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

Cheryl Guttman Krader, BS, Pharm

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As cases of diabetes increase worldwide, the disease is accompanied by a precipitous increase in its most common complication, diabetic retinopathy (DR). At the same time, the aging population is growing, which is significant considering that the risk of developing DR increases the longer individuals live with diabetes and that the consequences of DR are unique in older patients.

In a recently published article, Dr Ashay D. Bhatwadekar and colleagues reviewed these issues to increase awareness and identify the best strategies for patient care.

“Understanding age-related retinal changes that increase vulnerability to DR in older individuals and age-related therapeutic challenges is essential for optimizing treatment of DR within the senior population,” said Dr Bhatwadekar, an associate professor of ophthalmology at the Eugene and Marilyn Glick Eye Institute, Indiana University School of Medicine, in Indianapolis.

“Proper treatment of DR in [senior patients] could reduce the overall burden of diabetes.”

The authors pointed out that the retinal structure is altered with age in several ways. Macular blood flow decreases by 20% on average and the retina becomes thinner, with the change in thickness especially affecting the inner nuclear layer. In addition, the response of the microglia to injury slows, Müller cells become more susceptible to oxidative stress and the extent of lipofuscin accumulation in retinal pigment epithelial cells increases.

“The changes in blood flow that occur with aging may worsen ocular perfusion abnormalities in diabetes, and proliferation of microglia in the outer retina can contribute to proinflammatory responses,” Dr Bhatwadekar said.

There are also age-related metabolic changes affecting the retina that are relevant for the development of DR. Disease-specific pathophysiologic mechanisms, such as accumulation of advanced glycation end products and the polyol pathway that contribute to oxidative stress, take advantage of the aging retina’s vulnerability that is associated with a defunct antioxidant defence system.

In addition, the effects of the VEGF pathway, which promotes angiogenesis, vascular permeability, and inflammation, could be augmented in the eyes of elderly individuals by the presence of a decreased retinal blood flow, Dr Bhatwadekar explained.

Other DR pathogenic pathways that may be exacerbated by aging-related alterations relate to protein kinase C activation and hexosamine.

Clinical studies of DR in aging individuals highlight the heightened concerns in senior patients. Not only does the prevalence of DR increase with age, but available evidence points to associations with depression and cognitive decline.

The article reviews current treatments for DR and diabetic macular oedema, including a discussion of their mechanisms and role in clinical care. In addition, summary information is presented about emerging treatments that are being investigated in both preclinical and clinical trials. These include aldose reductase inhibitors that work by inhibiting the polyol pathway, a treatment that increases expression of sirtuin 1, protein kinase C inhibition and gene therapy to introduce VEGF genes. In addition, there is interest in sodium-glucose cotransporter 2 inhibition and angiopoietin-2 inhibition.

Highlighting the therapy-related challenges occurring in the senior population, the article discusses problems with medication adherence and age-related changes in drug pharmacokinetics and pharmacodynamics.

Anatomic and physiologic changes that occur with aging and the effects of medications that are commonly used by elderly individuals can lead to decreased absorption of orally administered drugs with the potential for reduced efficacy. Thus, the need may arise to consider modifications in the dosing regimen or delivery method.

As noted in the article, an increase in proteases within the vitreous that has been noted with aging suggests there may be age-related pharmacokinetic differences in drugs administered by intravitreal injection. Changes in drug distribution within the eye also may occur, and the potential for age-related differences in systemic distribution, drug metabolism and elimination also needs to be considered when investigating medications administered via an extraocular route.

Older individuals are more prone to medication nonadherence, which should be considered in their use of oral medications and in maintaining follow-up when receiving in-office treatments for diabetic eye disease.

“In the future, it is necessary to consider all of the above factors [when] treating senior patients with DR,” Dr Bhatwadekar said. “Special programs directed toward tailoring and monitoring therapy may provide a better therapeutic outcome for [elderly patients].”

Dr Bhatwadekar is an ad hoc pharmacist at PCA Pharmacy. He reports no other relevant conflicts of interest.

Leley SP, Ciulla TA, Bhatwadekar AD. Diabetic retinopathy in the aging population: A perspective of pathogenesis and treatment. 

. 2021;16:1367-1378. doi:10.2147/CIA.S297494

Articles

Confronting issues unique to aging may lead to better outcomes.

Managing senior-specific complications of diabetic eye disease

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.

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

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

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

Several innovations are revolutionising surgical care in paediatric ophthalmology, according to Dr Janet L. Alexander, an assistant professor of ophthalmology and paediatrics at the University of Maryland School of Medicine in Baltimore, Maryland, United States.

Speaking at the Women in Ophthalmology 2021 Summer Symposium, Dr Alexander presented a series of rapid-fire cases to discuss four such paediatric innovations: antenatal 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.

One case involving a child born with Norrie disease highlighted the value of antenatal surgical planning to enable intervention prior to complications. A 30-year-old woman in her second trimester of pregnancy presented with carrier status for 

 mutation. Amniocentesis confirmed foetal 

 mutation, and the ultrasound showed no foetal retinal detachment. Labour was induced at 34 weeks’ gestation for early retinal treatment.

As well as having Norrie disease, the baby was diagnosed with bilateral vitreous haemorrhages at birth, and underwent bilateral treatment with intravitreal anti-vascular endothelial growth factor therapy and peripheral retinal laser. Six months later, both eyes demonstrated robust light perception vision with an attached retina.

Dr Alexander noted that the case was a reminder that it is never too early to start antenatal surgical planning. “Prenatal surgical planning requires proactive and timely genetic testing to identify surgical candidates, counselling for female carriers of high-risk genetic traits, and involvement of geneticists and genetic counsellors,” she said.

Dr Alexander discussed the benefits and drawbacks of descemet stripping automated endothelial keratoplasty (DSAEK) versus penetrating keratoplasty (PK) with reference to 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 paediatric eyes,” Dr Alexander said. “However, DSAEK graft positioning can be very difficult in paediatric patients, and complications such as graft folds; detachment and dislocation; pupillary block; endothelial immune rejection; and steroid response can occur.”

There are advantages to choosing ECP over trans-scleral ciliary ablation to treat refractory glaucoma in paediatric patients, according to Dr Alexander. She presented a case involving a 7-year-old child who had sustained a traumatic cataract, then presented with 20/250 vision and elevated intraocular pressure (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 favourable safety profile compared with the trans-scleral technique. “For example, phthisis in the absence of retinal detachment occurs in over 30% of eyes treated trans-sclerally but in less than 1% of eyes that undergo ECP,” Dr 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 1–2 years. In addition, ECP can lead to the serious complications of hypotony, retinal detachment and vision loss.

Fundus photo 1 month following laser treatment for Norrie disease. (

According to Dr Alexander, preoperative evaluation with UBM enables cataract surgery planning and helps to prevent intraoperative surprises. Dr 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 whilst 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.

Dr Alexander said that knowledge of the absorbed cataract had guided appropriate surgical techniques. “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 might complicate cataract surgery and can inform the surgical approach. Dr 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.

Dr Alexander concluded by observing that quantitative UBM is an innovation that further enhances the clinical utility of this procedure. Quantitative UBM uses algorithms to analyse the images and generates information that helps clinicians interpret the images. The algorithms are also capable of suggesting clinical diagnoses and prognostic features, such as the risk of complications.

Dr Alexander has no related relevant financial interests to disclose.

Several recent cases demonstrate how advancements in planning, imaging and surgical approaches can enable positive outcomes in very young patients.

Author | Cheryl Guttman Krader, BS, Pharm

Articles

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

Study finds virtual reality paradigm viable for orientation, mobility testing

Recent innovations are improving surgical outcomes in young patients

Managing senior-specific complications of diabetic eye disease