Cheryl Guttman Krader, BS, Pharm

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Findings from a study demonstrating that erythropoietin receptor (EPOR) signaling plays a protective role in mitigating loss of retinal function following vascular loss and repair provide support for further investigations of erythropoietin (EPO) as a 

 neuroprotective agent, according to Mary Elizabeth Hartnett, MD.

Hartnett, the study’s first author, Colin Bretz, PhD, and other colleagues in her laboratory at the John A. Moran Eye Center, University of Utah in Salt Lake City, conducted their research comparing transgenic mice with hypoactive EPOR signaling and their wild type littermates and using a murine model of oxygen-induced retinopathy (OIR).

The results are reported in an article published in the March 2020 issue of the 

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“Erythropoietin is well known as a hematopoietic hormone, but there has been growing interest in its potential neural, vascular, and tissue protective effects,” said Hartnett, professor of ophthalmology and visual sciences at the University of Utah.

Hartnett said thecurrent research provides evidence that EPOR signaling may be important in reparative processes following retinal injury such as from vascular loss and remodeling.

Hartnett noted the researchfocused the effects of EPOR signaling on retinal repair after injury rather than testing a role for EPO.

As a first step, the researchers compared retinal structure and function in the transgenic and wild type animals under normal conditions. 

These investigations showed that the two groups had similar results in electroretinography testing and visual acuity. Differences were noted in neural retinal structure, however, showing that the transgenic mice had thinner inner and outer plexiform layers as well as a greater number of amacrine cells.

“Our findings of structural differences between the animals with hypoactive EPOR signaling and the controls led us to dig deeper and use the murine OIR model to test our hypothesis that EPOR signaling could be important in 

 neuroprotection,” according to Hartnett.

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In the OIR model, mice are placed into a high- oxygen environment that causes loss of retinal vessels and vessel growth into the vitreous. 

After several days, the animals are returned to room air, and subsequently the pathology is repaired so that there is regrowth into the retina of lost vessels and disappearance of the vessels in the vitreous.

The OIR experiment showed that after the animals were returned to room air, the transgenic mice with hypoactive EPOR signaling had fewer amacrine cells and reduced numbers of rod bipolar cell ectopic neurites than the wild type controls. The structural differences between the two groups corresponded with the finding that the transgenic mice had reduced b-waves on electroretinography.

“These observations indicate that EPOR signaling is important for the repatterning of retinal neurons that occurs during the repair process after retinovascular loss, which maintains connectivity of rod bipolar cells from the inner nuclear layer to extend directly to the rod photoreceptors in the outer nuclear layer and limit b-wave loss,” said Hartnett.


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Hartnett and her colleagues are studying the role of EPOR signaling in vascular development and regulation of angiogenesis modulated by the vascular endothelial growth factor receptor-2.

To understand if EPO treatment in infants at risk for ROP might have neuro- or vasculoprotective effects, they are planning to obtain OCT images from children enrolled in the Preterm Erythropoietin Neuroprotection Trial (PENUT; NCT01378273) at the University of Utah. PENUT randomized premature infants to high-dose EPO or placebo administered from 24 hours after birth through 32 weeks postmenstrual age.

The trial’s main objective was to investigate whether EPO might have a brain neuroprotective effect. 

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The recently published results of the primary end point analysis, conducted when participants reached 2 years of age found no significant difference between the EPO and placebo groups in the incidence of severe neurodevelopmental impairment.

Treatment with EPO also had no effect on the development of ROP, but the study did not evaluate neural retina.

“The children enrolled in PENUT are now reaching 5 years of age, and we are interested to see if early treatment with EPO may have had an effect on retinal structure,” Hartnett concluded. 


Dr. Hartnett has no financial disclosures related to this topic.

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Investigators find treatment with EPO shows no effect on the development of ROP.

Erythropoietin offers hope as retinal neuroprotective agent

There is no question that the Merit-based Incentive Payment System (MIPS) is a complex program that involves time-consuming reporting. 
In addition, cataract surgeons aiming to avoid a MIPS payment penalty may be particularly concerned about how intraoperative use of pass-through medications could affect their score.

Cathleen M. McCabe, MD, and Denise M. Visco, MD, MBA, recently discussed MIPS with 

® and offered encouraging information for their colleagues.



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Surgeons will find it reassuring that for 2020, 98% of physicians did enough reporting to earn a bonus, said Visco, president and medical director of Eyes of York in Pennsylvania.

Regarding pass-through medications, she and McCabe agreed that the benefits of using these agents, which include intracameral phenylephrine 1%/ketorolac 0.3% (Omidria), dexamethasone intraocular suspension 9% (Dexycu), and dexamethasone intracanalicular insert 0.4 mg (Dextenza), outweigh any potential negative impact on the MIPS cost measure.


The MIPS score, which ranges from 0 to 100, is calculated based on reporting in 4 areas: quality, improvement activities, promoting interoperability, and cost. 

Quality accounts for 45% of the score; interoperability, 25%; and improvement activities and cost, 15% each. A physician needs a final score of 45 to avoid a penalty.


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Visco observed that among the 4 categories, reporting for quality is the most burdensome. Because of its weight, this measure can’t be ignored in an attempt to stay above the threshold score for avoiding a penalty. 

However, she described expending too much effort to achieve perfection as an exercise with diminishing returns.

“The negative adjustment and bonus programs are a budget-neutral process, and with nearly all physicians qualifying for a bonus, there is not much penalty money in the pool. 

For example, based on 2018 reporting, the maximum bonus for 2020 will be just 1.68%,” explained Visco, who is also president of the American College of Eye Surgeons.

“The extra resources spent trying to increase one’s score cost more than you will receive in the way of a higher bonus. You are spending dollars to chase cents.”

Visco suggested that it might be most worthwhile to focus on improving the score for promoting interoperability, which can ultimately help streamline a practice’s overall functions, such as patient communications and services.

“The ability to upload information into the electronic health record and ensuring that your record is compatible with others and protects patient information are worth accomplishing,” she said.“

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These functions may also decrease the amount of quality reporting necessary to keep your MIPS score above the penalty level.”

Concern about the effect of using pass-through medications on the cost measure is misplaced, according to Visco and McCabe. Looking at the impact from a broader perspective reveals why the thinking is flawed, they said.

The mission of all surgeons and practices is to provide high-quality care that will result in a high degree of patient satisfaction, said McCabe, who is chief medical officer at Eye Health America and medical director of The Eye Associates in Bradenton, Florida. The use of intracameral phenylephrine/ketorolac or intraocular dexamethasone suspension in cataract surgery can help surgeons achieve those goals.

“Using intracameral phenylephrine/ketorolac has benefits for increasing case efficiency, reducing the need for additional interventions, improving outcomes, and increasing patient satisfaction,” she said.

Visco cited research showing the agent’s benefits, including the results of a recently published study she conducted. 

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The findings revealed that intracameral phenylephrine/ketorolac reduced rates of cystoid macular edema, breakthrough iritis, and postoperative pain.

 “All those issues bring patients back after surgery and therefore add to the cost of care,” she said.

Visco added that surgeons who question whether they might see the same benefits in their practices should consider findings from postmarket studies showing that intracameral phenylephrine/ketorolac decreases complications during cataract surgery and reduces the need for pupil expansion devices.

“If the added cost of using intracameral phenylephrine/ketorolac has any negative impact on the MIPS cost score, it is likely to be minimal, and its effect on the total score is likely just a drop in a larger bucket, having a minuscule impact on the amount of any bonus received,” Visco said.

Furthermore, a long list of comorbidities excludes difficult cases from the cost analysis, McCabe pointed out.

“The comorbidities include hypertension, diabetes, epiretinal membrane, history of intraocular inflammation, synechiae, and many others,” she said.

Outside of MIPS, surgeons should consider a generous manufacturer rebate program for intracameral phenylephrine/ketorolac. “This opportunity to improve the center’s financial status has taken on an even greater importance now that most surgery centers were closed for many weeks because of COVID-19 [coronavirus disease 2019],” she said.

Briefly discussing the Ambulatory Surgical Center Quality Reporting (ASC) Program, Visco mentioned that owners of Medicare-certified ASCs filing at least 240 claims annually for 2020 must report on 4 of the 5 following quality reporting measures to avoid reduced payments in 2021: ASC-9 (Endoscopy/Polyp Surveillance: Appropriate Follow-Up Interval for Normal Colonoscopy in Average Risk Patients), ASC-11 (Cataracts: Improvement in Patient’s Visual Function within 90 Days Following Cataract Surgery), ASC-12 (Facility 7-Day Risk-Standardized Hospital Visit Rate After Outpatient Colonoscopy), ASC-13 (Normothermia), and ASC-14 (Unplanned Anterior Vitrectomy).

“Although only measures 11, 13, and 14 have relevance to cataract surgery, it is important to also pick either ASC-9 or ASC-12 and include it in the reporting, even if you are entering a 0 in the numerator and the denominator,” Visco concluded.



Read more by Cheryl Guttman Krader, BS, Pharm

Dr McCabe is a speaker and consultant for Omeros, EyePoint Pharmaceuticals, and Ocular Therapeutix, and she receives research support from EyePoint Pharmaceuticals and Ocular Therapeutix.


Dr Visco is a speaker and consultant for and receives research support from Omeros, and she is a consultant for Ocular Therapeutix.


1. Visco DM, Bedi R. Effect of intracameral phenylephrine/ketorolac 1.0%/0.3% on postoperative cystoid macular edema, iritis, pain, and photophobia following cataract surgery. 

. Published online Mar 26, 2020. doi:10.1097/j.jcrs.0000000000000193

Bonuses are the norm and not risked by pass-through medication use


Surgeons discuss MIPS, impact of pass-through medications

Dr. SiegfriedResearch aiming to elucidate the underlying factors for oxidative damage to the trabecular meshwork in glaucoma has led to studies of alterations in gene expression that may ultimately guide the development of genetic therapy for glaucoma, said Carla J. Siegfried, MD, recipient of the 2018 Shaffer Prize for Innovative Glaucoma Research.

	Providing a history of her research, Dr. Siegfried said initial studies conducted in humans and non-human primates showed increased oxygen levels in the posterior segment, around the lens, and in the anterior chamber angle in eyes that had undergone vitrectomy and lens extraction compared with unoperated eyes.

	The findings supported the hypothesis that excess oxygen may be the source of reactive oxygen species causing oxidative damage to the trabecular meshwork. Dr. Siegfried received the Shaffer grant to further explore this idea by trying to establish an oxidative stress model in rabbits. It turned out that rabbits were not a tenable model because of surgical complications, she noted. 

Rabbit trabecular meshwork (TM) laser microdissection technique. A. Eosin-stained anterior chamber angle section with TM region precisely delineated (green). B. Excision of TM tissue by laser microdissection. Bar: 100 microns. (Images courtesy of Carla J. Siegfried, MD)

	Nevertheless, the project was productive because it led to the refinement of a novel laser-based technique for trabecular meshwork microdissection. With this new method of precise excision, it was possible to obtain specimens suitable for other studies, including genetic analysis that has propagated a new branch of research.

	“We are now studying alterations of gene expression within trabecular meshwork tissue in glaucomatous eyes, and specifically exploring the impact of oxidative damage in African Americans,” said Dr. Siegfried, Jacquelyn E. and Allan E. Kolker, MD, Distinguished Professor of Ophthalmology, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis.

	“We know that compared with Caucasians, African Americans are at higher risk for developing glaucoma and glaucoma-related blindness,” she added. “With the identification of a genetic basis underlying these differences–together with advances in gene therapy that can target the trabecular meshwork cells–there is tremendous potential for new therapeutic interventions.”

	This innovative laser microdissection technique, developed by Dr. Siegfried and her core collaborators, has been applied to obtain trabecular meshwork cells and genetic material from human eyes, including glaucoma patients undergoing trabeculectomy and cadaver eyes from donors with and without glaucoma.

	These samples have undergone genetic analysis using RNA sequencing confirmed with quantitative polymerase chain reaction analysis in collaboration with Washington University’s Genome Technology Access Center.

	Although only a limited number of samples have been analyzed, the RNA sequencing identified decreased expression of a certain protein in trabecular meshwork specimens from African Americans compared with Caucasians.

	“This is a newly identified protein that has never been studied in the trabecular meshwork,” Dr. Siegfried explained. “We have developed hypotheses about its function and how it may relate to pressure regulation and transmission of fluid across the trabecular meshwork. Now we are conducting further investigations to obtain evidence to support those ideas.

	“Although genome-wide association studies have identified target genes that might explain racial disparities in glaucoma, genetic variation may be quite different in the target tissue compared to whole genome analyses,” she added. “Therefore, translational research with clinical correlation is critical.”

	In their ongoing work, Dr. Siegfried and colleagues are also expanding the genetic analysis of trabecular meshwork specimens from African American and Caucasian eyes in order to confirm that the difference in protein expression observed in the pilot study is real.

Research aiming to elucidate the underlying factors for oxidative damage to the trabecular meshwork in glaucoma has led to studies of alterations in gene expression that may ultimately guide the development of genetic therapy for glaucoma, said Carla J. Siegfried, MD, recipient of the 2018 Shaffer Prize for Innovative Glaucoma Research. 

Author | Cheryl Guttman Krader, BS, Pharm

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