
The diameter of retinal veins seem to be linked directly to the severity of 

, and assessing the retinal veins may be a part of diagnosing and managing the disease, according to the investigators of the ScrEening the Retina in Patients wIth COVID-19 (SERPICO-19) study. 

The authors based their rationale for this cross-sectional, single-center study on the fact that COVID-19 already has been associated with microvascular alterations in other areas of the body.

 The authors used fundus photographs to screen the fundi of patients with COVID-19 to detect any retinal and vasculature changes and assess possible correlations with clinical parameters.


Surgery during the COVID-19 pandemic: Staying sharp

“The arteries and veins of the retina represent a window on the vascular system, as they are exposed to the same pathological processes and show changes in many systemic diseases,” the investigators stated.

Moreover, investigators noted that alterations of the retina are also commonly seen in patients with viral diseases.

“These pathologic phenomena can occur due to a direct cytopathic effect of the microorganism on retinal neurons as in case of cytomegalovirus, or secondary to a damage to the microvasculature when the virus targets the vessels endothelium like in HIV retinopathy,” they said. “Interestingly, SARS-CoV-2 is able to infect endothelial cells and has been detected in the retina.”



Eliminating risk of endophthalmitis during intravitreal injections for patients wearing masks


Patients who were admitted to the Department of the Luigi Sacco Hospital with a diagnosis of SARS-CoV-2 infection were asked to participate in the study. 

The control group was comprised of hospital and university staff who had not been exposed to the virus.

The investigators, led by lead author Alessandro Invernizzi, MD, determined the mean diameters of the arteries and veins in patients with COVID-19 and compared them to the unexposed subjects; the covariates considered were age, sex, ethnicity, body mass index, smoking/alcohol consumption, hypertension, hyperlipidemia, and diabetes.

Invernizzi is with the Eye Clinic, Luigi Sacco Hospital, ASST Fatebenefrateli-Sacco, in Milan, Italy.

COVID-19: Practices falling short of pre-pandemic levels



Fifty-four patients and 133 unexposed subjects ultimately were included in the analysis. The investigators reported that the retinal findings in the patients with COVID-19 included hemorrhages (9.25%), cotton wool spots (7.4%), dilated veins (27.7%), and tortuous vessels (12.9%).

The mean arterial and venous diameters were significantly (

<0.0001, respectively) greater in the COVID-19 patients compared to unexposed subjects (98.3 ± 15.3 µm vs 91.9 ± 11.7 µm and 138.5 ± 21.5 µm vs 123.2 ± 13.0 µm, respectively). 

Multiple regression analysis showed that the venous diameters were associated positively with COVID-19 in severe (coefficient 30.3, 95% confidence interval [CI] 95%, 18.1–42.4) and non-severe (coefficient 10.3, 95% CI, 1.6–19.0) cases compared to unexposed subjects. 

In the patients, the venous diameters were correlated negatively with the time from the onset of symptoms (coefficient −1.0, CI 95%, −1.89 to −0.20) and positively with the disease severity (coefficient 22.0, CI 95%, 5.2–38.9).

“In summary, we found that COVID-19 can induce important changes at the level of the retina, most of them affecting the retinal vasculature and particularly the veins,” the investigators concluded. “The entity of such changes was correlated directly with the disease severity and seemed to affect patients early in the disease course.”

They did point out, however, that they could not determine if the retinal changes resulted from the virus or if they were due to the immune response of the host. 



Pearls for practicing in the COVID-19 era



However, they suggested that the diameter of the retinal veins may be useful to monitor the inflammatory response and/or the endothelial damage in COVID-19 and recommended that retinal changes be investigated in future prospective studies to understand their possible applications in the diagnosis and management of COVID-19.


​ 
Invernizzi has no financial disclosures related to this content.




1. Invernizzi A, Torre A, Parulli S, et al. Retinal findings in patients with COVID-19: Results from the SERPICO-19 study. EClinicalMedicine 2020; 

https://doi.org/10.1016/j.eclinm.2020.100550

Articles

Investigators have found that the diameter of retinal veins may be linked directly to the severity of COVID-19. Assessing the retinal veins may be a part of diagnosing and managing the disease.  

SERPICO-10 study details COVID-19 impact on retina

This article was reviewed by Charles Wykoff, MD, PhD

The results achieved with intravitreally injected gene therapy for neovascular 

 with ADVM-022 (Adverum Biotechnologies) indicate that the treatment is well tolerated and exhibited robust efficacy and durability in the patient population.

ADVM-022 may help solve the significant treatment burden associated with the treatment of neovascular AMD that includes frequent trips by patients to undergo intravitreal injections of various anti-vascular endothelial growth factor (VEGF) agents.

“Perhaps most important is the finding that the frequency needed to achieve optimal outcomes is often not realized in the real world,” noted Charles Wykoff, MD, PhD, who is in private practice in Houston, Texas.



Same-day exams with anti-VEGF therapy key to QoL, cost savings for wet AMD

This adeno-associated virus (AAV) gene therapy vector comprises an AAV7m8 capsid, a promoter to achieve protein expression, and a codon-optimized cDNA to drive aflibercept (Eylea, Regeneron Pharmaceuticals) that is delivered to the intravitreal space. 

Two preclinical studies have demonstrated the long-term protein expression in nonhuman primates that extended up to 21 and 30 months after 1 intravitreal injection.

Wykoff suggested that 1 solution to this undertreatment is the establishment of an intraocular biofactory that produces an anti-VEGF agent using gene therapy to deliver long-term efficacy, which is what ADVM-022 was designed to do.



Easing patient comfort, pain perception of intravitreal injections


Wykoff reported the updated 24-week results on behalf of the OPTIC investigators. OPTIC (NCT03748784) is a phase 1, 2-year multicenter dose-ranging study of ADVM-022 in neovascular AMD with the primary assessment of safety and tolerability of 1 intravitreal injection. 

Patients in cohorts 1 and 2 received oral steroid prophylaxis to prevent ocular inflammation and respective doses of ADVM-022 of 6 x 1011 vg/eye and 2 x 1011 vg/eye. 

Patients in cohorts 3 and 4 received a topical steroid for prophylaxis; cohorts 3 and 4 were treated with doses of ADVM-022 of 2 x 1011 vg/eye and 6 x 1011 vg/eye. Patients could receive rescue therapy, if needed.

The durations of the follow-up periods differed among cohorts: 6 patients in cohort 1 were followed for a median of 60 weeks, 6 patients in cohort 2 a median of 36 weeks, and cohort 3 a median of 20 weeks.

The current evaluation, which extended to April 1, 2020, showed no serious safety issues at 24 weeks. Low-grade inflammation associated with treatment was seen often and responded to topical steroids. The patients in cohort 3 had fewer adverse events compared with the others, he noted.



Taking a deeper dive: Novel gene therapy approaches to treat ocular disease

The inflammatory events in the 6 patients in cohorts 1 and 2 were low grade and responsive to oral steroids; 2 patients in both cohorts remained on topical steroids for extended periods. 

In cohort 3, treated with topical prophylaxis, 1 of the 6 patients continues steroid treatment at week 20; 3 patients were still taking the initial prophylactic steroid.

Regarding the best-corrected visual acuity (BCVA), the mean change in cohort 1 was -2.7 letters over a median of 60 weeks and the central subfield thickness (CST) decreased by 26.2 μm; no patients needed rescue therapy. 

In cohort 2, the mean BCVA change was -2.8 letters over 36 weeks and the CST improved by 40.8 μm; 2 of the 6 patients received rescue therapy. 

In cohort 3, the mean change in the BCVA was an increase of 6.8 letters over 20 weeks and the CST improved by 137.8 μm; 1 of the 5 patients who completed 20 weeks received rescue therapy.

Subjects in cohorts 1, 2, and 3 had been treated with frequent anti-VEGF injections before treatment with ADVM-022. Only 3 patients received rescue injections.



ASRS 2020: Trial shows faricimab blocks Ang-2 and VEGF-A

The study demonstrates that ADVM-022 is well tolerated and shows robust efficacy; the low-grade inflammation that develops frequently is responsive to steroid eye drops, and there is no need for oral baseline prophylaxis. It further shows that 1 office-based dose of ADVM-022 could reduce the anti-VEGF patient burden in neovascular AMD.

The ADVM-002 Infinity double-masked phase 2 study of recent-onset diabetic macular edema is underway with patients randomly assigned to 1 intravitreal injection of the treatment compared with 1 aflibercept injection. Patients’ conditions will be followed.

Wykoff reported performing research for and serving as a consultant to Adverum Biotechnologies.

Intravitreal gene therapy continues to be well tolerated and shows robust efficacy

Targeting AMD patient treatment burden



This article was reviewed by Justine S. Paradis, PhD



The results of a preclinical study indicate there is hope for an effective treatment for the GNAQ-driven metastatic uveal melanoma, an aggressive form of the disease.

The treatment relies on 2 components, the MEK inhibitor trametinib or the second generation RAF/MEK inhibitor VS-6766 (Verastem Oncology) combined with defactinib, a focal adhesion kinase (FAK) inhibitor (Verastem Oncology), that work better together than apart for controlling uveal melanoma.



Light-activated agent novel option for uveal melanoma 

The importance of this potential treatment is underscored by the fact that uveal melanoma is the most frequently occurring ocular cancer in adults, and it becomes metastatic in 50% of patients in whom it develops. The survival rate currently is 2 years, with only 8% surviving following metastasis to the liver.

“To date there is no effective treatment for metastatic uveal melanoma, and there is an urgent need to identify novel precision therapies for advanced and metastatic uveal melanoma patients,” according to Justine S. Paradis, PhD, a postdoctoral fellow at the Moores Cancer Center at the University of California San Diego.


Trametinib is an inhibitor of MEK kinase activity, and VS-6766 is a second-generation RAF/MEK inhibitor blocking both the MEK kinase activity and the ability of RAF to phosphorylate MEK. 

The investigators explained that VS-6766 blocks MEK signaling without the compensatory activation of MEK, which differs from how other inhibitors work.

Defactinib (VS-6063) is an oral small-molecule inhibitor of FAK and PYK2 that is being evaluated as a potential combination therapy for various solid tumors.



Pearls for managing care of high-risk uveal melanoma patients

The combination of the 2 inhibitors induces apoptosis of the uveal melanoma cells, which in turn leads to rapid tumor regression in the uveal melanoma xenografts. When the 2 agents were used alone, the tumor growth was inhibited, but the size of the tumors did not shrink. 

In addition, this combination approach also decreased the tumor burden in models of uveal melanoma liver metastasis.

The investigators described that FAK and MEK inhibition combined showed “synergistic cytotoxic effects” in metastatic uveal melanoma cells.



The investigators used the combination of the MEK and FAK inhibitors in a xenograft mouse model in which the animals were treated for 20 days and found that the tumor volume decreased when the 2 were used together. 

In contrast, when used alone, the inhibitors only stabilized the tumor size, with a limited apoptotic response.



Conjunctival melanoma: Unlocking mysteries of disease

In a mouse model of liver metastasis, in which the animals were treated for 21 days, the investigators reported that the metastatic burden in the animals was reduced. The combination of the 2, they reported, very importantly “nearly eliminated all metastatic lesions.”

The team is evaluating residual disease and tumor burden progression after the treatments were stopped.

J. Silvio Gutkind, PhD, distinguished professor of pharmacology and associate director for Basic Science at Moores Cancer Center at the University of California San Diego, and senior investigator of the study, said results should lead to human trials.

“The study identified and reinforced FAK as a viable pathway to inhibit downstream from the GNAQ pathway, which is constitutively active in uveal melanoma,” he said. “We observed that cotargeting of FAK and RAF/MEK signaling led to tumor collapse in uveal melanoma xenograft and liver metastasis models in vivo.”



Liquid biopsies: Not yet ready for prime time in uveal melanoma 

Pharmacological inhibition of FAK and MEK inhibited the growth of uveal melanoma cells and had cytotoxic effects leading to tumor collapse in uveal melanoma xenograft and liver metastasis models in vivo.

The results emphasized the importance of cotargeting with FAK and RAF/MEK to provide a new network-based precision therapeutic strategy.

The signal-transduction-based precision therapy data support clinical testing of the combination inhibition in metastatic uveal melanoma.

VS-6766 and defactinib are also being studied clinically to treat low-grade serous ovarian and 

 mutant non–small cell lung cancers and colorectal cancer.

A phase 2 study of VS-6766 and defactinib in uveal melanoma is expected to commence in late 2020. 


Paradis has no financial interest in this subject matter.

Combining RAF/MEK signaling pathway inhibitor with FAK inhibitor raises bar

Options give 1-2 punch to metastatic uveal melanoma

Cheryl Guttman Krader is a contributor to Dermatology Times, Ophthalmology Times, and Urology Times.

​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ 

This article was reviewed by Savak Teymoorian, MD, MBA

Early experience with the new intracameral bimatoprost 10-μg implant (Durysta, Allergan) in clinical practice indicates that it is a valuable addition for treating patients with ocular hypertension and 

, according to Savak Teymoorian, MD, MBA.

“Our aim in managing patients with ocular hypertension and glaucoma is to control their IOP so as to mitigate disease progression without adversely affecting quality of life,” said Teymoorian, a cataract and glaucoma specialist at Harvard Eye Associates in Orange County, California.



IOP homeostasis in glaucoma: Looking below the surface

“In deciding on our interventions to achieve that goal, it is necessary to balance the risks and benefits of each treatment option. It is clear to me that with its IOP-lowering efficacy and ability to address the drawbacks associated with topical drops, the benefits of the sustained-release prostaglandin significantly outweigh any risk associated with its administration.”

® that he implanted the bimatoprost product into approximately 55 eyes within the first month of using it. 

The satisfaction shared by patients is something novel in the glaucoma segment of his practice and is rewarding.

“Ophthalmologists who perform cataract surgery are used to seeing patients who are extremely happy because of the outcomes of their procedure, but gratification is rare among patients being treated for glaucoma. The recipients of the bimatoprost implant, however, are extremely happy because they have been able to eliminate or reduce their topical medications and the inconvenience, [adverse] effects, and cost associated with their use,” he said.


Study results show that surgical system decreases IOP in patients with POAG


Adherence with topical medications is well recognized as a key barrier to successful management of glaucoma. The issues underlying Adherence are multifaceted, Teymoorian said.

“Noncompliance can occur because of a plethora of factors. Some patients do not get their prescription filled, some don’t remember to use their medications, and some do not instill them properly,” he explained.

“The ability to take the responsibility for treatment away from the patient is one of the reasons why the minimally invasive glaucoma procedures have done so well. The value of the bimatoprost implant is similar in that regard,” he added.

The ability to reduce ocular surface toxicity from topical drops is another benefit of the bimatoprost implant.

“Minimizing or eliminating the number of topical medications a patient is using allows the ocular surface condition to improve. As a result, patients are more comfortable, their vision is better, and they can also eliminate or reduce their need for artificial tears and any other medications that they are using to manage dry eye signs and symptoms,” he said.


Examining ocular allergy, quality of life​ 


Patients who are on topical medications for IOP-lowering, regardless of where they are on the continuum of glaucoma severity, may be considered as candidates for the bimatoprost implant. 

However, Teymoorian noted that so far he has selected patients who are taking a topical prostaglandin analogue and who are pseudophakic in particular because they will likely have a deep anterior chamber, enabling safe and proper placement of the implant, and cataract development will not be an issue.

“My accumulating experience with the product is reinforcing its efficacy, safety, and benefits. The more I see how it allows me to discontinue all or some topical medications and how happy patients are, the more I am willing to offer the implant to patients,” he explained.



The implantation procedure should be done with the eye topically anesthetized and under aseptic conditions. 

Depending on their comfort level and facility, clinicians can choose to perform the procedure either in a surgery center using an operating microscope, or a slit lamp in an in-office procedure room.



Traditional glaucoma surgery in the era of MIGS procedures


When injecting the bimatoprost implant in the surgery center where the patient is lying under the microscope, Teymoorian said he has the patient’s head tilted up at about 30° and asks the patient to sit up immediately after the injection as these positions promote settling of the implant into its targeted location in the inferior angle.

“It has been remarkable to me that as soon as the injection is done, patients note how easy it seemed, tell me that they felt nothing, and ask when can they have the second eye procedure,” Teymoorian said. “I take these as signs that the procedure is well tolerated. The key is to make sure the patient is comfortable.”

Changes to existing topical medications and scheduling of the first postinjection follow-up visit are individualized, taking into account medication burden and glaucoma severity. 

Patients on a topical prostaglandin alone or a topical prostaglandin plus one adjunctive medication whose IOP has been well controlled may have both agents discontinued if they have mild-to-moderate glaucoma, and they will likely be asked to return 7 to 10 days postinjection.



Glaucoma drug delivery devices enter new frontier



Patients with more severe disease and on multiple medications are seen within a few days after the procedure and are weaned more slowly off existing topical drops according to the level of their IOP.

“Initially I thought the implant would be something that could simply replace a topical prostaglandin. However, as I treat more patients who are on multiple medications, I am realizing that some can do very well being taken off more than just the prostaglandin,” Teymoorian said. “The experience with patients who can stop multiple medications highlights the efficacy of the implant and also the problem of noncompliance for patients who are on topical drops. Clearly, even those individuals who are well intentioned may not be administering their medications properly.”



The implant is approved for one-time administration. Clinical trial experience indicates that the IOP-lowering benefit can last from 4 months to 2 years or more, and research is underway to collect data that will support FDA approval for repeat injections.

“Ongoing management for patients who begin to lose the IOP-lowering effect from the bimatoprost implant is something that we will need to address in the future,” Teymoorian said. “But while we think about what we might do tomorrow, we need to plan and execute for today. Even if I think it is a one-time treatment for now, I find no reason to hesitate using the implant in appropriate patients when I consider its many benefits and minimal risk.”



Glaucoma 360: Lowering IOP using the MIMS solution

Anticipating the opportunity for repeat injections, he noted it is exciting to think that early treatment with the bimatoprost implant holds promise for preserving vision and quality of life for glaucoma patients over the long term.

Teymoorian concluded that, in theory, disease control should be much better for patients who are being treated with the implant than for those who are on topical therapy because the implant ensures consistent medication delivery, while with topical treatment clinicians have to assume patient adherence.

“Consistently effective IOP control increases the likelihood that we will be able to slow or even halt glaucoma progression,” he said.


Teymoorian is a consultant, speakers’ bureau member, and investigator for Allergan.

Sustained release helps mitigate disease progression without impacting quality of life.


Long-acting prostaglandin implant creating shift in IOP-lowering therapy

harmaceutical representatives share what keeps them up at night within the ophthalmic and glaucoma space while attending the 2020 

Chris Adams, Diopter Corp (CEO); Daria Lemann-Blumenthal, BELKIN Laser Ltd (CEO); Victor Chan, MB, MS, director of U.S. Surgical Device Commercial Marketing (Santen, Inc); Ramin Valian, vice president of International Glaucoma, Reimbursement and Pipeline (Allergan).

Videos

Pharmaceutical representatives share what keeps them up at night within the ophthalmic space.

What keeps you up at night in ophthalmology: Part II

evaluating and treating problems with the tear film and ocular surface

At in-person conferences (back when we did such things) colleagues would approach me all the time to say that, while they agree that 

 is important, they just don’t know how to start integrating it into their busy surgical practices.

There are a number of diagnostic and treatment protocols available, including DEWS II

, and the ASCRS Cornea Clinical Committee’s algorithm.

Amid pandemic, friendly bugs can help protect the eye from infection​ 

The ASCRS algorithm is particularly helpful for surgeons, as it focuses on OSD in the perioperative setting.

To further simplify the advice already available in these protocols, I would advise starting with performing a better diagnosis in three simple steps:

Start routinely giving patients a symptom questionnaire such as the ASCRS modified SPEED II preoperative questionnaire.



Staff can administer and score this one-page questionnaire, with no investment of money or the surgeon’s time.

Simply looking at the scores for every patient will provide great insights about the breadth of the problem, even if you do nothing about it at first.


Instead of starting your slit lamp exam at the lens, focus a few millimeters before the lens to examine the eyelid margin, lashes, and meibomian gland orifices.

Stain with two vital dyes: Lissamine green for the lid margin, conjunctiva and cornea; and fluorescein for the cornea. Using these dyes is quick and inexpensive.


Add one diagnostic tool at a time.

A great one to start with is dynamic meibomian imaging (LipiView or LipiScan, Johnson & Johnson Vision). 

Not only does it provide actionable clinical information about the meibomian gland structure, but the images also help educate the patient about MGD.



When at first you don't succeed with MGD patients, keep trying


Before acquiring treatment technology, minimize the risk and ramp-up time by simply keeping a list of patients with MGD who would benefit from treatment.

Other diagnostic tools to consider include MMP-9 testing (InflammaDry, Quidel) to indicate whether an immunomodulator drop is needed (or being used compliantly, if already prescribed) and osmolarity testing (TearLab).

Each of these tests adds about 2 minutes of technician time.

These three steps are a great starting place for surgeons who want to integrate OSD into their practices.

In addition to contributing to patient care and better surgical outcomes, these steps also resonate well with patients and make your practice stand out.

Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II report executive summary. The Ocular Surface 2017;15;3;802-12.

Milner MS, Beckman KA, Luchs JI, et al. Dysfunctional tear syndrome: Dry eye disease and associated tear film disorders - new strategies for diagnosis and treatment. 

Starr CE, Gupta PK, Farid M, et al; ASCRS Cornea Clinical Committee. An algorithm for the preoperative diagnosis and treatment of ocular surface disorders. 

Cynthia Matossian, MD, FACS, advises on how ophthalmologists can start performing a better diagnosis of ocular surface disease in three simple steps.

Where to start with treating OSD patients


This article was reviewed by Melinda Chang, MD

Artificial intelligence (AI) is slowly being integrated into ophthalmology and other medical fields.

“In machine-guided medical research, a specific research question is not needed as in traditional medical research, because the research can be data-driven,” said Melinda Chang, MD, an attending physician in the vision center at Children’s Hospital Los Angeles and an assistant professor of clinical ophthalmology at the Keck School of Medicine at the University of Southern California. “Analysis with machine learning can predict new data, identify new patterns, or learn the best action.”

AI, Chang explained, is useful in medicine for classification and prediction, for example, for classifying images as they correspond to diseased persons or controls.



Artificial intelligence in medicine: The good, the bad, and the ugly


The technology can detect papilledema from fundus photographs and characterize visual function and ocular motility in nonverbal individuals via eye tracking, Chang said.

 in which 15,846 fundus photos (14,341 for training and validation and 1505 for external testing) were obtained with digital cameras at 24 centers nationally and internationally. 

An AI model was developed to classify the images as normal, papilledema, or a nonpapilledema abnormality of the optic disc.

The study found that the accuracy of the model for differentiating papilledema from nonpapilledema images was 87.5%, the sensitivity was 96.4%, and the specificity was 84.7%. When the accuracy was compared between normal images and those of any optic disc abnormality, the accuracy was 91.8%.

The study’s authors concluded that this model was most useful for identifying any optic disc abnormality and could be used in emergency departments or neurosurgery clinics to rule out papilledema without consulting with ophthalmology, Chang recounted.



Teaching AI algorithms to identify corneal pathology: The future is now


In an eye-tracking system, while a patient is viewing a visual stimulus on a computer monitor, an infrared camera records the corneal and pupillary light reflexes from each eye, which enables the direction of gaze to be calculated at any time point with high spatial and temporal resolution, she said.

Eye tracking has been studied to assess vision in nonverbal patients, eg, pediatric patients, those who are impaired neurologically, and those with developmental disorders.Its capabilities in visual rehabilitation and for measuring the degree of strabismus also have been assessed. 

Chang focused on children with cortical visual impairment (CVI), ie, vision loss due to damage to the post-geniculate visual pathways in the brain.

“This is the most common cause of pediatric visual impairment in the US and developed countries,” she said.



 Blockchain technology aims to drive big data to 'train' AI

CVI risk factors include prematurity, hydrocephalus, seizures, hypoxic ischemic encephalopathy, and other neurologic conditions.

Children with CVI have visual deficits that may differ from children with ocular causes of visual impairment. 

For example, CVI causes more difficulty with low contrast; motion sensitivity may be spared in some children with CVI; and when in environments that are visually complex, children with CVI may have more difficulty seeing, she explained.

“Having an understanding of these unique visual deficits is important when guiding therapy. We know that these patients have the capacity to improve over time, but the factors that drive improvement are unclear,” Chang said.

Visual stimulation therapy is widely used, but no controlled trials have been conducted to assess the efficacy of visual stimulation.

“Establishment of an objective method for assessing visual stimulation (and other therapies) is important for pediatric patients with CVI,” she emphasized.



AI screening: Allowing physicians to see eye more clearly from afar



Chang demonstrated patterns of fixation in children with CVI using these technologies. A child who served as a control was seen to be fixating on a baby’s eyes and hands in a brightly colored photo of that baby in a ball pit. 

In contrast, a child with CVI was seen to be fixating mostly on the brightly colored balls with fewer fixations on the baby’s face in the same photo.

“The child with CVI appears to prefer looking at bright colors rather than faces,” she commented.

Problems with low contrast were demonstrated in a second substantially darker photo in which a child with CVI fixated only once on a low-contrast object (bird) compared with a normal child who focused numerous times on a low-contrast human face in addition to the bird.

Another type of visual deficit was demonstrated in a photo with a highly complex background in which a child with normal vision had many fixation points in contrast to a child with CVI who had no fixation points within the complex image; the child with CVI had many more fixation points when the picture was significantly simplified with a plain background. 



Making the most of imaging in examination of pediatric patients



“These findings demonstrate the crowding effect in CVI, in which vision is worsened by visually complex scenes and distractors,” Chang explained.

Without machine learning, Chang and associates were able to do simple analysis to determine that children with CVI had several visual deficits compared to controls, such as decreased contrast sensitivity and increased saccadic latency. 

The investigators will use AI combined with eye tracking to identify other visual and oculomotor abnormalities, and potentially identify new deficits specific to CVI.

“The model will help determine the relative importance of various features such as color, background, faces, motion, and contrast, among others, in facilitating vision in children with CVI,” she said.


The challenges of examining visual fields in children

Any information gained from such an analysis will help identify therapeutic targets and features that can be used to monitor disease severity and treatment efficacy.

“AI is a powerful tool with the potential to automate image analysis for neuro-ophthalmic conditions. Eye tracking facilitates visual assessment in nonverbal individuals, including children with CVI,” Chang concluded. 


e:mchang@chla.usc.edu
Chang has received grant funding from th

e Children’s Eye Foundation of AAPOS and the Knights Templar Eye Foundation.


1. Milea D, Najjar RP, Jiang Z, et al. Artificial intelligence to detect papilledema from ocular fundus photographs. 

. 2020;382:1687-1695. doi: 10.1056/NEJMoa1917130

Technology with potential to improve treatment and evaluation of cortical visual impairment.


Cutting-edge neuro-ophthalmology: Combining artificial intelligence, eye tracking


This article was reviewed by Aaron Y. Lee, MD, MSCI



Artificial intelligence (AI) screening systems of 

 are not all created equal, and as a result, their performances differ.

Researchers compared several AI screening systems using the US Department of Veterans Affairs (VA) screening program. The results highlight the need for independent validation studies before clinical use, according to Aaron Y. Lee, MD, MSCI, from the University of Washington in Seattle.



Artificial intelligence: The good, the bad, and the scary


Initially, 23 companies were invited to participated in the masked study. Several agreed to participate and contributed AI models: ADCIS (Advanced Concepts in Imaging Software), Airdoc, Eyenuk, Retina-AI Health, and Retmarker.

The investigators extracted data from the VA teleretinal screening program for VA Puget Sound in Seattle and the Atlanta VA Health Care System in Georgia, including the images and the original VA teleretinal grades. 

This created a data set of 311,604 images from 23,724 patients with diabetes for the full data set and a subset of about 7000 images that was set aside for arbitration. All the patients had type 2 diabetes and no previous diagnoses of the disease. 

The 7 algorithms were run, and the output indicated whether the patients should be referred. The performances were then compared with the VA teleretinal grades. 

In the subset used for arbitration, 2 ophthalmologists graded the images independently and a retinal specialist performed masked arbitration, according to Lee.



 Teaching AI algorithms to identify corneal pathology: The future is now

A few baseline differences were seen between the Atlanta and Seattle groups. Investigators found a 10-fold difference in the proliferative DR (PDR) rate between the 2 locations. 

In Atlanta, dilatation is a routine practice, but, Lee noted, that is not the case in Seattle. This resulted in a large discrepancy in the rate of ungradable images between the 2 sites.

The algorithm output, he explained, was set for no DR versus the presence of any degree of DR because of the VA’s practice pattern.



Analysis of the full data sets from both sites showed an overall high negative predictive value and a low positive predictive value.

In the arbitrated data set, the VA teleretinal grader was compared directly with the AI models: Algorithm A had a significantly lower sensitivity but higher specificity, B had lower sensitivity and specificity, C and D had the same sensitivity but lower specificity, E and F had significantly higher sensitivity and lower specificity, and G could not be differentiated from the VA grader.

Lee explained what he considers to be the most important finding: the performance of the sensitivity of the various algorithms with different severities of retinopathy.



Blockchain technology aims to drive big data to 'train' AI

“The VA grader demonstrated 100% sensitivity for moderate and severe non-PDR [NPDR] and PDR. Algorithms E, F, and G were statistically similar to the VA grader for moderate NPDR or higher, and these algorithms were carried forward for future analysis,” he said.

The investigators simulated a 2-stage screening system to measure the amount of labor savings in a cost analysis if the 3 algorithms were implemented within the VA. The cost of an ophthalmologist reading the images would be about $15 per encounter.

A limitation of this study is that some analyses, including cost, are applicable to the VA setting.

According to Lee, the investigators found that dilation may be important to reduce the rate of ungradable images.

“The algorithms varied tremendously in performance despite having regulatory approval and/or having been clinically deployed somewhere,” he concluded. “It is important to understand that the AI models in the context of the underlying disease prevalence in order to understand the negative and positive predictive values. We believe that external, independent validation with real-world imaging is crucial before deployment, even after algorithms receive regulatory."
approval.”



Lee is a consultant to Genentech, Verana Health, and Topcon.

Dilation may be an important step to reduce the rate of ungradable images

AI algorithms: a work in progress

This article was reviewed by Russell N. Van Gelder, MD, PhD

Neuronal cell replacement therapies remain a challenge in retinal diseases. Some fish and salamanders have the innate ability to regenerate retinal tissue after injuries and, as Russell N. Van Gelder, MD, PhD, pointed out, if researchers could harness this ability in humans, the possibilities would be great for repairing or replacing damaged tissue in a wide variety of retinal diseases. Stem cells are the key to cell replacement therapies.

“Stem cells are cells that have not terminally differentiated and still have the potential to become many types of terminal cells,” said Van Gelder, from the Department of Ophthalmology at the University of Washington in Seattle. “We all started as embryonic stem cells in the earliest phases of development.”



Retinal pathologies challenging to image with current technologies

Van Gelder went on to explain that there are now methods to create equivalently totipotent stem cells from individual induced progenitor stem cells derived from an individual’s blood or epithelial cells.

“The overarching goal is to create a cell type that needs replacement from a stem cell precursor,” he said.

This ability would unlock possibilities for repairing tissue damaged by disease



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