the CNV leakage. Different dual gene expression cassettes were compared in rats to deliver optimal intraocular concentrations of the 2 treatments.

“Electrotransfection of plasmids resulted in sustained intravitreal production of aflibercept or decorin in the vitreous during the 2-week study compared with rapid elimination of the 2 therapies after intravitreal injections,” investigators said.

Both plasmid and intravitreal aflibercept reduced the incidence of grade 3 CNV lesions to 11% and 29%, respectively, compared with 59% in untreated rats. The percentage of eyes with at least 1 clinically relevant lesion also decreased in both treatment groups (39% and 63%, respectively compared to 97% in untreated).

In a like manner, plasmid- or intravitreally administered decorin reduced the incidence of grade 3 CNV lesions to 36% and 24%, respectively, compared to 59% in untreated rats with 60% and 66% of eyes having at least one clinically relevant lesion compared to 75% in untreated rats.

Eyevensys previously demonstrated the safety of its platform with a plasmid coding for an anti-tumor necrosis factor protein tested in 18 patients with non-infectious uveitis. The most common adverse event was mild subconjunctival hemorrhage that last for a short period.

Compared with viral gene therapy, the advantages of EYS809 for treating wet AMD include no need for subretinal surgery, easy delivery, the lack of immunogenicity related to the vector, the possibility of repeated dosing to extend treatment effect if needed, and no limited cargo capacity allowing for the delivery of 2 therapeutic proteins. Moreover, EYS809 only transfects the ciliary muscle cells in contrast to potentially any cell in the eye being transfected following intravitreal injection of viral vectors offering a limited risk of retinal damage.

“This non-viral gene therapy sustained drug delivery approach to deliver anti-VEGF proteins to the eye could be a viable alternative to repeated intravitreal injections that have been associated with poor visual outcomes in patients with wet AMD,” investigators concluded. “The combined effect of aflibercept and decorin, expressed from the EYS809 dual-gene plasmid, is expected to provide benefits over aflibercept alone by also reducing CNV and subretinal fibrosis.”

This article is adapted from Orhan’s presentation at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual meeting. Orhan is an employee of Eyevensys.

EYS809, a non-viral gene therapy sustained drug-delivery product that delivers anti-vascular endothelial growth factor to the eye, may replace the need for repeated intravitreal anti-VEGF injections and improve vision in patients diagnosed with wet age-related macular degeneration. 


Non-viral gene therapy eases treatment burden in wet AMD

Corneal collagen crosslinking (CXL) appears to be a beneficial therapy that stops progression of keratoconus in children, according to Dr William J. Johnson, an ophthalmologist in Tifton, Georgia, United States. This is good news because keratoconus is generally more aggressive in paediatric patients. In addition, he noted, penetrating keratoplasties performed in children are associated with a guarded prognosis.

“CXL has provided a mechanism to arrest progression and avoid end-stage disease,” he said. However, caveats for CXL include the ability to adequately test paediatric patients preoperatively, sedation requirements and insurance coverage barriers.


Dr Erin D. Stahl, section chief and paediatric ophthalmologist at University of Missouri-Kansas City School of Medicine and associate professor of ophthalmology at the University of Kansas School of Medicine, joined Dr Johnson in conducting the study at Children’s Mercy Hospital in Kansas City, Missouri, US.

The medical records of the patients who had undergone CXL at Children’s Mercy Hospital were reviewed retrospectively. CXL was performed in all patients using the KXL system (Avedro) with Photrexa riboflavin preparations (Glaukos).

Following a superficial keratectomy and application of topical vitamin B2 every 2 minutes for 30 minutes, ultraviolet (UV)-A light (365 nm, 3 mW/cm2) was applied for 30 minutes with vitamin B2 continuing to be applied every 2 minutes during the UV light exposure. In patients whose corneas were too thin for endothelial protection despite application of hypotonic vitamin B2 to induce corneal oedema, the UV light was blocked for part of the treatment, he explained.

The primary outcomes were the best-corrected visual acuity (BCVA), complications, treatment failure and length of follow-up. If available, the tomographic and topographic data also were reviewed.


In 2015, a 13-year-old patient received a diagnosis of keratoconus based on retinoscopy reflex and topography and a marked increase in cylinder in the left eye (+2.25 x 075). Later that year, the cylinder again increased (-7.50 + 4.00 x 080) and the VA decreased to a BCVA of 20/30.

In 2017, the patient underwent bilateral CXL; the central corneal thicknesses were 439 µm and 478 µm in the right and left eyes, respectively. In 2019, at age 19, the cylinder had stabilised, the myopia in the left eye had decreased and the BCVA was 20/25.

The study included 43 eyes of 27 patients (mean age at surgery, 15 years; median follow-up, 328 days). “The logarithm of the minimum angle of resolution BCVA improved modestly from 0.3 preoperatively to 0.1 postoperatively,” Dr Johnson said. Due to the small sample size, this was not statistically significant.

Postoperatively, many patients were fitted with a scleral contact lens, a particularly helpful adjunct when trying to provide optical rehabilitation in patients with keratometry beyond typical contact lens therapeutic ranges and an effort to manage their, often irregular, astigmatism. The pachymetry and the topographic and tomographic data remained largely stable overall from preoperative to postoperative measurements.

When the investigators evaluated cases with a minimum of 6 months of follow-up, 26 eyes were included, the median preoperative and postoperative BCVA had a similar trend and the pachymetry was stable. The topographic/tomographic data improved, although not significantly.


Dr Johnson emphasised the need to follow the cohort over the long term despite the encouraging short-term safety and efficacy results. Although the treatment is designed to arrest progression of keratoconus, continued observation is needed.

“The goal is to reach a point where a penetrating keratoplasty or even a partial-thickness deep anterior lamellar keratoplasty is not necessary at all,” he said. “At the very least, the idea is to shepherd them through their younger years, during which time there is a higher risk of corneal transplantation side effects.”

A secondary outcome in these patients was a determination of whether CXL provided a safe and effective treatment that delayed progression to corneal transplantation and also strengthened the potential future graft-host junction to decrease the risk of recurrence in any future grafts, Dr Johnson explained. He pointed out that although shorter protocols may be desirable to decrease anaesthetic exposure or operating room utilisation, efficiency should not override efficacy in these protocol assessments going forward.

Moreover, Dr Johnson believes the safety of the treatment was demonstrated. One surgical complication resulted from an aggressive postoperative healing response that caused scarring. One episode of hydrops was likely progression of the keratoconus, given that it was more than a year after the surgery, which may occur in a small percentage of patients after CXL.

The short-term results suggested the effectiveness of CXL. One patient who lived a fair distance from the surgical centre did not have access to a practitioner who was able to fit a scleral contact lens, so they underwent a penetrating keratoplasty to facilitate RGP fitting. “There may be a need for more penetrating keratoplasties or partial-thickness transplants in this cohort in the future, but, to date, only one has occurred,” Dr Johnson said.


Dr Johnson pointed out that CXL in a paediatric population has been a safe procedure at their institution. “Many findings in the FDA [Food and Drug Administration]-approved CXL studies are similar to our current results, including stability, modest although nonsignificant BCVA improvement and few complications,” he concluded. “Clinical judgment is a fixture in managing paediatric keratoconus and CXL because of the difficulty in obtaining definitive data in this patient population.”

This article is adapted from Dr Johnson’s presentation at the 2020 virtual annual meeting of the American Academy of Ophthalmology. Dr Johnson has no financial interest in this subject matter

Studies show that corneal crosslinking could be a beneficial treatment in paediatric patients with keratoconus. 

Corneal crosslinking outcomes appear to justify its use in paediatrics


Dr Glenn J. Jaffe, professor of ophthalmology, Dr Robert Machemer, Distinguished Professor of Ophthalmology, Chief, Division of Retinal Ophthalmology at the Duke University School of Medicine, discusses the key points of his virtual presentation," Risuteganib Modulates Multiple Transcription Factors regulated by Hydroquinone in Human RPE Cells (Allegro)," including targeting neurodegenerative diseases with risuteganib, minimizing damage to the retina when compromised and the need for newer treatment therapies to target different pathways.

Dr Glenn J. Jaffe discusses the key points of his virtual presentation on targeting neurodegenerative diseases with risuteganib, minimizing damage to the retina when compromised, and the need for newer treatment therapies to target different pathways.

Targeting neurodegenerative diseases using risuteganib 

The results of the phase III TENAYA and LUCERNE trials showed that faricimab (Hoffman-La Roche) met the primary efficacy endpoints of noninferiority to aflibercept (Eylea, Regeneron Pharmaceuticals) in the change in the best-corrected visual acuity (BCVA), durability, and safety for treating patients with neovascular age-related macular degeneration (AMD), according to

Robyn Guymer, a professor of ophthalmology at Melbourne University and deputy director of the Centre for Eye Research Australia in Melbourne.

These 2 clinical trials are large identical randomized, double-masked, investigations that are evaluating the dual inhibition of angiopoietin-2 and vascular endothelial growth factor-A by faricimab. 

This drug, as Guymer explained, is the first bispecific antibody designed for intraocular use that may synergistically promote vascular stability and reduce treatment burden through extended durability in patients with neovascular AMD.

Patients in these 112-week studies were treatment-naïve and randomized 1:1 to faricimab 6.0 mg up to every 16 weeks after 4 initial every-4-week doses or aflibercept 2.0 mg every 8 weeks after 3 initial every-4-week doses.

After the initial dosing and assessments of the disease activity, the patients receiving faricimab were treated at fixed intervals, i.e., every 16 weeks, every 12 weeks, or every 8 weeks. 

The patients treated with faricimab then followed a personalized treatment interval, that is, a protocol-driven treat-and-extend regimen with interval adjustment that was based on individualized treatment responses as assessed by the prespecified anatomic and functional criteria at study drug dosing visits up to week 108.

The primary efficacy endpoint was the change in the BCVA compared with baseline averaged over weeks 40, 44, and 48 and compared with aflibercept. The secondary safety endpoints were the proportions of patients treated every 8, every 12, and every 16 weeks; the proportion of patients who had increases of 15 letters or more or who did not have losses of 15 letters or more; and the changes in the BCVA and central subfield thickness (CST) over time.

The safety endpoints were the incidence and severity and non-ocular adverse events.


The TENAYA and LUCERNE trials included 671 and 658 patients, respectively.

The investigators reported, “Both studies met the primary endpoint, with faricimab demonstrating every 12-week-dosing intervals or longer in about 80% of patients during the first year.

The durability of the treatment was demonstrated up to every 16 weeks at week 48. Meaningful reductions in the CST with faricimab up to every 16 weeks were comparable to aflibercept dosed every 8 weeks through week 48.

Faricimab was well tolerated with few intraocular events in 2.0% of patients randomized to faricimab and 1.2% assigned to aflibercept. No vasculitis or occlusive retinitis developed.

A noteworthy focus of the TENAYA and LUCERNE trials was the examination of individualized treatment tailored to individual patients with an eye toward reducing the treatment burden and maintaining efficacy compared with aflibercept dosed every 8 weeks.

Both trials will continue out to 2 years to continue the evaluations of the efficacy, durability, and safety of faricimab.


This article is adapted from Guymer’s presentation at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual meeting. She is a consultant to Hoffmann-LaRoche.

Robyn Guymer, PhD, MBBS, highlights the latest trial results for faricimab, the first bispecific antibody designed for intraocular use in treating patients with neovascular age-related macular degeneration.

TENAYA, LUCERNE trials show faricimab reaches primary endpoints

This article was reviewed by Dr Amy K. Hutchinson.

As myopia rates continue to soar to epidemic levels worldwide, research has found that the use of orthokeratology and multifocal contact lenses provide clinically meaningful reductions in progression of the refractive error. Ophthalmologist Dr Amy K. Hutchinson recently commented on this. “Both lens types are thought to have a similar mechanism of action to slow myopic progression, and that mechanism is to eliminate peripheral hyperopic defocus and induce peripheral myopic defocus,” she said.

Peripheral hyperopic defocus occurs when myopia is corrected by monovision glasses or contact lenses. The central light rays focus on the fovea and provide a clear image, but peripheral light rays focus behind the plane of the retina, which is thought to play a role in myopia progression, she explained.

Genetics analysis may predict myopia in children

According to Dr Hutchinson, in support of this, clinical observations show a “significant reduction in myopia progression when bifocal glasses, multifocal contact lenses or overnight orthokeratology lenses are used to reduce the peripheral hyperopic defocus”. When measuring myopia progression, the result is expressed as the percentage of the changes in dioptric progression or axial lengthening between a treatment and control group; a 50% slowing is considered ideal and over 30% acceptable.

The centre distance design is used most often in multifocal lenses, in which the central area of the lens focuses the image on the fovea. “The peripheral area has a more positive power resulting from either distinct concentric rings or a gradual progressive increase toward the periphery,” Dr Hutchinson explained. This design provides the wearer with clear central vision and both eliminates the peripheral hyperopic defocus and introduces peripheral myopic defocus, which decreases the stimulus for myopic progression associated with monovision glasses and contact lenses.

Exploring possibilities of myopia prevention and control in the US

Currently, the MiSight multifocal contact lens by Cooper Vision is the only United States Food and Drug Administration-approved contact lens for myopia control. It has concentric peripheral rings that include a +2.00 D add. In a 3-year study, the lens slowed myopia progression in children (aged 8-12 years; refractive errors up to -4.0 D) by 59% and axial elongation by 52% compared with age-matched control children.

Other spherical and toric multifocal lenses are available for off-label use. Dr Hutchinson noted that evidence has suggested that higher add powers may result in better control of myopia progression. These lenses have been shown to slow myopia progression by -9.7–70% and slow axial elongation by 0–79%.

Orthokeratology lenses are worn overnight and temporarily reshape the cornea. “This technology uses a reverse-geometry rigid gas-permeable contact lens in which the base curve radius is flatter than the central corneal curvature, and the secondary curve is steeper than the base curve radius,” said Dr Hutchinson.

The central corneal flattening focuses the image on the fovea and eliminates the need for the patient to wear correction during the day. The lens steepens the mid-peripheral cornea and induces myopic defocus on the peripheral retina, thus controlling the myopia.

AAO: Myopia progression slowed with orthokeratology, multifocal lenses

The lenses, which are most useful for patients with low to moderate myopia, have demonstrated a 30–80% slowing of axial elongation. Slowing of the dioptric progression is not usually reported because the lenses cause a temporary shift in the refractive shift. There is some evidence that these lenses might be useful to treat anisometropia as well.

In the US, orthokeratology lenses are approved for wear overnight but not for myopia control, whilst in Europe, the Menicon Bloom lens (Menicon) is CE-marked for the control of myopia progression, one version being for nightly use and a second type designed for daily use.

However, safety with overnight contact lens wear has been a pervasive concern. There has only been one large retrospective study to estimate the incidence of microbial keratitis associated with overnight orthokeratology lens wear.

Based on the upper confidence interval of this study, the expected incidence of microbial keratitis is no more than 50 per 10,000 patient years, or 1 in 200 years of wear. However, avoiding the use of tap water is recommended. Overall, despite the reported success with contact lens wear to slow myopia progression, questions remain unanswered, including the ideal time to begin treatment, recommended treatment duration and what the rate of rebound myopia is with discontinuation of contact lens wear.

Dr Hutchinson is professor of ophthalmology and director of paediatric ophthalmology, Emory University School of Medicine, Atlanta, Georgia, US, and chief of ophthalmology at Children’s Healthcare of Atlanta. She has no financial interest in this subject matter.

Orthokeratology and multifocal contact lenses provide clinically meaningful reductions in progression of myopia, research shows, but some questions, such as the ideal treatment duration, remain unanswered.

Myopia progression can be slowed with multifocal and orthokeratology lenses 

I interviewed retina expert Dr Konstantinos Balaskas about the applications of 

artificial intelligence (AI) in ophthalmology

. The opportunities for patients and healthcare professionals alike are great, but hurdles remain before AI can be fully integrated in real life: economic, ethical and data-privacy issues to name but a few.

How can AI be applied to retinal diseases?

Well, I think AI is quite a broad term. The type of AI that has generated a lot of excitement in recent years is called ‘deep learning’. This is a process by which software programs learn to perform certain tasks by processing large quantities of data.

Deep learning is what has made ophthalmology a pioneer in the field of implementing AI in medicine, because we are increasingly reliant on imaging tests to monitor our patients. Particularly in my subspecialty of interest, medical retina, imaging tests such as optical coherence tomography (OCT) are performed very frequently and have provided the material to train and test and then apply AI decision support systems.

Measuring visual fields with cloud-based AI platform

In retina particularly, some of the most common causes of visual loss in the Western world, such as age-related macular degeneration (AMD) and diabetic retinopathy, are conditions that require early detection, prompt initiation of treatment and regular monitoring in order to preserve vision. And that is where AI decision support systems can help to improve access to care and ensure optimal clinical outcomes for our patients.

An example is the AI decision support system that was developed in a collaboration between Moorfields Eye Hospital, where I am based, and Google DeepMind. It is able to read OCT scans, interpret them, provide a diagnosis and make management recommendations. The other area where AI shows promise is in the development of personalised treatment plans for patients by being able to predict their response to treatment and their visual outcomes over a period of time.

What do you see as the greatest opportunities for real-life implementation that can improve clinical outcomes?

Referring again to those common conditions that threaten vision, such as AMD and diabetic retinopathy, AI decision support tools, once validated and once they have gained regulatory approval as medical devices, can help improve access to care. They can, for example, assist health practitioners in the community in diagnosing diseases early.

In the United Kingdom, where OCT scans are widely available in high street optician practices, an AI tool would be particularly useful to assist them to interpret scans correctly and identify disease at an early stage. Similarly, in diabetic retinopathy, where patients require regular screening and monitoring of their disease, AI tools can significantly increase the efficiency of the screening programmes.

Some such applications already exist, particularly in diabetic retinopathy – they can be of particular use for diabetic retinopathy screening programmes, such as in under-resourced healthcare settings. Other indications for the application of AI monitoring, like AMD, are in advanced stages of development, but have not yet been implemented in real life.

Are there any challenges with integrating AI into retina diagnostics and treatments?

Definitely, there are quite a few. I have a personal academic interest in the field called implementation science, which looks at the gap between developing a medical device such as an AI decision support tool and actually deploying it in real-life clinical practice.

The potential barriers that we need to overcome for the tool to be deployed in a meaningful way to improve outcomes for our patients go beyond testing and validation. These include economic evaluations: how would such an automated decision support model affect the finances of a healthcare system, so that it could provide good value for money or achieve cost savings?

The next consideration is human factors, particularly how these models of care that rely on AI are perceived and accepted by patients and practitioners; what is the level of trust in these technologies? And what level of information and education of patients and the general public is required to build confidence in their use? Then there are considerations around training and the technical infrastructure to support these tools.

Ethical and data-privacy issues, as well as medico-legal considerations, are also important: who is responsible for decisions made by an AI algorithm rather than a human? How do these tools affect the way healthcare professionals diagnose and manage disease?

There is a phenomenon called automation bias, where practitioners are sometimes more likely to defer to the recommendation of the AI tool, even perhaps against their better judgement. And there is the issue of interpretability—the ‘black box’ phenomenon—in many instances these AI tools are opaque in their functioning.

We do not fully understand how a specific recommendation is reached, whether that is a diagnosis or a management recommendation, and that lack of transparency can exacerbate the medical, legal and ethical issues that were mentioned earlier. In summary, there are several hurdles to overcome before AI tools can be deployed in real life in a way that is safe and will improve clinical outcomes.

How do you envisage life will change for ophthalmologists in the future?

This is an interesting question. I share a positive optimistic vision of AI in medical practice. Our field is becoming increasingly complex and we need to process data from various sources when we are assessing our patients: data from the many imaging modalities, genetic data and the various types of omics, such as proteomics and the emerging field of oculomics, where features on the eye examination can be indicative of problems with systemic health. Even data from home vision monitoring devices will become increasingly available.

Precision management to revolutionise glaucoma diagnosis and treatment

Processing and making sense of all this data in order to develop a personalised treatment plan for each individual patient can be a daunting task. AI could become a very useful aid and, as described in the Topol review on AI commissioned by Health Education England, provide the gift of time to patients and practitioners, giving them the chance to discuss and decide together what the optimal treatment plan is, informed by the processing of high-dimensional complex data sources.

1. Campbell JP, Mathenge C, Cherwek H, et al. AI to reduce ocular health disparities: moving from concept to implementation. 

Konstantinos Balaskas, MB BS, MD, FEBO, MRCOphth

Dr Balaskas is a retinal expert at Moorfields Eye Hospital, London, UK, and director of the Moorfields Ophthalmic Reading Centre and AI Analytics Hub. He has a keen academic interest in new ways of delivering care in ophthalmology, including tele-medicine, ‘virtual’ clinics, remote monitoring and AI decision support. He has no financial disclosures.

Ophthalmology, with its heavy reliance on imaging, is an innovator in the field of artificial intelligence in medicine.

Ophthalmology: A pioneer in the field of artificial intelligence

 patients have a clear refractive outcome in mind, with an expectation of how their vision should function. Without question, correcting astigmatism is a part of that equation and nailing the refraction is also imperative for a premium outcome. Surgeons seek to offer the best technology available that will consistently deliver what patients demand, which means a solution that minimises the likelihood of missing the refractive target.

Looking at 10 years of dry eye disease flares

More than half of cataract patients present with greater than 0.75 D of astigmatism,

 yet globally, toric IOL adoption remains below 5%.

 The reasons for this are found in the myriad of challenges with toric IOL implantation, including the limited power options with the toric IOLs currently available. Another barrier is that surgical planning for astigmatic management is complex and tools that facilitate accurate calculations may be cost-prohibitive for some surgeons.

Surgical misalignment and post-implantation rotation make toric lenses less effective – each degree of misalignment reduces the effectiveness of astigmatic correction by 3.3%.

 One study observed that, at the 1-month postoperative mark, 19% of monofocal toric IOLs and 18% of multifocal toric IOLs had rotated by more than 10 degrees.

Additionally, surgically induced astigmatism can reduce the effectiveness of the correction, with axis shifts inducing misalignment. In spite of surgeons’ best efforts, there remains some uncertainty in the attempted versus the achieved correction with toric IOLs.

Small-aperture or pinhole optics offer specific advantages in an IOL. The IC-8 IOL (AcuFocus) is a one-piece, hydrophobic, acrylic, posterior chamber monofocal IOL that applies the small-aperture principle to extend the depth of focus, which in turn provides an increased range of vision from far to near.

This is achieved by the ability to eliminate unfocused peripheral light rays, allowing only the central rays to focus on the retina.

 At the same time, the small-aperture design provides extended depth of focus that makes the implant more tolerant of sphero-cylindrical residual refractive errors compared with multifocal implants.

Examining the stability of a new aspheric IOL in cataract patients

The IC-8 has been shown in multiple studies to tolerate up to 1.50 D of corneal astigmatism,

 whereas with multifocal lenses more than 0.75 D of residual sphere compromises visual acuity, spectacle independence and, ultimately, patient satisfaction.

 The small-aperture design is symmetrical, thereby eliminating the need for axis alignment.

This lens provides a simple solution for mitigating low to moderate astigmatism that is unaffected by surgically induced astigmatism. With a larger so-called landing zone, the IOL by nature is more forgiving than other technologies. Its design enables it to provide 3.00 D of extended depth of focus and tolerate up to 1.00 D deviation from the target manifest refraction spherical equivalent.

A one-piece, hydrophobic, monofocal IOL uses the small-aperture concept to provide a good alternative to the toric IOLs currently available.