Cheryl Guttman Krader, BS, Pharm

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This article was reviewed by Subhransu K. Ray, MD, PhD

nterim data from a cross-sectional study raise concerns that repeated intravitreal injections of an anti-VEGF agent may be associated with a decline in cognitive health.

The findings from the first 143 patients with 

 enrolled in the Brain Health Assessment in Macular Degeneration (BHAM) study were presented by Subhransu K. Ray, MD, PhD, at the virtual meeting of the American Society of Retina Specialists. 

He reported that patients who received higher cumulative anti-VEGF injections performed significantly worse on a test of cognition.



Saving memories: Do anti-VEGF agents contribute to cognitive loss?

“It is essential to remember that our study does not establish a causal link between cumulative doses of anti-VEGF injections and cognitive function, but the data demonstrate an association between higher treatment number and increased risk of mild cognitive impairment,” said Ray, who is with Bay Area Retina Associates, Clinical Trial Center, in Walnut Creek, California.

Ray added that investigators are continuing to enroll patients in this study, and these initial findings need to be validated using other cognitive tools and assays.

“Furthermore, we need to evaluate confounding factors such as the impact of even moderate vision loss in one eye,” Ray pointed out. “In addition, we have begun a prospective trial that is following 200 patients who are just initiating anti-VEGF injections.”


The BHAM study was undertaken considering that anti-VEGF agents injected into the vitreous are detectable in the systemic circulation at biologically active levels, that there is direct communication from the vitreous cavity to the central nervous system (CNS) in rare pathological states, and that VEGF has an essential role in CNS health.

“However, very little is known about how the normal vitreous-CNS barrier is affected by repeated intravitreal injections of anti-VEGF compounds,” Ray said. “Furthermore, despite the fact that millions of intravitreal injections are performed yearly in the United States, there have been no formal studies assessing the impact of these repeated injections on cognitive performance in this vulnerable age group.”

(AAO) Considerations when using anti-VEGF for treating AMD



Ray wrote the BHAM study protocol that is enrolling patients aged 65 to 85 years with BCVA of 20/50 or better in at least 1 eye and a diagnosis of AMD. 

Patients were ineligible if they had any history of CNS disease or previous systemic anti-VEGF exposure. The study is targeting enrollment of 100 patients with dry AMD and 300 patients with 

Cognitive performance was evaluated using the Brain Health Assessment (BHA) test, which was developed at the University of California, San Francisco, School of Medicine and validated for use in research dementia care centers. 

The BHA test is a 10-minute, tablet-based tool that has been shown to have high specificity and high sensitivity for detecting dementia and early cognitive impairment, exceeding the sensitivity of the Montreal Cognitive Assessment. 

It includes subsets of memory, executive function and speed, visuospatial skills, and language. Results are generated as an age-adjusted Z-score.


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“The experience in our study using the BHA test also shows that cognitive testing can be effectively performed within the flow of a retina clinic,” Ray said.

Based on their BHA Z-score, patients in the study were categorized into groups of low, moderate, and high likelihood of having mild cognitive impairment. 

They were also stratified into 4 groups based on the number of intravitreal anti-VEGF injections they received: 0 (n = 38), 1 to 10 (n = 41), greater than 10 (n = 64), and greater than 20 (n = 51).

Mean age was similar for the 4 injection subgroups (range 77.1 to 78.2 years), but the percentage of patients with a BHA score placing them at high likelihood of having mild cognitive impairment was higher in the group that had received greater than 10 intravitreal injections compared with both the group who had no injections and the group who had received 1 to 10 injections (45.3% versus 34.2% and 36.5%).

 In the group that had received greater than 20 injections, 49% of patients had a high likelihood of mild cognitive impairment, Ray said.



AAO 2020: Considerations when using anti-VEGF for treating AMD


Another analysis compared the mean Z-scores among the 4 intravitreal injection groups. It found that the Z-score was significantly lower (indicating higher likelihood of having mild cognitive impairment) for both the patients who had received greater than 10 injections and those who had received greater than 20 injections versus those who had none.

Ray noted that because of the limited sample size, analyses were not done to investigate potential differences in Z-scores with patients divided according to anti-VEGF agent received. 

Furthermore, many patients switched anti-VEGF agents during the course of their treatment.

“Once the full enrollment is completed, we hope to be able to address several factors at a more granular level, including whether choice of anti-VEGF agent had any impact,” Ray said. “More importantly, we hope that the final data set will help us to address potential confounding factors, including the impact of vision loss itself on the BHA score.”



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Ray added that investigators also hope to further refine the analysis of injection number versus injection duration and even age-dependent risks.

“In the end, whether there is or is not a statistically significant risk associated with anti-VEGF injections, we feel this is a question that needs to be formally addressed,” he said.

In addition, Ray suggested topics for future studies to explore a potential biologic basis of an effect of intravitreal anti-VEGF injections on cognitive function. These would include targeted neuroimaging of the hippocampus in patients with high cumulative anti-VEGF exposure, careful examination of optic nerve integrity prior to and after repeated intravitreal injections, further preclinical studies, and direct evaluation for anti-VEGF agents in post-mortem CNS tissues and CSF from patients who have received numerous intravitreal anti-VEGF injections.

“Developing such assays is complicated and time consuming, but might be valuable as we pursue longer acting and constitutively expressed anti-VEGF agents,” he said.



Probe of IRIS registry: Anti-VEGF injections key treatment for PDR


Ray cautioned that clinicians should not allow this very preliminary interim analysis to alter treatment protocols, but rather to use it to be aware of a patient’s mental health during the course of therapy. 

“Frankly, limiting appropriate anti-VEGF therapy resulting in unnecessary vision loss may be more of a risk factor on cognition,” he said.

In extending thanks to his colleagues for supporting the research, Ray said that any retina clinics interested in additional information or participating in the BHAM clinical trial may reach out to him at sray@bayarearetina.com.



Ray has no relevant financial interests to disclose.

Articles

Interim data from a cross-sectional study raise concerns that repeated intravitreal injections of an anti-VEGF agent may be associated with a decline in cognitive health.

Study results link frequent anti-VEGF injections, risk of cognitive impairment

Several innovations are revolutionizing surgical care in pediatric ophthalmology, according to Janet L. Alexander, MD.

Speaking at the Women in Ophthalmology 2021 Summer Symposium, Alexander presented a series of rapid-fire cases to discuss 4 innovations affecting multiple subspecialities of pediatric ophthalmology. 

It takes a village to beat visual system diseases in children

The innovations included prenatal surgical planning to address congenital hereditary disease, endothelial keratoplasty, endocyclophotocoagulation (ECP) to treat refractory glaucoma, and ultrasound biomicroscopy (UBM) as a tool for guiding complex cataract surgery.

Fundus photo 1 month following laser treatment for Norrie disease. 

(Images courtesy of Janet L. Alexander, MD)


A case involving a child born with Norrie disease highlighted the value of prenatal surgical planning for allowing intervention prior to complications. 

 During her second trimester of pregnancy, a 30-year-old woman presented with carrier status for 

 mutation. 

Amniocentesis confirmed fetal 

 mutation and the ultrasound showed no fetal retinal detachment. Labor was induced at 34 weeks gestation for early retinal treatment.

The child received a diagnosis of Norrie disease and bilateral vitreous hemorrhages at birth and underwent bilateral treatment with intravitreal anti-VEGF therapy and peripheral retinal laser. 

Six months later, both eyes demonstrated robust light perception vision with an attached retina.

Physicians finessing the pediatric eye examination

Alexander, an assistant professor of ophthalmology and pediatrics at the University of Maryland School of Medicine in Baltimore, noted that the case is a reminder that it is never too early to start prenatal surgical planning.

“Prenatal surgical planning requires proactive and timely genetic testing to identify surgical candidates, counseling for women carriers of high-risk genetic traits, and involvement of geneticists and genetic counselors,” she said.


Benefits and drawbacks of descemet stripping automated endothelial keratoplasty (DSAEK) vs penetrating keratoplasty (PK) were discussed through a case involving a 4-year-old child who presented with a cloudy cornea 2 years after undergoing cataract surgery. 

The child received a diagnosis of bullous keratopathy and underwent DSAEK.

“Compared to PK, DSAEK is associated with stronger wound integrity, less astigmatism, and faster visual recovery. It also avoids the need for stripping of the host endothelium in pediatric eyes,” Alexander said. “However, DSAEK graft positioning can be very difficult in pediatric patients, and complications such as graft folds, detachment and dislocation, pupillary block, endothelial immune rejection, and steroid response can occur.”

Collagen crosslinking provides corneal stability in young patients


Advantages can also be cited for choosing ECP vs transscleral ciliary ablation to treat refractory glaucoma in pediatric patients. 

Alexander presented a case involving a 7-year-old child who had sustained a traumatic cataract, then presented with 20/250 vision and elevated IOP despite maximal medical treatment, selective laser trabeculoplasty, and goniotomy.

The most remarkable feature of ECP is that it is minimally invasive and has a more favorable safety profile compared with the transscleral technique.

“For example, phthisis in the absence of retinal detachment occurs in over 30% of eyes treated transsclerally but in less than 1% of eyes that undergo ECP,” Alexander said.

Other advantages of ECP include avoidance of late infectious complications, such as wound leak and endophthalmitis.

However, ECP has a modest success rate, and its benefit is somewhat short-lived. 

Outcomes data show that it effectively reduces IOP in about 30% of eyes, and about half of those eyes maintain IOP control for 1 to 2 years. In addition, ECP is not devoid of serious complications—hypotony, retinal detachment, and vision loss can occur.


Preoperative evaluation with ultrasound biomicroscopy enables cataract surgery planning and helps avoid intraoperative surprises, according to Alexander.

Alexander demonstrated these points with several case examples. In one case, a 1-month-old child presented with bilateral cataract, but cataract surgery was postponed for 3 months while the child underwent treatment for comorbid heart failure. 

Repeat imaging prior to the scheduled cataract surgery showed that crystalline lens thickness had decreased dramatically over time.

Knowledge of the absorbed cataract guided appropriate surgical techniques, Alexander said.

Physicians measure contrast sensitivity in patients with cataract

“Cataract surgery planning with UBM allows surgeons to evaluate IOL position, the lens periphery, and the ciliary body,” she said. “Importantly, it allows us to avoid surprises, including absorbed cataract, foreign bodies, masses, cysts, or membranes.”

Other cases involving uveitic cataracts showed how imaging with UBM can document pathology that can complicate cataract surgery and inform the surgical approach. 

Alexander presented a series of eyes in which UBM revealed the presence of a cyclitic membrane, pupil synechiae, and calcified plaque on the anterior capsule.

Alexander concluded that quantitative UBM is an innovation that further enhances the clinical utility of UBM. 

Quantitative UBM uses algorithms to analyze the images and generates information that helps clinicians interpret the images. 

A patient’s eye movements can unlock diagnosis

The algorithms are also capable of suggesting clinical diagnoses and prognostic features, such as the risk of complications.


Alexander has no related relevant financial interests to disclose.

Techniques, technologies minimize complications and guide counseling, care.

Improving surgical outcomes for pediatric patients

Treatment-naive nonexudative macular neovascularization (MNV) is now recognized as a state of 

 that can be accurately detected with swept-source optical coherence tomography angiography (SS-OCTA).

Although nonexudative MNV is asymptomatic, it is important to identify these lesions because they seem to be a precursor for the development of exudative disease, according to Philip J. Rosenfeld, MD, PhD.

Rosenfeld discussed the detection, natural history, and management of treatment-naive MNV in a presentation at the 2021 Ohio Ophthalmological Society Virtual Annual Meeting.

Improving macular pathology detection in telemedicine screening

“A double-layer sign (DLS) or shallow, irregular retinal pigment epithelial elevation (SIRE) on the structural OCT B-scan is a characteristic feature of these lesions,” said Rosenfeld, a professor of ophthalmology at Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine in Florida. “Finding these lesions in eyes with dry AMD is important because they have a high risk of conversion to exudative AMD. So far, we have not been able to predict which eyes are likely to progress to exudation based on anatomic changes. Therefore, close follow-up and at-home monitoring [are] crucial in these patients to prevent vision loss.”

Rosenfeld highlighted his message about monitoring with a case history involving a patient who presented in January 2020 with large drusen and 20/40 visual acuity (VA) OU. 

Routine SS-OCT showed structural elevation of the retinal pigment epithelium (RPE) consistent with drusen in the right eye but no evidence of exudation. 

Nonexudative MNV was detected with SS-OCTA imaging, where the areas of confluent drusen corresponded to a DLS seen on individual B-scans. 



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Segmentation of RPE-Bruch’s membrane on the SS-OCTA angiographic flow map showed the patient had 3 independent neovascular complexes.

The patient was counseled to return for follow-up in March 2020, but because of the COVID-19 pandemic, she canceled that appointment. A rescheduled visit in April was also canceled. 

In May, 4 months after her January appointment, she presented to the emergency department because of sudden vision loss in the right eye. Examination showed count-fingers VA and identified a massive submacular hemorrhage along with exudation.

“This situation could have been prevented by home monitoring and even better by home OCT monitoring that could have showed exudation developing long before the hemorrhage occurred,” he said.



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Rosenfeld credited the ability to detect MNV to the work by Ruikang Wang, PhD, of the University of Washington in Seattle, who developed an optical microangiography algorithm that enables flow detection in OCT images. 

Using specific segmentation strategies, clinicians can identify subclinical MNV lesions using a number of different slab configurations with different boundaries. 

For the purposes of his study, Rosenfeld used a slab that extended from the outer retina (OR) to the choriocapillaris (CC), which is termed the ORCC slab.

Rosenfeld noted that the presence of subclinical MNV had been described in the 1990s in eyes that had undergone indocyanine green angiography (ICGA). 

The ability to identify these lesions equally as well using noninvasive SS-OCTA imaging was demonstrated by Rosenfeld and colleagues in a study of patients with asymptomatic, intermediate AMD in one eye and exudative NV AMD in the fellow eye.

Subsequently, Rosenfeld and colleagues went on to investigate the prevalence and natural history of nonexudative MNV in dry AMD. 





For this study, they included patients with dry AMD in one eye and a fellow eye with exudative AMD. 

In the eyes with dry AMD, they found a 14-fold increased risk of developing exudation within 2 years among eyes with nonexudative MNV compared with eyes that did not have subclinical MNV.

Overall, if the fellow eye had exudative AMD, the prevalence of a nonexudative MNV in an eye with dry AMD was 13%. The prevalence was similar in eyes with either intermediate AMD or geographic atrophy.

Follow-up of eyes with nonexudative MNV showed that the lesions can grow without becoming exudative. 

Anti-VEGF treatment was administered when symptomatic fluid developed associated with a decrease in vision, and the treatment was effective in resolving the fluid and improving VA, but there were no obvious effects on lesion morphology for type 1 MNV, which comprised 93% of the lesions.



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Search for anatomic changes that predict exudation


Studies conducted to find possible biomarkers to predict exudative conversion have so far shown no association with size or growth of the MNV prior to exudation or with changes in volume of pigment epithelial detachments associated with the MNV prior to exudation, choriocapillaris flow deficits, or the surrounding choroidal vasculature.

“Additional potential predictors we are looking at include flow velocity within the MNV or in the choriocapillaris around the MNV and changes in choroidal blood flow,” he noted.

Rosenfeld explained that in the phase 2 FILLY study investigating pegcetacoplan for the treatment of geographic atrophy, the adverse event analysis showed that new-onset exudation developed in a dose-dependent fashion, occurring in 21% of eyes treated monthly with the investigational agent, in 9% of eyes receiving treatment every other month, and in only 1 eye (1.2%) in the sham-treated control group.

A post hoc review of images obtained at baseline showed the DLS was present in 73% of eyes that developed exudative AMD versus in 32% that did not develop exudation.

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“These eyes with the DLS had subclinical neovascularization, but we were not prepared to capture these eyes at baseline,” Rosenfeld explained. “Now, in the phase 3 trials investigating pegcetacoplan, DLS at baseline is being identified, and these eyes are being followed carefully for the development of exudation that will be treated with anti-VEGF therapy.”

However, Rosenfeld added that the take-home message from FILLY “is that the VA outcome was just as good in eyes that developed exudation compared to those that did not because they were treated promptly with and responded very well to anti-VEGF therapy.”


This article is based on Rosenfeld’s presentation at the 2021 Ohio Ophthalmological Society Virtual Annual Meeting. Rosenfeld receives research support from and is a consultant to Carl Zeiss Meditec and is chairman of the steering committee of the Advanced Retina Imaging Network, which is a global consortium of clinical researchers, and the Zeiss Medical Technology business group.

1.Roisman L, Zhang Q, Wang RK, et al. Optical coherence tomography angiography of asymptomatic neovascularization in intermediate age-related macular degeneration. 

. 2016;123(6):1309-1319. doi:10.1016/j.ophtha.2016.01.044

2.Yang J, Zhang Q, Motulsky EH, et al. Two-year risk of exudation in eyes with nonexudative age-related macular degeneration and subclinical neovascularization detected with swept source optical coherence tomography angiography. 

 2019;208:1-11. doi:10.1016/j.ajo.2019.06.017

3.Shen M, Zhang Q, Yang J, et al. Swept-source oct angiographic characteristics of treatment-naive nonexudative macular neovascularization in amd prior to exudation. 

4.Liao DS, Grossi FV, El Mehdi D, et al. Complement C3 inhibitor pegcetacoplan for geographic atrophy secondary to age-related macular degeneration: a randomized phase 2 trial. 

 2020;127(2):186-195. doi:10.1016/j.ophtha.2019.07.011

5.Wykoff CC, Rosenfeld PJ, Waheed NK, et al. Characterizing new-onset exudation in the randomized phase 2 FILLY trial of complement inhibitor pegcetacoplan for geographic atrophy. 

 Published online March 10, 2021. doi:10.1016/j.ophtha.2021.02.025

Option detects treatment-naive nonexudative macular neovascularization in eyes with dry age-related macular degeneration

Swept-source OCT imaging assists dry AMD treatment 

Analyses of data collected in the American Academy of Ophthalmology (AAO) Intelligent Research in Sight (IRIS) Registry suggest that US ophthalmologists, and specifically retina subspecialists, responded appropriately to patient-care guidelines issued by AAO leadership at the start of the coronavirus disease 2019 (COVID-19) pandemic, said Steven D. Schwartz, MD.

“The investigation showed a decrease in patient visit volume following the release of the AAO statement on March 18, 2020, but also suggested that urgent and emergency patients were appropriately prioritized and well cared for,” said Schwartz, the Ahmanson Chair in Ophthalmology at the UCLA Stein Eye Institute in California.

“Data pertaining to anti-VEGF injections for patients with highly active disease suggest they received careful, individualized management without an adverse effect on their visual outcomes,” he said.


Although individual ophthalmologists may vary in their experiences and perceptions of how the pandemic affected their patients and practices, the analyses of the IRIS Registry data sought to gain broader insight on these issues by analyzing real-world evidence, Schwartz explained.

“Ultimately we all strive to improve patient care in our practice of ophthalmology. We were interested in determining how ophthalmology responded to the pandemic and if the interruption it caused to in-person visits led to patient harm,” he said.

The analyses were conducted by Verana Health, the end-to-end data and technology partner for the AAO IRIS Registry.

Theodore Leng, MD, MS, an associate professor of ophthalmology at Byers Eye Institute at Stanford University School of Medicine in Palo Alto, California, led the analysis team for this research at Verana Health, where he is a consulting ophthalmologist.


The AAO letter on March 18, 2020, which came from AAO CEO David W. Parke II, MD, stated it was essential that all ophthalmologists cease providing treatment other than urgent or emergency care.

Analyses of daily patient visits from January 2020 to June 27, 2020, showed a decrease in the prepandemic volume, which averaged 214,000 visits per day, immediately after March 18, 2020. 

The decline continued, reaching a trough on April 10at approximately 34,000 visits per day, and then visits per day began to rebound as areas of the country started to open up.

“Clearly, the letter from AAO leadership was the seminal event modifying our behavior as a specialty,” Schwartz said.

Further analyses showed parallel patterns in the numbers of visits for new and returning patients.

Commenting on the similarity, Schwartz said that it showed both groups of patients had their issues prioritized above any perceived COVID-19 exposure risk.

Another analysis investigated changes in patient visits to retina practices versus to nonretina specialists and optometrists. 

The results indicated that retina subspecialists continued to care for the urgent/emergency patients with vision-threatening conditions, accounting for an increased percentage of overall patient visits at the height of the visit slowdown in April. 

Compared with January through March when visits to retina subspecialists accounted for approximately 20% of the total visits, subspecialists’ share of the total volume had nearly doubled in April, reaching 38.5%.

Additional analyses considered potential geographic variations in the visit trends and showed no differences among providers in urban, suburban, or rural locations. 

However, a state-by-state analysis found that the largest decline in patient visit volume during the spring slowdown occurred in the Northeast region of the United States.

Furthermore, in contrast to the overall rebound in patient visits that began in late April, the decline in the Northeast persisted through late June. 

An analysis focusing on the 5 states without “stay-at-home” orders (Arkansas, Iowa, North Dakota, Nebraska, and South Dakota) showed declines in patient visit volume that tracked with that of the overall nationwide behavior.

“It was appropriate to see the largest decline in patient visits in the Northeast, which was hit hardest by the pandemic during the spring,” Schwartz said. “The data for the states with no stay-at-home order suggest that as a field, ophthalmologists trusted our leadership and followed scientific recommendations, including rebounding with cautious care and putting patient safety at the fore.”


Analyses of anti-VEGF injection data showed that in the 12 weeks leading up to March 18, 2020, approximately 1.5 million injections were recorded in the IRIS Registry, a weekly average of 122,785 injections. 

During the 12 weeks after March 18, the total number of injections received decreased to approximately 1.2 million, averaging just below 100,000 per week.

Recognizing that patients receiving anti-VEGF injections represent a range of diagnostic severity across a broad range of treatment strategies and diagnoses, another analysis was undertaken that focused on the sickest patients.

“This approach included 39,819 eyes that had received one injection in the same eye monthly during the 5-month period before March 18 and was expected to be more instructive of how practices responded to the pandemic,” Schwartz said.

The results showed that nearly 50% of the group continued to receive monthly injections during April through June, and approximately 40% of the group received at least 1 injection during the 3-month study period. 

Overall, vision was stable in all 3 subgroups, Schwartz reported.

Mean distance visual acuity was 20/50- in the prepandemic period and remained at 20/50- among patients who received monthly injections and in the subgroup that received at least 1 injection. It fell only by approximately 1 line in the group that went untreated. 


E: sdschwartz@mednet.ucla.edu
Schwartz is on the board of directors of Verana Health and one of the founding directors.

Visits, elective procedures decreased as physicians responded to COVID-19 guidelines.

Cheryl Guttman Krader, BS, Pharm

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Study results link frequent anti-VEGF injections, risk of cognitive impairment