PIE POST (EURETINA 2021 Edition) - Day 4

Action Against Myopia EURETINA Takes

Experts advocate less screen time and healthier indoor lifestyle for children

by Nick Eustice

The first session of the last day of this year’s EURETINA virtual conference began bright and early, with each of us focused intently on our screens. Coincidentally, on the subject of “Better Patient Counselling: Using Epidemiological Evidence in Day-to-Day Clinical Practice”, most of the speakers’ focus was on those very screens we were all using, and what effect they have on our eyes.

During the past year, it is no secret that people everywhere have been spending more time indoors, more time in front of screens, and more time absorbing artificial blue light than in years past. And these big changes in patients’ lives, and the life of their eyes, formed the predominant underlying theme of the morning’s discussion.

Effects of quarantine in children’s vision

The session opened with co-chair Dr. Caroline Klaver, who spoke on the topic of quarantine and its relationship to myopia. The lifestyles of most

people on earth have changed as a result of COVID-related lockdowns, and it is fair to say that this change has not been for the better. This is especially true for children, in whom the onset of myopia is most likely to occur. As we know, lifestyle is a key contributor in instances of myopia, and these behavioral changes that have taken place due to disease prevention measures lead Dr. Klaver to present data on what she terms “the risky business of lockdown”.

Many studies have shown that outdoor exposure significantly reduces myopia instances among children. Near work, being an activity where the focus of the eye remains at a very short distance, has been shown to increase the chances of developing myopia. Thus, years ago, Dr. Klaver introduced a rule of thumb for childhood lifestyle in order to avoid the onset of myopia: for every 20 minutes of near work, children should look at a distance for at least 20 seconds. Additionally, it is recommended that children have two hours of outdoor time every day.

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The first report which Dr. Klaver encountered concerning myopia and quarantine was published in March of this year. This survey was conducted among a large sampling of Chinese children, who were, of course, among the first to experience widespread quarantines as the COVID pandemic began to spread.

The study, conducted before and after the severe lockdown in China, showed an alarming increase in myopia among children aged six to eight. Interestingly, and also sadly, the older children in the sampling, aged nine to 13, had already shown such a high instance of myopia that the lockdown did not appear to have had nearly so severe an impact upon them.

Rules for smartphone usage among children

What happened to these children during lockdown? Why, the very thing that has been a difference with everyone’s life in lockdown: long, extended hours of uninterrupted screen time became far more common, while outdoor time became increasingly scarce. Few children received even one hour of outdoor time after the outbreak of COVID 19, while even fewer were able to get the recommended two hours. While all children showed an increase in screen time, among those children who were already myopic, the increase was substantially greater.

Interestingly, the type of screen being viewed during screen time has a big effect on myopia as well. Smartphones and tablets are the most common types of screens which children are likely to use, and also potentially the most damaging.

A sophisticated study conducted among Dutch teenagers used a background

app on their smartphones, which measured all aspects of use, including light circumstances, reading distance, and the clarity of their screens. This study revealed that a high number of cell phone use in over 20 minutes had a direct correlation to axial length. Similar studies on desktop computers showed substantially less correlation between myopia and screen time. In fact, the desktop screens demonstrated less correlation than reading a book.

Dr. Klaver recommended a series of rules for smartphone use among young people, in line with WHO guidelines. Children under the age of two should not be exposed to them at all, while those from ages two to five should have under an hour of screen time each day. For children between six and 10, less than two hours per day is recommended, while from 10 to 15, less than three hours is suggested. For both of those groups, however, breaks are strongly recommended every 20 minutes.

The dangers of blue light

Later in the session, Dr. Cécile Delcourt expounded on the dangers of screen time by presenting the impact of blue light on eye health. Blue light corresponds to the shorter wavelengths of the visible spectrum and is therefore of higher energy intensity than other colors. While more intense, invisible light such as ultraviolet light is absorbed largely by the cornea and the lens, blue light is the most energetic part of the light which is absorbed primarily by the retina.

This high-energy light, when received in concentration by the retina, is harmful to photoreceptors and retinal pigment epithelial cells. This can lead to macular degeneration, as well as harmful generation of reactive oxygen species. Additionally, too much blue light can

lead to melatonin imbalance in the brain, leading to potential sleep disorders.

While our eyes are accustomed to a great deal of naturally occurring blue light in the form of sunlight, of which blue light represents about 24% to 30%. But there is a potential danger of increased blue light exposure due to modern technology, screens in particular. Conventional incandescent light bulbs and halogen lights were of far higher wavelength, thus presenting very little blue light. However, contemporary LED lights provide a tremendous amount of blue light. These are used more and more in our homes and businesses, and most notably, they provide the light source for virtually all computer, tablet, and smartphone screens.

The concern over the potential harm caused by blue light has led to various efforts to shield the eye from blue light. While blue-blocking eyeglasses, designed to filter out blue light, have experienced an explosion in sales growth worldwide, Dr. Delcourt pointed out that there are not yet any studies to demonstrate their efficacy. Thus, the concern over blue light leads us to the same conclusion as concerns over myopia: limiting screen time limits harm.

Aim for a healthier indoor lifestyle

While maintaining social distance is important in reducing the risk of pandemic infection, it is important to remain focused on other aspects of our health as well. Due to the need to remain indoors for such extended periods of time, as many have during the past two years, it is easy to forget the harm that longterm engagement with LED screens can have on our vision. It is, therefore, more important than ever to improve patient education on these dangers.

“A rule of thumb for childhood lifestyle in order to avoid the onset of myopia: for every 20 minutes of screen time, children should look at a distance for at least 20 seconds.”

A True Visionary

by Hazlin Hassan

The digital revolution in healthcare and the use of deep learning and artificial intelligence (AI) can play an important role in making predictions in diagnosis and treatment needs — experts said during a session on ‘Retinal Imaging, Artificial Intelligence and Big Data’ during the last day of the EURETINA 2021 Virtual Congress.

Machines can see the future

Machine learning classifiers can predict treatment demand and may help in patient-specific treatment plans in the near future. “More and more research is being carried out on how AI can be used in ophthalmology,” said Prof. Raphael Sznitman, ARTORG Center for Biomedical Engineering Research, University of Bern, Switzerland.

He shared a study that has gone beyond being able to identify just a few biomarkers to 39 biomarkers in one shot, and with high accuracy. In this study, a multi-disease automatic detection platform was developed by applying convolutional neural networks constructed in a customized two-step strategy that can classify 39 types of common fundus diseases and conditions

based on color fundus images. It is capable of predicting the probability of each disease and displaying heat maps providing deep-learning explainability in real-time.

“But if we consider things now that are in the direction of predicting treatment responses, we’re seeing more and more work in this direction,” Prof. Sznitman said.

A study was conducted to assess the potential of machine learning to predict low and high treatment demand in real life in patients with neovascular agerelated macular degeneration (nAMD), retinal vein occlusion (RVO), and diabetic macular edema (DME) treated according to a treat-and-extend regimen (TER).

The study revealed that it is possible to predict low demand reasonably well at the first visit, before the first injection. Anemia can also be detected from retinal fundus images via deep learning.

The invasiveness of diagnostic tests for anemia and the costs associated with screening for it mean that the condition is often undetected. Automated anemia screening based on fundus images could help patients with diabetes and for whom

anemia can increase morbidity and mortality risks.

To summarize, AI can be used in identifying known biomarkers, predicting treatment responses, and discovering new insights into patients and their diseases, he said.

Identifying biomarkers for AMD

Optical coherence tomography (OCT) scans play an important role in diagnosing and managing sight-threatening macular diseases such as age-related macular degeneration (AMD). But a detailed analysis of OCT scans in clinical routine can be time-consuming.

Now, AI can be leveraged to identify biomarkers for AMD in OCT scans.

AMD is a major social concern, said Dr. Clarisa Sanchez, University of Amsterdam, Netherlands.

An estimated one in seven Europeans over the age of 70, and one in three Europeans over the age of 80, is at risk of developing advanced AMD. Of these cases, over 1/3 will develop severe

How artificial intelligence and big data are revolutionizing the future of retinal healthcare

visual impairment or blindness and, therefore, early detection of progression to advanced AMD is critical to maximizing visual and functional outcomes, warned Dr. Sanchez.

“Accurate phenotyping of early or intermediate AMD using AI can help in risk stratification for prompt intervention and optimal treatment selection, clinical endpoint definition for the development of early AMD intervention, as well as patient selection for clinical trials,” she added.

A study sought to develop and validate a deep learning model for the segmentation of 13 OCT features associated with neovascular and atrophic AMD, using 2,712 annotated B-scans. Results showed that the quality of the automatic segmentation matches that of experienced graders for most features, exceeding human performance for some features.

The application of this model could ultimately lead to increased speed of interpretation, a reduction of cost, and improved personalized care for the patient.

“Although we still need to further validate this method, AI can help us in biomarker detection and quantification,” concluded Dr. Sanchez.

Can AI replace human grading of diabetic retinopathy?

All eligible patients in the U.K. have digital photographs taken every year, and they are either referred to hospitalized services if there’s significant retinopathy or reviewed annually with further photographs.

With more than two million diabetics in England — and this number is increasing as in most countries — this generates

more than 10 million images that need human grading, which is costly and labor intensive.

“The solution could be AI applications which are used to read retinal photographs and separate those with disease from those without,” said Prof. Adnan Tufail, consultant ophthalmologist, Moorfields Eye Hospital, U.K.

However, some facial recognition algorithms that were developed using predominantly white males performed poorly when tested on females and non-whites, he noted. “Given similar pigmentary variations at the back of the eye, there are concerns that similar issues may arise with different races or different camera types,” he said.

A study on whether automated diabetic retinopathy (DR) image assessment could replace human graders in the English National Screening Program was carried out. It showed that the software achieved acceptable sensitivity for referable retinopathy when compared with human graders and had sufficient specificity to make them cost-effective alternatives to manual grading to triage the presence of DR, he said.

In conclusion, emerging machine-learning algorithms may be cost-effective but need validation.

Predicting AMD treatment outcomes

Can machine learning classifiers predict long-term treatment responses? This was

a question posed by Dr. Martin Zinkernagel, Department for Ophthalmology, Inselspital, Bern, Switzerland, during the session.

“One of the major unmet needs in the treatment of neovascular AMD is the prediction of treatment demand, and thus treatment response to anti-VEGF,” Dr. Zinkernagel said. This would allow not only to counsel patients accordingly, but would also help to tailor individualized treatment in order to avoid under or overtreatment, he added. “The goal of our study was to assess the potential of machine learning to predict low and high treatment demand,” he added.

This was a retrospective study with a total of seven and 10 eyes of 625 patients. The patients were divided into a group with lower demand for anti-vascular endothelial growth factor (anti-VEGF) therapy, a group with high demand for anti-VEGF treatment, and an additional group with intermediate demand. In this study, both classifiers showed a fair performance for predicting both low and high demand.

“In conclusion, we could show in this study that AI can help to predict antiVEGF treatment demand in patients with neovascular AMD,” noted Dr. Zinkernagel.

The decision-making process of the trained classifiers largely relies on biomarkers, rather than segmentation data, which is in keeping with clinical decisionmaking.

“Future work is directed at predicting changes of fluid volumes over time, and potentially the prediction of visual acuity gains from baseline data,” he concluded.

“More and more research is being carried out on how AI can be used in ophthalmology.”

— Prof. Raphael Sznitman, Switzerland

Bleeding Eyes

Tackling subretinal hemorrhage — treatment options and promising studies

by Tan Sher Lynn

In some cases of wet age-related macular degeneration (AMD), fragile new vessels bleed into the eye, causing a large hemorrhage, which is toxic to the light-sensing cells and can lead to permanent scarring and severe sight loss. During the fourth and last day of the EURETINA 2021 Virtual, retina specialists from Europe shared their knowledge in managing this issue.

Available treatment options

According to Dr. Aude Couturier from the University of Paris, France, massive submacular hemorrhage (SMH) is an uncommon and severe complication of neovascular age-related macular degeneration (nAMD), and may also occur in polypoidal choroidal vasculopathy. Its natural history is poor, with a mean final visual acuity (VA) of 20/1600. However, no clinical guidelines are currently available for the management of SMH.

“Treatments options currently available include intravitreal anti-vascular endothelial growth factor (antiVEGF) injections alone or pneumatic displacement of perfluorocarbon gas injection with or without recombinant tissue plasminogen activator (tPA), or vitrectomy plus tPA and gas,” said Dr. Couturier. tPA is known as the “clot buster” drug.

“Anti-VEGF injections can be used to treat small subretinal hemorrhage and when the blood is mainly located under the retinal pigment epithelium (RPE). In cases where there’s massive and recent subretinal hemorrhage, vitrectomy with tPA is an established technique to

manage it, especially if the hemorrhage is recent and the blood is located mainly above the RPE. In some cases, tPA and gas are also used in addition to vitrectomy and tPA,” she noted, adding that in all cases treated with pneumatic displacement, surgeons have to keep in mind the high risk of recurrence. AntiVEGF injections may be needed during surgery and monthly after the operation in all cases to avoid the recurrence of subretinal hemorrhage.

RPE grafting is another way to manage SMH, especially when it’s too late for pneumatic displacement and there’s no resorption, but the retina appears to be viable, according to Dr. Jan Van Meurs from Rotterdam, Netherlands.

He also noted that the risk of proliferative vitreoretinopathy (PVR) is much lower with recognition and removal of the vitreous cortex remnants (VCR).

“Autologous RPE transplantation for exudative AMD is here and it works,” said Dr. Van Meurs. However, stem cells-derived RPE is not yet established, as surgical and immunosuppression challenges remain.

The TIGER trial: Surgery and anti-VEGF vs. anti-VEGF injections only

The TIGER (vitrectomy, subretinal tissue plasminogen activator, and intravitreal gas for submacular hemorrhage secondary to exudative age-related macular degeneration) study is a randomized, observer-masked, active-control surgical trial involving 210 participants in 70 centers across

Europe — funded by leading research charity Fight for Sight, and supported by EURETINA.

Led by Dr. Timothy Jackson, professor of retinal research at King’s College London, UK, the study aims to compare the outcomes of surgical intervention plus anti-VEGF treatment versus the use of anti-VEGF only.

Half of the participants will be allocated to pars plana vitrectomy, subretinal tPA, intravitreal SF6, gas injection, and aflibercept group; while another half will be allocated to the aflibercept monotherapy group commencing at baseline. All participants will receive aflibercept at months 1 and 2, then bimonthly up to month 12, with metaanalysis performed at 12 months. The primary outcome is measured as a gain of at least 10 Early Treatment Diabetic Retinopathy Study (ETDRS) letters at 12 months.

“Surgical intervention includes phacoemulsification if needed, vitrectomy, and induced vitreous detachment. Subretinal tPA is prepared by mixing alteplase 10 mg with 10 ml diluent (water), and further diluting it with saline to give the final concentration of 100 μg per ml. tPA is injected subretinally to cover the entire SMH via a very fine bore cannula (38G or less) up to a maximum of 0.25 ml (25 μg),” Dr. Jackson explained.

Dr. Jackson shared that although the planned recruitment commencement date of January 2020 was missed due to the COVID-19 pandemic, the trial had finally started with three sites and five patients recruited so far.

To Peel or Not to Peel

The role of ILM peeling in vitreoretinal diseases

by Tan Sher Lynn

Internal limiting membrane (ILM) peeling plays an important role in increasing success rates in macular and vitreoretinal disease surgeries. During the last day of the EURETINA 2021 Virtual, vitreoretinal specialists from Spain shed light on the importance of ILM peeling in various retinal conditions.

ILM peeling in macular holes

Macular holes (MH) can result from an injury or a medical condition that affects the eye, such as high myopia. ILM peeling has been shown to improve closure rates of MH and prevent postoperative reopening.

However, some authors argue against ILM peeling as it can result in a number of changes in retinal structure and function, and may not be necessary in all cases. The evidence base for peeling of smallsized MH is less robust as well, noted Dr. Marta S. Figueroa from Madrid.

“ILM peeling seems not useful for MH less than 400μm. Hence, it is recommended to always peel the ILM in large MH, traumatic MH, and myopic MH, especially those associated with posterior staphyloma, myopic retinoschisis, and localized retinal detachment,” she said.

“A recent meta-analysis of 5,480 MH surgeries has shown a significantly lower

rate of MH reopening after ILM peeling (1.18%) than surgery without ILM peeling (7.12%),” explained Dr. Figueroa.

She noted that there are currently no prescribed parameters for the optimum extent of ILM to be peeled. Most surgeons peel a one-disk diameter radius of ILM around the hole (range: 0.5-3). Enlarging the ILM peel area can result in hold closure in failed, chronic, large, traumatic, and myopic MH.

hole with good anatomic and functional outcomes,” she added.

ILM peeling in epiretinal membranes

The treatment of symptomatic epiretinal membrane (ERM), or loss of vision and/ or metamorphopsia, involves surgical removal by peeling of the ERM. As ILM is adherent to the ERM, it is sometimes removed together with it, according to Prof. José M. Ruiz-Moreno from the Castilla La Mancha University.

“Another way to increase the closure rate for failed, traumatic and myopic MHs is to use plasma rich growth factors (PRGF). The foveal sparing ILM peeling is particularly useful in stage 1 or impending MH. Its use has also been reported in stage 2 MH to reduce the damage from ILM peeling around the

He noted that even though ERM removal with ILM peel has similar visual outcomes as ERM removal without ILM peeling, peeling the ILM ensures more complete removal of the ERM and is associated with a lower rate of recurrence, reducing the need for repeat surgery. “Nevertheless, the possibility to induce microscotomas must be resolved,” he stressed.

ILM peeling in tractional myopic maculopathy

According to Prof. Jose Garcia-Arumi from the Universidad Autònoma Barcelona,

“A recent meta-analysis of 5,480 MH surgeries has shown a significantly lower rate of MH reopening after ILM peeling (1.18%) than surgery without ILM peeling (7.12%).”

— Dr. Marta S. Figueroa, Madrid, Spain

50% of myopic foveoschisis will develop MH or MH retinal detachment.

“Surgery is indicated when there is a decrease in visual acuity (VA) or foveal detachment. Foveal detachment is a risk factor for post-op MH and worse post-op VA. The technique we employ includes vitrectomy, posterior hyaloid dissection, foveal sparing ILM peeling, and gas tamponade,” he shared.

Dr. Garcia-Arumi noted that in myopic MH, surgery improves VA and decreases retinal detachment risk. However, the closure rate of myopic MH is low and it worsens with posterior staphyloma and foveoschisis.

“In myopic patients, symptomatic foveoschisis and MH with/without retinal detachment are the major indications for surgery,” he explained. “Small gauge surgery with ILM foveal sparing dissection and gas tamponade is a good option for symptomatic myopic foveoschisis. Inverted flap ILM dissection technique increases the rate of MH closure and VA improvement,” he concluded.

ILM peeling in primary rhegmatogenous retinal detachment

Meanwhile, Dr. Lluis Arias Barquet from Vilanova la Geltru said that indications in rhegmatogenous retinal detachment (RD) that warrant an ILM peel are

macular hole RD in high myopes, RD with concomitant MH, RD with proliferative vitreoretinopathy (PVR), and the prevention of postoperative EM.

“The goals of doing an ILM peeling is to remove remains on the retinal surface and remove scaffold for glial cells profillation,” explained Dr. Arias Barquet. “ILM peeling can cause adverse effects, such as dissociated optic nerve fiber layer (DONFL) and potential damage on inner retinal layers. However, there’s no proven detrimental effect on VA,” he added.

He and his colleagues did a retrospective study at Bellvitge University Hospital to determine the post-op incidence of ERM in 140 patients with primary RD. Patients were equally divided into the ILM peeling group and control group and were examined with swept source optical coherence tomography (SS-OCT).

Results showed that ERM was detected in 46% of patients in the non-ILM peeling group but only 1.8% of patients in the ILM

peeling group. Retinal dimples are found in 41% of patients in the ILM peeling group. The study also showed that SSOCT is helpful to detect and monitor postop ERM, and allows the differentiation of three types of ERM.

“We can conclude that ILM peeling in initial RD surgery prevents ERM development,” he said.

ILM peeling in diabetic macular edema

Vitreomacular traction is a relevant factor in the generation and maintenance of diabetic macular edema (DME).

“DME surgery should be considered based on the vitreous status,” shared Dr. Alfredo García Layana from the Clínica Universidad de Navarra. “In general, the presence of anterior-posterior traction may be an indication for pars plana vitrectomy (PPV) in DME. However, surgery is controversial in cases of tangential traction,” he said.

Dr. Alfredo

He added that in general, patients with poor preoperative best-corrected visual acuity (BCVA) will have higher BCVA gains after PPV. “In contrast, patients with greater retinal thickness, poorer glycemic control, subretinal fluid, lack of external limiting membrane (ELM) integrity, and disruption of the ellipsoid zone will have poorer final absolute BCVA,” Dr. García Layana said.

When the patient has non-tractional DME, it is proposed that the removal of the vitreous with or without ILM peeling improves the oxygenation of the retina. “There is no consensus regarding PPV when there is no traction. For that reason, surgery should only be considered in cases unresponsive to intravitreal treatments and without posterior vitreous detachment (PVD),” he explained.

“The guidelines of the EURETINA society suggest that ILM peel has a role in the presence of anterior-posterior traction,” noted Dr. García Layana. “But in cases of tangential traction due to an epiretinal or hyaloid membrane, surgery should be considered only when the response to anti-vascular endothelial growth factor (anti-VEGF) or dexamethasone implants is incomplete. Meta-analyses on non-tractional DME have found that ILM peeling offered no advantages related to BCVA change. But the anatomical outcome will be better than functional results,” he concluded

“The guidelines of the EURETINA society suggest that ILM peel has a role in the presence of anteriorposterior traction.”

—

García Layana, Clínica Universidad de Navarra

Time to

Detox!

EU’s new medical device regulation aims to prevent medical devices toxicity

by Nick Eustice

In the final symposium at this year’s EURETINA conference, we returned to what had already been something of a hot topic: the European Union’s new Medical Device Regulation (MDR), which went into effect on May 26 this year. This administrative law has brought about changes throughout the world of retinal medicine, and its immediate impact is of primary concern within the EU. Due to the reach and influence of the European medical industry in an ever-closer global community, its impact will be of significance across the globe as well.

Addressing medical device toxicity

In this presentation, the question on the effects of the MDR was focused on the use of silicone oil. An important component in vitreoretinal surgery, silicone oil is useful in taking the place of displaced fluids from the retinal surface, helping to keep the retina in place. While the use of silicone oil is widespread in retinal surgery, it is not without its complications and controversies.

Thus, the symposium, entitled “Silicone Oil and Other Surgical Medical Devices Facing the New Regulation of the European Union: Is It the Answer to Toxicity?” attempted to address how these new policies may impact silicone oil’s role in surgery.

has introduced a far more robust standard of conformity. This entails a quality management plan, an independent evaluation of the device’s technical documentation, and most crucially, a required clinical evaluation. Dr. Pastor emphasized that this evaluation must be conducted by a clinician experienced in the device’s intended area of application. This should lead to a more practice-driven application of the regulatory process.

In addition, the MDR requires the disclosure of comprehensive consumer information for both patients and clinicians as well. The mandate requires a regularly maintained, publicly accessible database (Eudamed) in order to collect and document all adverse effects and periodic safety reports associated with the device.

Refining the use of silicone oils in vitreoretinal surgery

So with these new protections now in place, how does this affect silicone oils? Dr. Rosa M. Coca pointed out that there is a wide variety of silicone oils on the market currently, with varying degrees of viscosity and purification. Generally, silicone oils are a valuable tool to the retinal surgeon as their use can be more prolonged and often more effective than with the alternative, where gas is used.

At the same time, there are many concerns about the toxicity of silicone oils, to the extent that it has merited the origin of its own term, silicone retinopathy. Among various dangerous side effects are reduction in corneal endothelial cells, closed chamber angle, atrophy of the ciliary body, and glaucomatous atrophy of the optic nerve.

By way of introduction, the symposium’s chair, Dr. Jose Carlos Pastor, explained that a key aim of the MDR is to prevent the toxicity of medical devices. This, he explained, is far too common a problem, much more than most people would expect. Toxicity is an issue pervading all fields of medicine, not just ophthalmology.

So how does the MDR intend to address medical device toxicity? To begin with, it

All of these complications are believed to be related to the relative toxicity levels of various silicone oils. Further, histopathology suggests that the severity of these complications increases with the length of time in which the silicone oil was maintained within the eye.

These concerns, and the diversity of clinical trials and data, suggest that the MDR could be of enormous use in refining the use of silicone oils in vitreoretinal surgery. By streamlining and combining the data of a large volume of more rigorously mandated clinical trials, we can hope for a safer future in retinal surgery.

“Medical device toxicity is a common problem, much more than most people would expect. Toxicity is an issue pervading all fields of medicine, not just ophthalmology.”

Eyeing New Frontiers

New optogenetic approaches to restoring vision

by Olawale Salami

In patients with progressive degeneration of photoreceptors such as retinitis pigmentosa, there are limited options for vision restoration. Well, based on new data presented at the EURETINA 2021 Virtual, that is about to change.

Targeting photoreceptor degenerative diseases

Dr. Sonia Kleinlogl and colleagues at Optogenetics in Switzerland are targeting photoreceptor degenerative diseases, independent of underlying pathology.

“We are targeting bipolar cells instead of ganglion cells,” shared Dr. Kleinlogl. “This is because we want to achieve restoration of fundamental features of inner retinal signaling, with which we can restore, at least partially, about 30 parallel information channels that the retinal ganglion cells transmit to the brain, which then makes up our final visual perception.”

Dr. Kleinlogl added: “By this diversification of retinal ganglion cell output, we can restore direct cell activity, which senses motion detection or restore the on/off channels, which indicate light getting dimmer or brighter. We can restore some aspects of light adaptation.”

For the optogenetic toolbox, three elements are required: delivery vehicle, optogene, and a synthetic promoter protein.

The optogene, in this case, is a chimeric fully human protein designed from human melanopsin, resident in our photoreceptor ganglion cells. “To activate endogenous signaling in our target cells, the bipolar cells, we modified the intracellular domain of melanopsin with

that of the bipolar cell-specific MGluR6 receptor,” she shared. With this, light sensitivity can be triggered endogenously via the melanopsin photo switch in these cells.

In summarizing the results of these initial studies, Dr. Kleinlogl said: “We have experimental data that shows stable restoration of visual acuity and contrast sensitivity back to wild-type levels in mouse models of retinitis pigmentosa. These results are promising, and this gives us hope of restoration in humans.”

Dealing with long-term damage to retinal blood vessels in COVID patients

COVID-19 is not just a respiratory disease, and significant pathological manifestations have been documented in multiple organs, including the eye.

In addition to direct, virusinduced cellular damage, one of the features of COVID-19 is the ability of SARSCOV-2 to trigger an abnormal inflammatory response, cytokine storm, and a coagulation cascade leading to the formation of blood clots and severe complications.

In May 2020, Dr. Alessandro Invernizzi of the Department of Biomedical and Clinical Sciences, University of Milan, and colleagues, initiated a study collecting fundus images and medical history in patients admitted to

the hospital with a diagnosis of acute COVID-19 and in unexposed controls.

“Images had to be taken within 30 days of COVID-19 symptoms onset,” said Dr. Invernizzi. “Overall, we included 54 COVID-19 patients and 133 unexposed controls in our study and followed up patients six months post-discharge. We had patients with retinal vein occlusion, and these patients were not included in the study.”

On study findings, Dr. Invernizzi stated: “Our data analysis concluded that COVID-19 could affect the retinal vasculature, and signs of microangiopathy are common.” In addition, as compared to unexposed controls, major retinal vessels are tortuous, with increased diameters in both retinal arteries and veins measured in patients with severe COVID-19.

“We observed that there was a demonstrable return to normal diameter only in mild cases, suggesting longlasting structural alterations to the retinal vessels in severe COVID-19,” concluded Dr. Invernizzi. “Long-term monitoring may be required in patients recovering from severe COVID-19.”