Steve Verze is the first ever patient in the world to be supplied with a fully digital 3D printed prosthetic eye November 25 at Moorfields Eye Hospital in London. (Image courtesy of Moorfields Eye Hospital NHS Foundation Trust)

The Fraunhofer Institute for Computer Graphics Research IGD has used its propriety Cuttlefish:Eye software to 3D-print a prosthetic eye.

According to the company, scientists have managed to create models in a fraction of the time typically needed for fitting one. Fraunhofer's new technology will undergo clinical trials in the Moorfields Eye Hospital in London, where 40 patients will get 3D-printed prosthetic eyes.

The company noted that its process creates a 3D scan of the eye socket and a color-calibrated photo of the healthy eye to create the prosthetic eye's 3D model. Fraunhofer's Cuttlefish 3D printing driver is used to print the model on a multicolor, multimaterial 3D printer.

Fraunhofer noted that the process is made possible by the algorithms of Cuttlefish:Eye, a software solution from the Fraunhofer Institute for Computer Graphics Research IGD.

Working in close collaboration with the British company Ocupeye Ltd, the research team in Darmstadt has developed a unique process to create a virtual model from a scan of the eye socket together with a photo of the healthy eye. This serves as a reliable digital platform for 3D printing. The breakthrough technology to produce prostheses will now be fitted in patients for the first time in a clinical trial to be held at Moorfields Eye Hospital London.

Mandeep Sagoo, MD, PhD, a consultant ophthalmologist at Moorfields, pointed out that the company is 

excited about the potential for the fully digital eye.

“This has been a culmination of 4 years of development of sophisticated technology between Moorfields Eye Hospital, UCL Institute of Ophthalmology, Ocupeye Ltd and Fraunhofer,” he said. “We hope the forthcoming clinical trial will provide us with robust evidence about the value of this new technology, showing what a difference it makes for patients. It clearly has the potential to reduce waiting lists."

Ocular prostheses become necessary whenever an eye has had to be surgically removed for health reasons, such as a result of a serious injury or a life-threatening disease such as eye cancer, conditions that afflict more than 8 million people worldwide.

The method of individually measuring the eye socket and manufacturing the prostheses has remained largely unchanged for many decades. The invasive molding can be uncomfortable and in children a distressing experience that often requires a general anesthetic.

The process of handcrafting a prosthetic eye is time consuming and can result in a wait of several months, exacerbating what is already a stressful time for the patient. Utilizing leading-edge 3D printing technologies, the new process significantly speeds up production and provides patients with a quicker, better and an overall more comfortable experience.

The patient's 3D prothesis initial appointment begins with a 2.4 second, noninvasive, non-ionizing scan from a specially modified Optical Coherence Tomography ophthalmic scanner, which is manufactured by TOMEY Japan. The medical scanner is routinely used in a hospital environment.

The resultant scan of the eye socket and color-calibrated image of the healthy eye is seamlessly and digitally transferred to Fraunhofer IGD. Tomey has optimized its capability such that the socket of the removed eye is precisely measured and additionally a color-calibrated photo of the healthy eye is produced. Cuttlefish:Eye creates a 3D print model from this data in an equally short time.

The company noted the printers are controlled by the Cuttlefish universal 3D printer driver, which is characterized by its color consistency as well as realistic representation of even transparent materials. Fraunhofer IGD technology is used worldwide with many different types of printers. The 3D prostheses are printed by Lupburg based Fit AG which has many years of experience in additive manufacturing, especially in the field of medical technology. Once printed, the prostheses are inspected and given final polishing by a team of experienced ocularists. With a single 3D printer, Ocupeye can potentially fulfil the annual requirement of around 10,000 prostheses required for the UK market.

“Together with Fraunhofer, we have achieved the very first in human 3D printed prosthetic eye,” Gordon Bott, CEO of Ocupeye Ltd., said in a statement. “There now exists a complete technology that truly has the potential to reimagine prosthetic eye patients' expectations.”

Every step of the new manufacturing procedure has been subjected to strict quality controls. For example, the Cuttlefish:Eye software is certified as a Class 1 medical device. Extensive and exhaustive biocompatibility tests were performed on the 3D printing materials before the UK Medicines and Healthcare products Regulatory Agency -MHRA- provided a letter of approval for a clinical trial. The clinical trial will recruit around 40 patients to receive a 3D-printed ocular prosthesis; they will be examined several times by qualified clinical staff over the course of a year and be asked to report back on their experiences.

That is an important step that is bringing the project partners closer to fulfilling their vision. Namely to have the ability to routinely provide a realistic medical product to patients who require a prosthetic eye. This is made possible by a highly "disruptive" innovative process that begins with an optical coherence tomography medical device, manufactured by Tomey Japan and with their European HQ in Nürnberg. From the learnings already gained during the research and development phase, Tomey has adopted the enhanced functionality as standard and applied the enhancements to their next-generation devices.

Potentially with just one device per clinic and the deployment of a small number of geographically deployed 3D printers, the estimated global market demand for eight million people, approximately 0.1 percent of the world's population, could be met.

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Using its proprietary software, the company has been able to create models in a fraction of the time typically needed for fitting one.

Fraunhofer Institute creates 3D-printed prosthetic eye

The retina has many different subtypes of ganglion cells that respond to different stimuli. For example, some types are more sensitive to gradations or contrast, some respond to motion or specific directions, or to local edges.

“When all of that information is put together,” Yvonne Ou, MD, explained, “the retina can process all the visual information being presented.”

In addition to those subtypes, retinal ganglion cells (RGCs) can be classified as on- or off-center types. Off RGCs respond to decreases in light and on RGCs to increases in light,1 according to Ou, who is academic director, Glaucoma Division, and vice chair for postgraduate education in the Department of Ophthalmology at University of California San Francisco.

Experimental glaucoma studies have demonstrated that preferential damage occurs in the off RGCs in loss of synapses, dendritic retraction, and RGC responses. “We believe that there is selective vulnerability of alpha-off-transient RGCs in glaucoma, which has been identified in mice,” she said.

The next step was to determine what happens in humans. It seems that the off cells provide clues to ongoing damage from glaucoma in the retina, the so-called canary in the coal mine.

“Are the on cells the coal miners, ie, very hardy and resilient, and less susceptible to glaucomatous damage?” she queried, which then brought her to the next stage, assessment of visual function.

Visual field tests are subjective, uncomfortable, and difficult for patients. In addition, they require costly equipment. Ou suggested that using an objective measurement of the visual fields with a handheld electroretinography (ERG) device may be a better mousetrap for identifying any changes in the on and off RGC pathways.

“The on and off pathways have been explored with other ERG modalities in glaucoma and there is evidence that a flicker stimulus can separate the on and off pathways in mice and perhaps in nonhuman primates and humans,” she said.

Ou recounted a study in which a genetic glaucoma murine model had a decreased ERG response to a flicker stimulus that was more notable at the higher frequencies.2

“We found this to be especially interesting because it suggested that the off pathway is more vulnerable,” she said.

This technology is not currently standard of practice to assess visual function in patients with glaucoma because of the need for corneal electrodes, the equipment is bulky, and the examination is time-consuming.

When considering the practical application of the handheld device in the clinic, Ou and colleagues questioned if the handheld ERG can objectively detect relative changes in the on and off pathways.

In their study, the investigators tested photopic flash, flicker stimulus, photopic negative response, and the sinusoidal custom-written wave stimulus, the last of which is a sinusoidal wave at varying frequencies ranging from 50 to 0.3 Hz. The study included 59 eyes in the glaucoma group and 19 control eyes; the mean participant age was 69 years. The demographics of both groups were similar. The ERG response was measured using the RETeval device (LKC Technologies. The participants were presented with higher and lower sinusoidal frequency stimuli and the data analyzed.

Ou demonstrated the sinusoidal response obtained from the controls and patients using both 25- and 5-Hz frequency stimuli. She reported that at 25 Hz there was a clear decrease in the ERG amplitudes in the glaucoma patients compared with the controls. However, at 5 Hz no difference was seen between the 2 groups.

“Quantitation of the ERG response as a function of the sinusoidal stimulus frequency, showed separation between the controls and the glaucoma patients especially at the higher frequencies,” Ou said. “When we evaluated the percent difference from the controls, we saw about a 20% to 25% reduction in the higher frequencies in the ERG amplitudes.”

When patients were asked their opinions of the handheld ERG test compared with the standard visual field test, 55% of patients reported no discomfort performing the test compared with 27% of patients who reported no discomfort with the visual field test.

“When evaluating the on and off pathways using a novel stimulus and a handheld ERG device in patients with glaucoma compared with controls, the handheld ERG using a sinusoidal stimulus may provide an objective assessment that demonstrates greater off pathway susceptibility in glaucoma,” Ou concluded.

This article was adapted from Ou’s presentation at the 2021 virtual meeting of the 25th Annual Glaucoma Symposium. She has no financial interest in this subject matter.

1. Ou Y, Ullian EM, Wong ROL, et al. Selective vulnerability of specific retinal ganglion cell types and synapses after transient ocular hypertension. 

2. Harazny K, Scholz M, Buder T, et al. Electrophysiological deficits in the retina of the DBA/2J mouse. 

According to Yvonne Ou, MD, the test can objectively detect relative changes in the on and off pathways.

Using handheld ERG to measure visual function in glaucoma

Widefield fundus autofluorescence (FAF) can be very useful for confirming the diagnoses of rare disorders. Bardet-Biedl syndrome (BBS) is a disorder in which the affected patients can be obese and have hypogonadotropic hypogonadism, polydactylism, developmental delay, genitourinary abnormalities, renal disease, and retinal degeneration.

Kimberly Stepien, MD, associate professor of ophthalmology in the Department of Ophthalmology and Visual Sciences at the University of Wisconsin-Madison, explained that patients with BBS can often receive a misdiagnosis of a nonsyndromic disease, such as retinitis pigmentosa, despite having potentially life-threatening syndromic findings. These misdiagnoses can result in delayed screening for systemic problems. The retinas in patients with BBS can have findings that appear similar to those in patients with retinitis pigmentosa, such as classic bone spicules. However, more subtle retinal degenerative changes can be missed during a clinical examination.

“Widefield FAF can highlight peripheral degeneration and macular atrophy,” she said.

Stepien and colleagues reviewed the charts of 9 patients aged 18 to 65 years with genetically confirmed BBS for the medical and ocular histories, findings from the clinical examinations, and ocular imaging, including widefield Optos color fundus photos, FAF, and spectral domain optical coherence tomography.

The investigation found that before BBS was diagnosed, two-thirds of patients (6 of 9) received a diagnosis of a nonsyndromic inherited retinal disease despite the presence of systemic abnormalities and/or family histories that suggested a syndromic disease.

The examination of the 6 patients with a misdiagnoses showed only subtle peripheral pigment changes.

Widefield FAF showed varying patterns of speckled hypo-FAF in the periphery of all patients with BBS. In addition, macular abnormalities (ie, macular atrophy and bull’s-eye maculopathy) were seen in all patients and were highlighted by variable FAF changes, Stepien reported.

The investigators concluded, “Patients with BBS are often misdiagnosed with nonsyndromic disease despite having potentially life-threatening syndromic findings.

Along with detailed medical and family histories, specific imaging findings on wide-field FAF can aid in the diagnosis of BBS in adult patients with suspected inherited retinal diseases by better delineating macular degeneration patterns and unearthing extensive peripheral hypo-FAF changes when clinical examinations findings are subtle.”

This article is adapted from Stepien’s presentation at the Women in Ophthalmology 2021 Summer Symposium. She has no financial interest to disclose.

Widefield fundus autofluorescence detects subtle findings, which can result in better outcomes.


Distinguishing Bardet-Biedl syndrome from nonsyndromic inherited retinal diseases

Spect, a provider of end-to-end eye disease screening solutions, has received $3.5 million in series seed financing, led by Morado Ventures, XTX Ventures, 10X and AME Cloud.

The company's AI-enabled mobile telemedicine platform helps clinicians capture retinal images and screen for vision-threatening eye diseases, such as diabetic retinopathy, glaucoma and age-related macular degeneration (AMD) -- at a drastically reduced cost using medical assistants and nurse practitioners in primary care and at-home care.

This enables screenings to be completed in substantially less time and cost compared to seeing an eye specialist (such as an ophthalmologist or optometrist).

Mike Ricci, CEO and co-founder of Spect, noted that the eye is the body's check engine light.

“Retinal screening can prevent diabetic retinopathy, and give early warnings about heart attack, stroke, Alzheimer's, and Parkinson's,” he explained. “Sadly, despite this, people skip their annual eye screenings because it's costly and inconvenient."

That is a trend that, according to Ricci, has to stop.

“Spect solves today's retinal exam pain points so that millions of patients can, and will, get the preventative care they need,” he said.

Spect brings eye care to primary care, benefitting:

Patients: Spect improves patient health by making it easy to receive vital eye screenings. It also reduces time at the doctor's office, allowing for an annual eye screening procedure to be done in one visit, as opposed to needing to schedule additional follow-ups.

Clinics: Clinics can provide better care to patients in-house, without needing a referral; and Spect improves the quality of care metrics.

Ophthalmologists: Spect frees up doctors' time to focus on treatment, rather than on performing screening exams.

Payors: Vision-threatening diseases are caught earlier and treated with minor procedures, as opposed to expensive surgery and drug treatments down the line.

Diabetes impacts nearly one-third of the U.S. population, and many are affected by its related health complications. Diabetic Retinopathy is currently the leading cause of vision loss in American adults, impacting the lives of millions, yet preventable through regular eye check-ups. Despite that, 60% of U.S. patients skip their annual eye exam due to a dearth of appointment availability and a serious shortage of retinal specialists, which makes visits costly. Spect is positioned to address this critical healthcare gap because its technology makes treatment more affordable and accessible at the point of care.


Spect's platform creates a frictionless workflow that enables healthcare staff to obtain results in three minutes or less with an image gradeability above 95%.

Spect Imaging Device: Spect practices receive a small, portable, and easy to use device for doctors to carry in their pocket

Spect Telemedicine Platform: Spect trained specialists can guide clinicians how to use the Spect device, enabling seamless at-home testing options

Spect Retinal Image Grader: Spect's AI-enabled platform analyzes the results within minutes, instead of days

Spect's Dataset: Over 1.5 million images captured to date are on the platform and this dataset continues to grow

Spect's Business Model: Spect utilizes a SaaS licensing model, and there is no upfront or support cost to the customer

"Spect has tremendous power to scale by using artificial intelligence," Ash Patel, founding partner of Morado Ventures, said in a statement. "One day, Spect will be in our medicine cabinets at home, without the need for a specialist to perform an examination. "

Theodore Leng, MD, director of research at the Byers Eye Institute at Stanford, and a co-founder at Spect, noted that the implications of the company’s technology and dataset span far beyond the diagnosis of diabetic retinopathy because the retina tells physicians so much more about human health.

“The team is creating a new and scalable way to diagnose diseases that plague billions of people across the globe,” he said in a statement.

The company's AI-enabled mobile telemedicine platform helps clinicians capture retinal images and screen for vision-threatening eye diseases, such as diabetic retinopathy, glaucoma and age-related macular degeneration. 

Spect receives series seed funding for eye disease screening solutions

Visus Therapeutics Inc. is reporting positive topline results from VIVID, the company’s Phase 2 study of three novel topical ophthalmic formulations under investigation for the treatment of presbyopia.

According to the company, all three investigational candidates studied in VIVID achieved the endpoint of three lines of improvement in binocular near visual acuity without losing one line of distance vision with a minimum responder rate of 83% at one hour. A minimum of 35% of subjects in the study met this same endpoint at nine hours in all three formulations.

Additionally, all three formulations were well-tolerated and exhibited favorable safety profiles. Based on these positive outcomes, the company plans to commence Phase 3 pivotal trials shortly.

Rhett Schiffman, MD, MS, MHSA, co-founder, chief medical officer and head of research and development at Visus Therapeutics, said company officials are very encouraged by the VIVID study topline clinical data, which demonstrate that the company’s clinical development program has delivered drug candidates which provide a durable improvement in visual acuity with favorable tolerability and safety profiles.

“We know that presbyopia has a profound impact on quality of life for patients,” Schiffman said in a statement. “These positive results provide further confidence that we are well positioned to bring to market the longest-lasting eye drop in the presbyopia category, which would be a meaningful breakthrough treatment for these individuals. We are excited to initiate our Phase 3 pivotal trials.”

In the per protocol population, a minimum of 83% of subjects treated with BRIMOCHOL, BRIMOCHOL F or Carbachol F achieved the endpoint of 3 lines of improvement in binocular near visual acuity under mesopic conditions without losing 1 line of distance vision at 1 hour. A minimum of 82%, 52% and 35% of subjects met this same endpoint at 3, 7 and 9 hours, respectively.

In key secondary endpoints, BRIMOCHOL and BRIMOCHOL F achieved a mean improvement in binocular near visual acuity of a minimum of 18 ETDRS letters, almost 4 lines, as early as 30 minutes and a minimum of 12 letters at 9 hours.

BRIMOCHOL, BRIMOCHOL F and Carbachol F were well-tolerated with no unexpected adverse events. Adverse events exceeding 5% included temporary burning and stinging upon instillation, headache and brow ache. No serious adverse events were reported.

According to Ben Bergo, co-founder and CEO at Visus Therapeutics, the completion of the VIVID study marks an important milestone for the company.

“In light of the recent FDA approval of Allergan’s VUITY, the first pharmacologic approved for the treatment of presbyopia, it is truly exciting to see this category come to fruition,” Bergo said in a statement. “We are pleased the VIVID study data exceeded our expectations, demonstrating a clear opportunity to commercialize long-acting miotic formulations.”

The VIVID clinical trial (NCT04774237) was a double-masked, randomized, dose-ranging, multi-center, three-arm crossover study designed to evaluate the safety and efficacy of fixed-dose combinations of carbachol and brimonidine tartrate (BRIMOCHOL and BRIMOCHOL F) compared to a similarly formulated preservative-free carbachol.

The trial enrolled 85 subjects, ages 45 to 80, with emmetropic phakic and pseudophakic presbyopia at three U.S. sites. The trial was not designed to achieve statistical significance in any of these study populations. Full results from the VIVID study will be presented at future medical meetings.

According to Eric D. Donnenfeld, MD, founding partner of Ophthalmic Consultants of Long Island and Clinical Professor of Ophthalmology at NYU, the preliminary results are encouraging for millions of patients people living with presbyopia and the eye care professionals who treat them.

“Eye drops are emerging as an important new treatment option for correcting age-related loss of near vision,” he said in a statement. “I see tremendous clinical value in a long-acting, preservative-free eye drop that can improve near vision throughout the workday while avoiding the potential toxicity of preservatives. What’s really exciting is that these study results demonstrate the potential of drug candidates that can be studied in a larger treatment population.”

David Evans, OD, an optometrist at Total Eye Care in Memphis, Tenn., and a clinical investigator in the VIVID trial, noted that drugstore reading glasses currently are the most common treatment option for people as they lose their near vision with age.

“This means that many people aren’t getting regular comprehensive eye exams, and as such, more serious eye conditions are going undiagnosed,” he said in a statement. “The availability of a once-daily, preservative-free eye drop such as those evaluated in the VIVID study could attract millions of people into eye care practices nationwide, creating opportunities to not only improve visual performance but also advance eye health overall for this patient population.”

The VIVID study focuses on three novel topical ophthalmic formulations under investigation for the treatment of presbyopia

Visus Therapeutics reveals topline clinical data from Phase 2 VIVID study

In our seven-doctor retina practice we use a variety of imaging equipment; however, one of the constants is our reliance on spectral-domain optical coherence tomography (SD-OCT). Fifteen years ago, I was fortunate enough to train at the Tufts University/New England Eye Center with clinician-scientists who were instrumental in developing OCT technology. Now what stands out to me is the resolution we can obtain with SD-OCT, specifically the high-resolution SPECTRALIS multimodal imaging platform (Heidelberg Engineering, Inc.) is as good as that of our investigational devices from the early-to-mid-2000’s. I am eager to see where we will be in another 15 years.

Here I will overview our practice’s approach to managing diabetic eye disease.

Imaging is integral to the management of diabetic eye disease, therefore, all newly referred patients in our practice receive baseline imaging along with the clinical exam.1 What we do in the clinic should mirror, as best as possible, the best practices from randomized, controlled trials. Those lean heavily on angiography and especially OCT imaging to determine treatment selection and frequency. Therefore, baseline imaging almost always includes those two modalities at the minimum. We also, secondarily, may obtain ultra-wide color fundus photography (Zeiss and Optos platforms) in our offices where that technology is available.

The sequence of follow-up imaging is determined by disease severity and treatability, whether it be diabetic macular edema (DME), which is the most common manifestation of diabetic retinopathy (DR) which we treat, severe non-proliferative DR, or proliferative DR.2 Patients with disease for whom treatment is initiated we see more frequently to gauge their response.

The image registration we can obtain with SPECTRALIS is remarkable, and the TruTrack Active Eye-Tracking feature allows me to compare live images to understand progression. Rather than relying on maps, I prefer to scroll through the scans for a line-by-line comparison. This feature is especially helpful when initiating, changing, or adding treatment: for example, adding focal laser to an area of macular edema that is not responding to first-line anti-angiogenic therapy or adding a steroid for a patient who still has center-involving swelling despite frequent anti-angiogenic injections. When it comes to DME, we value the ability to objectively determine if treatment is providing a measurable improvement.

In the setting of proliferative diabetic retinopathy, I will occasionally perform repeat angiography; however, I generally do not repeat angiography frequently. Although overall, surgeons do less angiography than in the past, ultra-widefield angiography is important in the initial assessment of patients with suspected proliferative disease to ensure control and a complete laser pattern. In our practice, we use the Heidelberg Engineering Ultra-Widefield Module for that application in addition to other ultra-widefield platforms.

SPECTRALIS imaging is well tolerated by patients, and it can be done at any office visit. The patient remains seated in one spot while receiving OCT, angiogram, and ultra-widefield angiogram imaging at the same machine. Regardless of dilation status, we obtain a high-quality image, and the laser light wavelength is not overly bright as may be the case with other systems. For some widefield platforms, patients must be extremely dilated to obtain high-quality images and artifacts can be an issue. SD-OCT is by far the most utilitarian imaging modality available.

OCT and ultra-widefield color images play a key role in disease education, and I use them with all my patients to explain their disease process. In DME for example, I will show patients an example of a normal OCT versus their eye with a swollen macula. By seeing their image, they better understand their disease severity and how close to normal they are. Using the ultra-widefield color image, I point out the red dots that indicate DR explaining that they have bleeding in or in front of their retina and, depending on severity, that that may be treated.

I also love talking to patients about blood sugar control. I give all my diabetic patients one homework assignment: learn your hemaglobin A1c – whatever that number may be – and make a numeric goal with their endocrinologist or primary care doctor. Only about half of my patients know what their HbA1c is when they first come in. I tell them that blood sugar is the fuel for the diabetic fire; they can remove the fuel and put out the fire over time by controlling HbA1c. I explain that their disease comes from a combination of the duration and severity of their diabetes. I say, “if you have diabetes and intend to live—and see—for a long time, you must get your blood sugar under control to reduce your risk of vision loss.”

I am currently involved in a large initiative to democratize diabetic eye care by moving it into a non-traditional setting. Patient access and education are some of the biggest gaps in diabetes care. Repeated, patient-friendly messaging can go a long way to helping this significant public health problem. Diabetes is a US pandemic that preceded COVID-19 by many years and will be around long after COVID recedes. We must ensure that the approximately 50% to 60% of patients with diabeties who do not go to eye exams have a pathway to care and treatment.3 Having imaging that is high-quality, straightforward to obtain, and reproducible is a large part of their clinical care.

Diagnostic imaging is certainly required as part of the standard of care for managing diabetic eye disease. At the bare minimum, the physician must be able to obtain high resolution OCT images and high-quality angiograms to assess the initial anatomy and pathophysiology and to track treatment. Both of these we can perform with SPECTRALIS.

Eichenbaum is a partner in and director of Clinical Research, Retina Vitreous Associates of Florida in St Petersburg, Florida; a collaborative associate professor of ophthalmology at Morsani College of Medicine, University of South Florida, Tampa, Florida. Eichenbaum is a speaker for Genentech, Bayer, Allergan, Novartis, EyePoint, DORC, and Apellis; a consultant to Genentech, Regeneron, Allergan, Novartis, Alimera, Notal Vision, EyePoint, Gyroscope, Kodiac, RecensMedical, DORC, IvericBio, Apellis, KKR, Regenxbio, and Bausch + Lomb; an investigator with AsclepiX, Genentech, Regeneron, Bayer, Novartis, Opthea, Ocular Therapeutics, EyePoint, Mylan, Chengdu, Gemini, Gyroscope, Kodiac, NGM, RecensMedical, Alkahest, Ionis, IverisBio, Regenxbio and Unity; an equity/stockholder in Clearside, US Retina, Hemera Biopharmaceuticals, Boston Image Reading Center and Network Eye; and a founder of Network Eye.

1. Wong TY, Sun J, Kawasaki R. Guidelines on Diabetic Eye Care: The International Council of Ophthalmology Recommendations for Screening, Follow-up, Referral, and Treatment Based on Resource Settings. 

. 2018;125(10):1608-1622. doi: 10.1016/j.ophtha.2018.04.007.

2. American Diabetes Association. 10. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018; 41 (Suppl 1):S105-18.

3. AAO. Sixty Percent of Americans with Diabetes Skip Annual Sight-Saving Exams. News release. Oct. 20, 2016. https://www.aao.org/newsroom/news-releases/detail/sixty-percent-americans-with-diabetes-skip-exams. Accessed Sept. 27, 2021.

SD-OCT is providing reproducible, high-quality, registered images to assess the treatment response in macular disease. 

High-quality, repeatable imaging is the cornerstone of managing diabetic eye disease

The port delivery system is an ocular delivery system that is surgically inserted via the pars plana area in the superotemporal quadrant of the eye. It provides continuous delivery of ranibizumab to the posterior segment. It has a reservoir chamber where a higher concentration of ranibizumab is held, and there is slow release into the vitreous cavity. It has been approved for use in patients with neovascular AMD [age-related macular degeneration], although other indications, including diabetic macular edema, are also being investigated.

With the approval of Lucentis [ranibizumab] for the indications of neovascular AMD, the treatments for neovascular AMD were revolutionized. However, there still is a significant treatment burden for many of our patients who require frequent, often monthly, injections. The treatment burden for both the patients and the family can be quite high. In addition, although we’re delivering a nice bolus of anti-VEGF treatment, there is a waning of the amount of medication in the vitreous cavity. Therefore, a more sustained, endurable treatment modality was needed. Like most devices, the port delivery system was started in the preclinical stages, where it was developed and then tested in nonhuman subjects. Once its safety was verified, it went on to trials to verify safety in human patients, and then to look at the efficacy.

In the phase 2 LADDER study, the technique that was done in human patients initially showed an increased risk for vitreous hemorrhages. The technique for implantation was modified to include laser cautery of the corneal bed]. After this, the incidence of vitreous hemorrhages dropped precipitously. Prior to the amendment, there were 6 out of 10 cases of vitreous hemorrhage. After the amendment, there were no cases of vitreous hemorrhage out of 48 patients within the first month, which is generally considered the postoperative period. At 2 months, there was 1 patient who did have a vitreous hemorrhage.

Although the procedure is generally well tolerated, since it is surgical procedure, there are some potential complications that surgeons and patients should be aware of. Initially, in the LADDER study, there was a higher rate of vitreous hemorrhages. A modification of the procedure has since reduced those rates tremendously. Any surgery has a risk of infection, and with respect to the implant itself, if the conjunctiva is not closed properly or not covering the implant adequately, there is a possibility of the implant being exposed. Also, if the conjunctiva is very thin, there is a possibility of erosion. Therefore, presurgical evaluation and meticulous care to close the conjunctiva are very important.

When evaluating a patient preoperatively, you want to take note of a few things. Particularly, you want to take note of the conjunctiva to see if it’s very thin, and if there’s good mobility of the conjunctiva, so that you can adequately access the subconjunctival and sub-Tenon space. In addition, you also want to note any areas of potential scleral thinning, so that when you’re making your wound you’re aware, and so you don’t start making your wound too deep. In addition, you may also want to avoid those areas, so that there isn’t a risk of dehiscence or any other potential issues with the wound.

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Expert insight on the history of the port delivery system in neovascular AMD and how it has impacted patient experience and outcomes.

The Development and Safety of Port Delivery System in Retinal Diseases

Chronic cystoid macular edema (CME) following intraocular surgery is among the most frustrating postoperative complications for patients. A review of risk factors for CME found that approximately 1 in 400 cataract surgeries result in postoperative CME, and eyes with a history of uveitis or that have experienced intraoperative complications during surgery are more likely to develop postoperative CME.1,2

Retina and uveitis specialists are commonly tasked with addressing chronic postoperative CME, and it behooves us to know the latest innovations and management strategies. In this article, I provide an overview of CME’s real world presentation, discuss the pathophysiology of the condition, explore which factors drive treatment decisions, and review options for therapy. I also review 2 cases that illustrate the effects of prompt treatment.

There is no consensus definition of chronic postoperative CME. In broad terms, chronic postoperative CME occurs when there is evidence of persistent inflammation following intraocular surgery, for at least 6 consecutive months after surgery, and when continued therapy is required to keep such inflammation in check. Therapy includes topical, oral, and intra- or periocular corticosteroids, as well as steroid-sparing immunomodulatory agents.

When evaluating a case of suspected postoperative CME, retina specialists must exclude other entities that might present similarly. Postoperative chronic low-grade endophthalmitis (ie, Propionibacterium acnes endophthalmitis) can present similarly to chronic postoperative CME, and clinicians should look carefully for the presence of capsular plaques and may wish to run the relevant tests to rule out infection.

The positioning of an IOL should be assessed to evaluate for uveitis-glaucoma-hyphema syndrome, which can also contribute to chronic postoperative CME. Anatomical variables such as epiretinal membranes, vitreomacular traction, and traction due to vitreous prolapse to the wound should be assessed. In older patients, there should also be an index of suspicion for masquerade syndromes, such as intraocular lymphoma. It is appropriate to perform a basic uveitis workup in eyes suspected to have chronic postoperative CME, as sometimes there may be an underlying, previously undiagnosed etiology for inflammation which was exacerbated following the intraocular surgery.

Short-term inflammation is inevitable following ocular surgery, and for most patients, the standard postoperative topical steroid taper is sufficient to address this inflammation within about a month. In addition to the risk factors outlined above (ie, surgical complications, history of uveitis), glaucoma surgery, longer surgical times, and diabetes place patients at risk for chronic postoperative CME and prolonged recovery.3,4

In patients with chronic postoperative CME, the course is often punctuated by periods of rebound inflammation throughout steroid taper. This chronic inflammation may lead to a persistently compromised blood-ocular barrier. By reestablishing the integrity of the blood-ocular barrier early in the course of CME, ocular immune privilege may be restored, which helps in sustained resolution of inflammation.

Prompt and adequate treatment of chronic CME is key to facilitating patients' recovery. Inadequate treatment, either via underdosing or inadequate duration of dosing, may lead to recurrent CME. This can result in long-term visual decline in a sawtooth pattern, with progressively reduced visual improvement at the zenith despite anatomical improvement, and increased declines at the nadir.5 Moreover, long-term changes to macular anatomy with chronic CME can be seen on OCT imaging, such as disorganization of the inner retinal layers and disruption of the outer retinal layers.6

Local steroid therapy with periocular or intraocular steroids is often the mainstay of treatment of chronic postoperative CME. Systemic immunomodulatory therapy (IMT) may be considered when there are concerns of steroid-induced IOP elevations which can be seen with local steroid delivery. It can also be useful in bilateral cases.

Earlier and more aggressive use of local corticosteroids may, in my experience, lead to reduced duration and severity of postsurgical CME. Some patients experience resolution after a single or a few injections (either intravitreal or sub-Tenon) of local steroids, whereas others require long-term, frequent dosing due to multiple recurrences. When eyes are steroid responsive but require more than 3 to 4 local steroid injections per year for sustained control, I consider the patient to be a candidate for a long-term steroid implant, as long as they have not experienced a steroid-induced IOP elevation.

In my practice, I leverage the fluocinolone acetonide intravitreal implant 0.18 mg (Yutiq, EyePoint Pharmaceuticals) for patients with chronic recurrent postoperative CME whose disease has demonstrated a prior response to steroids and whose IOP is well controlled. I rarely use the surgically placed fluocinolone acetonide intravitreal implant 0.59 mg (Retisert, Bausch + Lomb) in such eyes due to the higher rate of IOP elevation, which may require incisional glaucoma surgery, but it is a valuable tool when there is very severe postoperative inflammation. It is important to counsel patients that rare breakthrough episodes of inflammation may occur despite the placement of a sustained release implant, and that in such cases adjuvant treatment with intravitreal triamcinolone acetonide or the intravitreal dexamethasone implant 0.7 mg (Ozurdex, Allergan) is helpful.

In patients with chronic, recurrent steroid-responsive CME, a long-term steroid implant such as Yutiq allows a reduction in treatment burden and sustained improvement in visual function and long-term preservation of retinal anatomy. It also enables reduced amplitude of fluctuations in retinal thickness as well as an associated saw-tooth functional decline.

Grewal has no financial disclosures related to this content.

1. Patel C, Kim SJ, Chomsky A, Saboori M. Incidence and risk factors for chronic uveitis following cataract surgery. 

2013:21(2):130-134. doi:10.3109/09273948.2012.752013

2. Llop SM, Papaliodis GN. Cataract surgery complications in uveitis patients: a review article. 

2018;33(1):64-69. doi:10.1080/08820538.2017.1353815

3. Sobrin L, Pistilli M, Dreger K, et al; Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study Research Group. Factors predictive of remission of chronic anterior uveitis. 

2020;127(6):826-834. doi:10.1016/j.ophtha.2019.11.020

4. Yang J, Cai L, Sun Z, et al. Risk factors for and diagnosis of pseudophakic cystoid macular edema after cataract surgery in diabetic patients. 

 2017;43(2):207-214. doi:10.1016/j.jcrs.2016.11.047

5. Jabs DA. Immunosuppression for the uveitides. 

2018;125(2):193-202. doi:10.1016/j.ophtha.2017.08.007

6. Grewal DS, O’Sullivan ML, Kron M, Jaffe GJ. Association of disorganization of retinal inner layers with visual acuity in eyes with uveitic cystoid macular edema. 

2017;177:116-125. doi:10.1016/j.ajo.2017.02.017

Prompt and adequate action is a key to facilitating the best recovery in patients. 

Weighing treatments for chronic postop cystoid macular edema

Fuchs endothelial corneal dystrophy is a progressive inherited condition that ultimately results in corneal edema and loss of vision. Up to now, treatment of patients with advanced disease involves corneal transplantation surgery. However, gene therapy may be a future option for these patients.

A team of investigators led by Hironori Uehara, MD, from the Phil and Penny Knight Campus for Accelerating Scientific Impact, University of Oregon, Eugene, and colleagues reported that CRISPR/cas9 prevented the disease in a mouse model.

The investigators reported their findings
in 

The problem in Fuchs’ dystrophy lies in a missense mutation in the 

 gene that leads to early-onset disease and progressive loss of vision resulting from edema and death of the corneal endothelial cells. Other mutations also are associated with Fuchs dystrophy, but the 

 missense mutant mouse model is the only one successfully created that has the key features of the disease.

In this mouse model, the investigators used a guide RNA targeting the start codon of the 

gene by non-homologous end-joint repair through CRISPR/Cas9. This approach blocked the gene expression at the translational level.

The strategy of targeting the start codon is sufficient for blocking gene expression at the translational level, which seemed a more direct approach than addressing targets farther downstream.

“The farther one targets downstream from the start codon, the greater the risk of missense mutations that result in viable mutant proteins with unknown activity. By targeting inside or near the start codon, this risk is minimized,” they explained.

“The results showed that intraocular injection of a single adenoviral vector achieved efficient and restricted delivery of CRISPR/Cas9 to adult post-mitotic corneal endothelium, leading to in vivo knockdown of the mutant 

 with long-term preservation of corneal endothelial density, structure, and function in the early-onset Fuchs dystrophy mouse model,” Uehara reported.

No adverse sequelae were observed on histologic evaluation or electroretinography images.

A major advantage of this gene therapy approach of COL8A2 start codon disruption is that no surgery is required to prevent vision loss in patients with early-onset Fuchs endothelial corneal dystrophy.

Another consideration is that because this treatment restored the phenotype in adult post-mitotic cells, the hope is that this method may be widely applicable to adult-onset diseases, the authors emphasized, even in tissues affected with disorders of nonreproducing cells.

The investigators commented on their results.

“This was the first study to demonstrate functional rescue with Cas9-mediated gene knockdown using start codon disruption. Future studies will explore the impact of this approach on endothelial and inflammatory gene expression using RNA-Seq and whether we can suppress activation of the unfolded protein response in endothelial cells.

In addition, prior to clinical development, gene therapy approaches will require optimization of gRNA and Cas9, understanding long-term effects, and refinement of the delivery strategy. Still, these results strongly suggest that our strategy can treat or at least prolong corneal endothelial life in early-onset Fuchs dystrophy, potentially eliminating the need for transplantation,” they concluded.

Uehara has no financial disclosures related to this content.

1. Uehara H, Zhang X, Pereira F, et al. Start codon disruption with CRISPR/Cas9 prevents murine Fuchs’ endothelial corneal dystrophy. eLife 2021;10:e55637; DOI: 

Successful treatment options can offer hope for patients with inherited disease. 

Investigators use gene therapy treatment of Fuchs in animal models

Nitrous oxide may help to suppress intraoperative anxiety and memory and decrease and stabilize vital signs.

Japanese physicians reported that the use of a low concentration of nitrous oxide anesthesia during cataract surgery, along with local anesthesia, did not result in respiratory depression, abnormal vital signs, or nausea. This application may be useful to suppress intraoperative anxiety and memory and decrease and stabilize vital signs, according to first author Santaro Noguchi, MD, from the Department of Ophthalmology, Saneikai Tsukazaki Hospital, Himeji, Japan.

Patients were included who underwent bilateral cataract surgeries. The investigators reviewed the cases of 37 patients for whom room air inhalation (air group) was used and the cases of 45 patients for whom 30% low-concentration nitrous oxide anesthesia (70% oxygen, total 6 L/min) at the start of surgery (nitrous oxide group) was used.

The investigators monitored the systolic and diastolic blood pressure levels and heart rates at the beginning and end of surgery and the mean oxygen saturation (% SpO2) intraoperatively. The patients completed a questionnaire immediately postoperatively regarding the intraoperative pain, anxiety, memory, and nausea measured using the Visual Analogue Scale.

The investigators reported that no patients had systemic symptoms or ocular complications that required treatment.

All of the changes observed between the nitrous oxide and air groups reached significance. The respective changes in the blood pressures were −5.38 ± 11.07 and 1.27 ± 13.61 mmHg (p=0.01); the changes in heart rates were −2.24 ± 6.76 and 0.89 ± 5.18 beats/minute (p=0.001); the intraoperative SpO2 levels were 99.05% ± 0.74% and 97.44% ± 1.31% (p<0.001); the intraoperative anxiety levels were 21.76 ± 23.2 and 37.17 ± 32.79 (p=0.002); and the intraoperative memory values were 55.24 ± 36.8 and 68.91 ± 33.81 (p=0.01). No nausea was experienced intraoperatively by any patients. No significant differences were seen in the diastolic blood pressures and degrees of intraoperative pain.

Based on these results, the authors concluded, “Low-concentration [nitrous oxide] anesthesia may not cause respiratory depression, abnormal vital signs, or nausea during cataract surgery. [Nitrous oxide] can suppress intraoperative anxiety and memory and decrease and stabilize vital signs.”

Noguchi S, Nakakura S, Noguchi A, et al. Examination of the safety and effectiveness of low-concentration nitrous oxide anesthesia in cataract surgery. 

.July 15, 2021.doi: 10.1097/j.jcrs.0000000000000749

Investigators conducted a retrospective consecutive study in which they compared the outcomes using this approach with the results achieved with local anesthesia alone during cataract surgery. 

Weighing treatments for chronic postop cystoid macular edema

Investigators use gene therapy treatment of Fuchs in animal models

Addition of nitrous oxide anesthesia: stress reduction during cataract surgery