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

Cheryl Guttman Krader, BS, Pharm

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Measures of functional vision, which refers to a person’s ability to use vision to perceive the environment and function in daily life, are needed to establish benefit of novel gene therapies for inherited retinal dystrophies (IRDs). To that end, a novel standardized orientation and mobility (O&M) course, the multiluminance mobility test (MLMT), was developed and validated to assess the response to treatment with AAV2-hRPE65 for patients with vision loss due to biallelic mutations in 

Researchers are now working to develop a virtual reality orientation and mobility (VR-O&M) test that could overcome the practical challenges associated with reliance on a physical course. In a recently published paper, Dr Tomas S. Aleman and colleagues reported on a study that provided proof-of-concept data supporting the use of a VR-O&M system to evaluate the potential for functional vision improvement using investigational therapies for IRDs.

“Our initial findings support further investment in time and resources to refine and validate the VR-O&M technique as an alternative to physical mobility courses,” said Dr Aleman, Irene Heinz-Given and John LaPorte Research Associate Professor in the Department of Ophthalmology at the Perelman School of Medicine, University of Pennsylvania in Philadelphia.

“Once basic VR-O&M tests are validated, the limitations of the current designs, such as lack of standardization and the inability of the VR instruments to explore the full range of our visual abilities, will need to be addressed,” he said.

Dr Aleman said plans were being made to evaluate the effects of gene therapy in an ocular disease, such as 

-LCA. It became obvious that a measure of the patient’s real-life behaviour was desirable and needed for endorsement of the safety and efficacy of the treatment by regulatory bodies, such as the FDA. The idea of the MLMT obstacle course was pursued as a paradigm that could determine whether the treatment had a positive effect on visual behaviour in a real-world simulated environment.

The course requires availability of a large space that is not available in most eye clinics. In addition, assembling the course is time-consuming and not easy.

Limitations for modifying luminance and obstacle size and position in ways that will accommodate testing of the diverse patterns of visual dysfunction and spectrum of severity of vision loss in patients with IRDs is another drawback of a physical course. Furthermore, test performance scoring is done manually by observers who review videos of the testing. The process is time-consuming and the observers must be masked to avoid bias, as patient confidentiality is not maintained in the recording.

A VR-O&M test using a commercially available headset and custom-designed software was pursued as a more flexible alternative.

“A VR testing paradigm requires a much smaller physical space, allows the opportunity for easily introducing virtually unlimited number of environmental modifications, and performance parameters are automatically detected and quantified,” Dr Aleman said. He added that the testing still involves a patient walking through a physical space, but the required area is much smaller than with the MLMT.

In developing the software for the VR-O&M, Dr Aleman and colleagues evaluated several different configurations in cohorts of both normally sighted control subjects and patients with 

-associated Leber congenital amaurosis (LCA). The test itself is similar to the MLMT, as it requires patients to follow arrows through a course while avoiding collisions with randomly placed obstacles. Subjects are fitted with hand trackers and foot trackers to record information. Performance on the VR-O&M course is scored based on the number of collisions and time taken to reach the course exit.

After testing the various configurations, a protocol was selected for further evaluation in 3 patients with 

-LCA, including 2 patients who performed the testing before and after receiving gene therapy. Results from the controls and the patients with LCA from testing done prior to gene therapy showed differences between the 2 groups in the illumination level needed to navigate the obstacle course as well as in the number of collisions that occurred and total time needed for completing the course.

Compared with their pretreatment performance, the patients who were retested after receiving gene therapy demonstrated improvements in required illumination, number of collisions, and total navigation time that corresponded with their improvements in cone- and rod-mediated sensitivities.

Aleman is a coauthor on intellectual property describing the virtual reality mobility test (PCT/US2019/ 029173 pending). He has no other relevant financial interests to disclose.

1. Aleman TS, Miller AJ, Maguire KH, et al. A virtual reality orientation and mobility test for inherited retinal degenerations: testing a proof-of-concept after gene therapy. 

 2021;15:939-952. doi:10.2147/OPTH.S292527

Articles

According to investigators, the virtual reality option could overcome hurdles associated with reliance on a physical course.

Study finds virtual reality paradigm viable for orientation, mobility testing

Results from a retrospective study of patients treated with amniotic membrane transplantation (AMT) for Stevens-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) highlight the risk for long-term ocular complications and the need for ongoing management.

Reviewing outcomes in a series of patients who underwent AMT during the acute phase of SJS/TEN, the investigators found that ocular surface structures were often affected by chronic sequelae that led to dry eye disease (DED) as a common complication.

“AMT over the ocular surface for the treatment of ocular involvement in the acute phase of SJS/TEN was first described in 2002. Since then, it has become the gold standard, and there have been many efforts to intervene early and aggressively with AMT. However, management of chronic ocular sequelae is just as paramount because these patients are at risk for developing severe dry eye and ocular surface disease,” according to Dr Tatiana S. Zanganeh, a third-year ophthalmology resident at San Antonio Uniformed Services Health Education Consortium, Joint Base San Antonio-Fort Sam Houston, Texas, and a captain in the United States Air Force.

“This management should be done by a cornea or DED specialist who has extensive knowledge of the available treatment options that include aggressive lubrication, topical or oral anti-inflammatory agents, serum tears, scleral contact lenses, or, if the condition is severe enough, total penetrating keratoplasty,” she added.

Outcomes using ocular AMT in the acute treatment of patients with SJS and TEN were evaluated by identifying patients with a histopathologically confirmed diagnosis admitted to Brooke Army Medical Centre at Fort Sam Houston between January 2006 and January 2020.

Of 112 patients admitted with SJS/TEN, 52 patients (102 eyes) were treated with ocular AMT. Management also included hourly topical lubricants, frequent topical corticosteroids, and antibiotics as clinically indicated.

Median time to AMT following onset of symptoms was 5 days (range, 3 to 6 days), and additional AMT was required for treatment of 64% of the eyes.

Follow-up of longer than 2 months from the date of initial AMT was available for 39 eyes of 20 patients.

Within the latter subgroup, TEN was the diagnosis for 17 patients, 2 were diagnosed with SJS, and 1 with SJS/TEN overlap. The 2 most common agents inciting the condition were antibiotics (n = 8) and antiepileptics (n = 8).

Visual acuity results at last visit for the eyes with chronic follow-up showed that 29 achieved BCVA of 20/40 or better. BCVA ranged between 20/40 and greater than 20/200 in 5 eyes and was 20/200 or worse in the remaining 5 eyes.

Complications involving the cornea and eyelid margin were seen in the majority of eyes at last follow-up.

There was a statistically significant reduction in the number of eyes with conjunctival involvement, although conjunctival complications were present in 14 eyes.

All eyes had involvement of eyelid skin at presentation compared with just 2 eyes at last follow-up.

Cornea complications at last follow-up included punctate epithelial erosions or epithelial defect, subjunctivization, and corneal scar, and some eyes required penetrating keratoplasty.

Conjunctival complications included punctate staining and scarring. Eyelid margin complications included forniceal shortening and meibomian gland dysfunction or trichiasis. Eyelid skin was normal in most patients, but some had mild scarring or lagophthalmos.

“No patients developed lagophthalmos, perhaps because eyelid skin sloughing was not deep enough to cause cicatrisation that would result in lagophthalmos,” Dr Zanganeh said.

A review of the chronic complications indicated factors contributing to the development of chronic DED in patients with SJS/TEN.

They include aqueous tear deficiency from lacrimal gland scarring leading to aqueous tear deficiency, decreased wettability of the corneal surface due to persistent punctate epithelial erosions or other corneal epithelial defects from limbal stem cell deficiency, and tear film instability arising from increased evaporative tear loss related to the destruction of mucin-producing conjunctival goblet cells and meibomian gland scarring.

Dr Zanganeh also described an approach for extending coverage of the involved tissues with AM.

Rather than using the self-retained cryopreserved amniotic membrane (Prokera; Biotissue) that only covers the cornea and perilimbal surface of the eye, a larger sheet of AM is used that can overlap the bulbar, palpebral, and forniceal conjunctiva as well as the eyelid margin.

The sheet of AM is secured to the eyelid skin with bolstered sutures and then accordion-folded into the forniceal spaces with a customizable symblepharon ring that is fashioned from sterile intravenous tubing.

Then, the sheet is draped over the entire ocular surface, folded into the opposite forniceal space, and draped over the opposite lid margin before it is secured to the eyelid skin.

“Originally, the procedure was done in the operating room with sedation, and it also resulted in suture trauma to the eyelid skin,” Dr Zanganeh concluded. “The technique has evolved, and the procedure can now be performed at the bedside under topical anaesthesia and using cyanoacrylate glue in lieu of sutures.”

Dr Zanganeh and her coauthors, Col Sheri L. DeMartelaere, MC, USA, and Col (Ret) Anthony J. Johnson, MC, USA, have no relevant financial interests to disclose.

Patients are at risk for developing severe dry eye and ocular surface disease.

Acute and chronic care required for eye with SJS/TEN ocular involvement

The two-day Bascom Palmer Eye Institute Angiogenesis, Exudation, and Degeneration 2022 virtual conference provided updates for clinicians and researchers on developments in imaging, translational research and clinical trials of treatments for retinal diseases. The 

 gathered several speakers to discuss their presentations.

Port delivery system extension study outcomes

Dr David Eichenbaum, director of research, Retina Vitreous Associates of Florida and collaborative associate professor of Ophthalmology, Morsani College of Medicine at the University of South Florida, St. Petersburg, and Dr Peter Campochiaro, George S. and Dolores Dore Eccles professor of ophthalmology and Neuroscience, Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland, discussed the Port Delivery System (PDS) with ranibizumab (Suvismo, Genentech) for treatment of neovascular age-related macular degeneration (nAMD).

Dr Eichenbaum reviewed his presentation on long-term outcomes based on data from patients followed for up to 4 years. He reported that overall, patients maintained their baseline vision, and thus efficacy was demonstrated.

Drilling down to look at individual data showed some heterogeneity in how well patients maintain disease control; about 90% of patients had excellent control of exudation and the remaining 10% had moderate or severe exudation sometime after PDS implantation. Recurrent exudation was most often subretinal fluid.

The rate of supplemental injections was low and the supplemental injections were most often given for a decrease in vision, which often occurred without exudation. Dr Campochiaro suggested the supplemental injection rate will be even lower in clinical practice, recognising that a drop in vision without exudation may be due to dry eye or a cause other than nAMD.

“One of the things that the port delivery system taught us is that sustained suppression of VEGF is really the correct way to treat this disease,” said Dr Campochiaro. Regarding safety, most adverse events of special interest occurred in the first 2 years. However, there are problems clinicians must continue to watch for, and those mostly involve the conjunctiva (erosion and retraction) and ocular surface.

Erosion is manageable but is important to watch for because it can lead to endophthalmitis, Dr Eichenbaum explained. Surgical and patient-related factors that can be associated with problems post-implantation were discussed, and it was noted that time will tell if a change in surgical technique implemented during the clinical trial program translates into a reduced rate of late erosions.

Additional data showed that patients strongly preferred PDS treatment over conventional injections. “I think this translation to patient happiness…is going to be a big impetus to offer this in clinical practice once surgeons in the community get experience with the PDS,” Dr Eichenbaum said.

Dr Jennifer K. Sun and Dr Jonathan F. Russell discussed the need for a new staging system for diabetic retinal disease. They spoke about the limitations of the Early Treatment Diabetic Retinopathy Study Severity Scale and the advancements that have occurred since its introduction that support the need for an updated staging system.

“The consensus of many of us in the field has been that our current staging system does not incorporate all the new insights that we have and all the imaging modalities that we can bring to bear on the retina,” said Dr Sun, associate professor of ophthalmology, Harvard Medical School, Boston, Massachusetts.

She said that a new system for rating the severity of diabetic retinal disease should be multidimensional and a more holistic scale that incorporates retinal, neural and vascular pathology and their contributions to visual function within a background of the molecular disease mechanisms and systemic health.

Dr Sun noted that an effort to create an updated diabetic retinal disease staging system is supported by the Juvenile Diabetes Research Foundation and The Mary Tyler Moore and S. Robert Levine, MD Charitable Foundation. She reviewed the work in progress and noted the update is the first step in the Restoring Vision Moonshot Initiative.

Dr Russell, assistant professor of vitreoretinal disease and surgery, University of Iowa, Iowa City, reviewed the advantages of using wide field swept-source optical coherence tomography angiography for evaluating patients with diabetic retinopathy and provided an overview of a proposed staging system that is based on this technology.

Drs Russell and Sun addressed the possibility that new staging systems will lead to the introduction of new terminology for describing diabetic retinopathy. They noted it might even result in a move away from using the latter term, which does not encompass the neural and other changes associated with diabetic retinal disease.

The latest findings from Phase 3 clinical trials investigating faricimab (Vabysmo, Genentech) for the treatment of nAMD and diabetic macular oedema (DMO) were discussed by Dr Robyn Guymer and Dr John A. Wells, chairman, Department of Ophthalmology, Palmetto Retina Center, Columbia, South Carolina. Dr Wells reviewed topline results from 48 weeks of follow-up in the TENAYA and LUCERNE nAMD studies that showed BCVA gains from baseline in patients being treated with faricimab 6 mg up to every 16 weeks were non-inferior to controls receiving aflibercept (Eylea, Regeneron) 2 mg every 8 weeks.

The durability of faricimab’s effect was highlighted by data showing that around 45% of patients were receiving injections every 16 weeks and almost 80% were being treated every 12 or every 16 weeks. Faricimab-treated patients also had greater reductions in central subfield thickness than the aflibercept groups.

Dr Guymer, professor of ophthalmology, University of Melbourne, East Melbourne, Australia, discussed data from 2 years of follow-up in the YOSEMITE and RHINE studies of faricimab treatment for DMO that also showed that faricimab administered according to a personalised treatment interval regimen greatly reduced injection burden and was associated with stable vision gains that were non-inferior to aflibercept 2 mg every 8 weeks or more regular faricimab injections.

She reported that at 2 years, around 60% of patients in the personalised treatment interval arm were being treated every 16 weeks and another 18% were receiving injections every 12 weeks. Vision gains achieved at 1 year were maintained at 2 years and reduction in central subfield thickness was better than with aflibercept.

Discussing safety, both Dr Guymer and Dr Wells highlighted the absence of cases of vasculitis or occlusive retinitis in the faricimab groups, which is important considering the occurrence of vasculitis with other new drugs, Dr Guymer said.

Dr Campochiaro is consultant to Genentech and the payment is made to the university. Dr Eichenbaum receives fees as a consultant and speaker for Genentech and receives grant support.

Dr Guymer is a paid consultant to Roche/Genentech. Dr Wells is a paid consultant to and receives grant support from Genentech. He also receives grant support from Regeneron. Dr Russell is a consultant to Carl Zeiss Meditec. Dr Sun has no relevant financial interests.

Developments in imaging, translational research and clinical trials of treatments for retinal diseases dominated discussion at the two-day Bascom Palmer Eye Institute Angiogenesis, Exudation, and Degeneration 2022 virtual conference.

Retina specialists review recent developments in research for retinal diseases

X-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease for which there is not only a major unmet treatment need but also a need for greater understanding and awareness of its personal and societal burdens, according to authors of a recent article.

Published online in June 2021, the 8-page article presents the findings from a literature search and review conducted to identify and describe the clinical, humanistic, and economic burdens of XLRP or RP in the United States, Japan, France, Germany, Italy, Spain, and the United Kingdom.1 Although the search found a paucity of relevant literature, it is reasonable to conclude from the available evidence that XLRP clearly carries a significant humanistic and economic burden, according to Nan Li, PhD, MHS, MD. Dr Li is the director of access at Janssen Retina DAS in Raritan, New Jersey, and a coauthor of the paper. 

“XLRP causes progressive vision loss, with many affected patients becoming legally blind by age 40,” Dr Li said. “Currently there are no approved treatments for XLRP, and unfortunately, we continue to see very limited data on this condition.”

Dr Li also noted that additional research on inherited retinal diseases (IRDs) is crucial to underscore the need for therapies and to highlight their potential to dramatically improve lives of patients and caregivers. “Our identification of the information gaps is an important first step in assessing how best to support people with these conditions,” she said. “Therapies are currently being developed, and that is crucial.”

However, if researchers, regulators, payors, and advocacy groups do not understand the needs of patients with diseases like XLRP, they may not truly realize the potential groundbreaking nature of future treatments and the myriad ways they can improve the lives of patients and their families, Dr Li said.

Dr Li said her group’s analysis of the published literature essentially shows the lack of knowledge about the many challenges patients face with early-onset and progressive vision loss due to XLRP.

“We could not identify any studies assessing the humanistic or economic burden of the XLRP form of RP specifically,” Dr Li said. “Given the scarcity of studies focusing on patients with XLRP, we looked to the evidence from studies of the wider RP population to infer conclusions about the burden of XLRP, and we did find articles relating to RP in general.”

From the latter publications, it was learned that with progression of RP, affected individuals experienced a range of psychosocial, functional, physical, and economic burdens. For example, the published reports showed that patients developed feelings of loss, isolation, and fear. They also suffered other negative effects on quality of life resulting from the loss of enjoyment from vision-related hobbies and pastimes. Inability to work because of their impaired vision bore psychosocial consequences for people with RP because of loss of social support as well as economic consequences arising from lost productivity.

“Extrapolating from the findings from the RP-related research and considering first that the onset of disease is earlier for XLRP than RP, and second that XLRP is associated with more rapid progression of vision loss, it is reasonable to expect XLRP may create a greater burden for patients and their caregivers than does RP,” Dr Li said.

The identification of the gap in research to characterize the burdens of XLRP is an important first step in assessing how best to support people affected by the condition. “Our hope is to more fully understand the myriad ways the therapies currently in development for XLRP can potentially improve the lives of patients and families,” Dr Li said. “There is so much more to uncover and know about XLRP and other IRDs and the people living with them.”

Dr Li and colleagues are working with patient advocacy groups to generate more evidence about the cost of these illnesses. In addition, they are looking closely at patient and caregiver well-being, including the emotional burden of disease.

“Last year we partnered with Retina International on a study to estimate the societal disease burden and economic impact of IRDs in the United States and Canada,” Dr Li said. “The study found that individuals living with an IRD incur significant economic costs and reductions in their quality of life.”

Dr Li also explained that families, friends, government, employers, and society end up taking on significant economic costs as well.

“As we look ahead, our Janssen team anticipates initiating more research on these topics, working hand-in-hand with our stakeholders and partners,” Dr Li said.

Li has no financial disclosures related to this content.

1. Chivers M, Li N, Pan F, Wieffer H, Slowik R, Leartsakulpanitch J. The burden of X-linked retinitis pigmentosa on patients and society: a narrative literature review. 

. 2021;13:565-572. doi:10.2147/CEOR.S297287

2. Gong J, Cheung S, Fasso-Opie A, et al. The impact of inherited retinal diseases in the United States of America (US) and Canada from a cost-of-illness perspective. 

. 2021;15:2855-2866. doi:10.2147/OPTH.S313719

Recent literature review reveals dearth of data, highlights need for more research.

Author | Cheryl Guttman Krader, BS, Pharm

Articles

Acute and chronic care required for eye with SJS/TEN ocular involvement

Retina specialists review recent developments in research for retinal diseases

X-linked retinitis pigmentosa: Unravelling the burdens of the inherited retinal disease

Study finds virtual reality paradigm viable for orientation, mobility testing