Genetic Testing Experiences of People Living with Inherited Retinal Degenerations: Results of a Global Survey.

INTRODUCTION: Obtaining a genetic diagnosis via genetic testing (GT) is a fundamental step in determining the eligibility of a patient to be enrolled in emerging clinical trials and research studies. Besides, the knowledge of genetic outcome allows patients to plan for significant life choices. However, critical barriers exist to an equitable access to genetic services globally. The objective of this study was to explore patient experiences while seeking genomic services for inherited retinal degenerations (IRDs). METHODS: An online survey was designed based on a focus group conducted by Retina International and including people affected by IRDs and their families living in different regions around the world. The survey was then circulated to 43 Retina International member organisations globally via email newsletters and social networks. The survey involved questions in relation to the accessibility, affordability, and timeliness of genomic services for IRDs as well as patient perceived awareness of genomic services for IRDs among healthcare professionals. RESULTS: A total of 410 respondents (IRD patients and caregivers) from over 30 countries across all continents responded to the survey. A considerable number of the patients had to go through a long and arduous journey to access GT and counselling services, wherein 40% had to visit more than 5 physicians, 27% had to visit more than 5 clinics, and 57% had to wait for more than 3 years before obtaining a genetic diagnosis. Furthermore, 46% of respondents reported not receiving genetic counselling prior to undergoing GT, and 39% reported not receiving genetic counselling after undergoing GT. Over 3/4th of the participants reported that they did not have to pay for their genomic services for IRDs. Thirty-seven percent of the respondents reported that their eye care professionals (ECPs) were either not aware of GT, remained neutral, or did not encourage them to undergo GT. CONCLUSION: Patients with IRDs do not have equitable access to best practice GT and counselling services. Greater awareness and training regarding IRDs and the benefits of GT and genetic counselling for patients and families are needed among ECPs. A best practice model on access to genomic services for IRDs is required.

Static Perimetry in the Rate of Progression in USH2A-related Retinal Degeneration (RUSH2A) Study: Assessment Through 2 Years.

PURPOSE: To evaluate disease progression using static perimetry (SP) in patients with USH2A-related retinal degeneration, including Usher syndrome type 2 (USH2) and nonsyndromic autosomal recessive retinitis pigmentosa. DESIGN: Prospective, observational cohort study. METHODS: A total of 102 patients with biallelic disease-causing sequence variants in USH2A with baseline best-corrected visual acuity (BCVA) letter score ≥54 were recruited from 16 clinical sites in Europe and North America. SP, BCVA, full-field stimulus thresholds, spectral domain optical coherence tomography macular scans, and fundus-guided mesopic microperimetry were performed at baseline and annually. The main outcome measures were total hill of vision (VTOT), hill of vision in the central 30° (V30), VTOT minus V30 (VPERIPH), and mean sensitivity. RESULTS: The average decline (95% CI) was 2.05 (1.40, 2.70) decibel-steradian (dB-sr)/y for VTOT, 0.48 (0.32, 0.65) dB-sr/y for V30, 1.53 (0.97, 2.08) dB-sr/y for VPERIPH, and 0.55 (0.40, 0.71) dB/y for mean sensitivity. Average percentage decline per year was 8.3 (5.5, 11.1) for VTOT, 5.2 (3.0, 7.4) for V30, 16.0 (9.5, 22.0) for VPERIPH, and 5.1 (3.5, 6.7) for mean sensitivity. Changes from baseline to year 2 in all SP measures were highly correlated (r's ranging from 0.52 [V30 vs VPERIPH] to 0.98 [VTOT vs VPERIPH]). CONCLUSIONS: Quantitative measures of SP declined significantly over 2 years in USH2A-related retinal degeneration. The annual percentage rate of change was greatest for VTOT and VPERIPH, whereas V30 and mean sensitivity changed least, reflecting earlier and more severe peripheral degeneration compared with central loss.

Association of No-Cost Genetic Testing Program Implementation and Patient Characteristics With Access to Genetic Testing for Inherited Retinal Degenerations.

IMPORTANCE: The benefits of no-cost genetic testing initiatives have not been characterized. The no-cost My Retina Tracker Genetic Testing Study (MRT-GTS) research registry for inherited retinal degenerations (IRDs) was launched in 2017 in the US. OBJECTIVE: To investigate the associations of MRT-GTS implementation and patient characteristics with access to genetic testing for IRDs. DESIGN, SETTING, AND PARTICIPANTS: In a cross-sectional design, analysis of new patients evaluated 12 months before (July 1, 2016, to June 13, 2017) and 12 months after (June 14, 2017, to June 30, 2018) MRT-GTS implementation at a single academic referral eye center was conducted. Participants included 369 patients with IRD. Data analysis was conducted from February to June 2020. MAIN OUTCOMES AND MEASURES: Change in rates of successfully obtaining genetic testing, odds ratios (ORs) of association between patient characteristics and obtaining testing, and days elapsed from clinic visit to reporting of results. RESULTS: Among 369 patients (mean [SD] age, 39.5 [20.8] years; 193 [52.3%] women), 144 were evaluated in the pre-MRT-GTS period and 225 in the post-MRT-GTS period. The baseline rate of successfully obtaining testing was 51.4% (95% CI, 42.6%-60.2%). The initiation of MRT-GTS was associated with a 28.9-percentage point increase in testing rate (95% CI, 16.7%-41.1%; P < .001). Patient characteristics that increased the odds of obtaining testing were eligibility for MRT-GTS (OR, 14.15; 95% CI, 7.36-27.24; P < .001) and worse visual acuity (logMAR +1.0; Snellen equivalent decrease from 20/20 to 20/200) in the better-seeing eye (OR, 1.92; 95% CI, 1.27-2.91; P < .01). Patients had decreased odds when identifying as Black or African American (OR, 0.10; 95% CI, 0.04-0.24; P < .001) or other race (OR, 0.37; 95% CI, 0.15-0.91; P = .03) compared with White race, and when the primary language was not English (OR, 0.13; 95% CI, 0.03-0.55; P < .01). The proportion of test results reported within 90 days was 81.5% (95% CI, 74.8%-86.4%) when eligible for MRT-GTS compared with 48.1% (95% CI, 35.6%-58.1%) when not eligible (P < .001). CONCLUSIONS AND RELEVANCE: In this study, the implementation of MRT-GTS was associated with an increase in the proportion of patients who successfully obtained testing, suggesting the potential clinical value of this approach. Patient-level demographic and clinical factors appear to be associated with decisions to pursue testing.

Inherited retinal degeneration current genetics practices - a needs assessment.

BACKGROUND: Clinical assessment of patients with IRD often includes thorough documentation of medical and ocular history in addition to genetics related practices like assessing the family history and genetic testing. Previous studies have demonstrated the genetic counseling needs of IRD patients are not being fully met, but there is a lack of literature showing the current genetics practices of ophthalmologists and optometrists in the U.S. The goal of this study is to assess the current genetics related practices being provided to patients with IRD. METHODS: Data from 51 survey participants were included in the analysis. The survey assessed their current practices of risk counseling to patients with IRD, their confidence level of ocular genetics, and resources they may utilize in the future. Descriptive statistics were used to summarize quantitative data while data from open ended responses were coded using thematic analysis generated through grounded theory. RESULTS: Responses suggest some discussion of genetics is occurring with IRD patients. However, there are limitations to these discussions given time constraints and lack of understanding of the genetics of IRDs and available testing. The study also revealed that there are minimal referrals to genetic counseling being made at this time, though there is interest in working with genetic counselors. Additionally, there is a need for continued education regarding the genetics related to IRDs. CONCLUSION: Future larger-scale studies are warranted to provide additional insight into these genetics related practices and where genetic counselors are needed in this field.

Why Miss the Chance? Incidental Findings while Telescreening for Diabetic Retinopathy.

PURPOSE: To report on incidental pathological findings met while screening for Diabetic Retinopathy (DR) in Diabetes Clinics (DC) by ophthalmologist-graded digital fundus imaging. METHODS: At the DC of Pescara (central Italy), for 3,859 eyes of 1,930 consecutive patients having not undergone fundus examination in the last year, two mydriatic fundus digital images, taken with a CenterVue DRS Digital Retinal Camera, were sent along with Best Corrected Visual Acuity, on a "store-and-forward" basis, to an ophthalmologist trained in DR screening, and graded according to the UK Diabetic Eye Screening Programme. Incidental fundus abnormalities other than DR were reported. RESULTS: No adverse event to mydriasis was reported. One hundred and eighty eyes (4.66%) were ungradable. Among the 3,679 gradable ones, 1,105 (30.04%) showed different degrees of DR (R1 to R3), and 126 (3.42%) maculopathy (M1). Any Age-Related Macular Degeneration was present in 387 eyes (10.52%), any optic disc and parapapillary area features suspect for glaucoma in 562 eyes (15.27%), any hypertensive retinopathy in 1,263 eyes (34.33%), vitreoretinal interface disease in 252 eyes (6.84%), myopic choroidopathy in 92 eyes (2.50%), disc pallor in 31 eyes (0.84%). Mean time was 5 min for screening, 2 min for grading. CONCLUSION: Teleretinography is a well-established, cost-effective procedure in DR screening. Along with increased attendance, locating a digital camera in a DC with a retina-specialist grader results in finding fundus pathologies also beyond DR, very similarly to fundus examination in an outpatient ophthalmic setting.

The assessment of retina in pregnant women with myopia.

OBJECTIVES: Myopia is associated with increased frequency of retinal degenerative changes which are the risk factors of intra- and postpartal ophthalmological complications. Aim of this study was to analyze the degenerative lesions detected in opthalmological examination (including peripheral retinal lesions) as a potential risk factors for eyes' status in terms of delivery in myopic women. MATERIAL AND METHODS: 254 pregnant women affected with myopia underwent opthalmological examination as a screening method to examine retina. In case of any degenerative lesions, the qualification for laser photocoagulation treatment was performed. Furthermore, study group was divided into two subgroups due to presence or absence of the retinal lesions and opthalmological outcomes compared. Follow up examination was performed in every patient from the study group between 3 and 6 months after the delivery. RESULTS: Among 508 eyes, retinal lesions were revealed in 69 women (121 eyes) what constituted for 23.8%. In remaining 185 patients results of the opthalmological examination were normal. Average maternal age was higher in group affected with degenerative lesions (p<0.001). Myopia in women with retinal lesions ranged between -0.25 and -12 dioptries (D), while in 43 cases of degenerative lesions qualified for laser photocoagulation this value ranged between -0.5 and -12.0 D (p=ns). Postpartal follow-up examination did not reveal any abnormalities in this group, as well. CONCLUSION: Degenerative retinal lesions are present in one fourth of pregnant women. Both the severity and type of the lesions are not associated with severity of myopia. Among pregnant patients, retinal lesions occur in patients with more advanced maternal age. opthalmological examination remains an important prophylactic modality in retinal disorders, especially in primary retinal detachment due degenerative disorders.

Quantitative Assessment of Microstructural Changes of the Retina in Infants With Congenital Zika Syndrome.

Importance: A better pathophysiologic understanding of the neurodevelopmental abnormalities observed in neonates exposed in utero to Zika virus (ZIKV) is needed to develop treatments. The retina as an extension of the diencephalon accessible to in vivo microcopy with spectral-domain optical coherence tomography (SD-OCT) can provide an insight into the pathophysiology of congenital Zika syndrome (CZS). Objective: To quantify the microstructural changes of the retina in CZS and compare these changes with those of cobalamin C (cblC) deficiency, a disease with potential retinal maldevelopment. Design, Setting, and Participants: This case series included 8 infants with CZS and 8 individuals with cblC deficiency. All patients underwent ophthalmologic evaluation at 2 university teaching hospitals and SD-OCT imaging in at least 1 eye. Patients with cblC deficiency were homozygous or compound heterozygotes for mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Data were collected from January 1 to March 17, 2016, for patients with CZS and from May 4, 2015, to April 23, 2016, for patients with cblC deficiency. Main Outcomes and Measures: The SD-OCT cross-sections were segmented using automatic segmentation algorithms embedded in the SD-OCT systems. Each retinal layer thickness was measured at critical eccentricities using the position of the signal peaks and troughs on longitudinal reflectivity profiles. Results: Eight infants with CZS (5 girls and 3 boys; age range, 3-5 months) and 8 patients with cblC deficiency (3 girls and 5 boys; age range, 4 months to 15 years) were included in the analysis. All 8 patients with CZS had foveal abnormalities in the analyzed eyes (8 eyes), including discontinuities of the ellipsoid zone, thinning of the central retina with increased backscatter, and severe structural disorganization, with 3 eyes showing macular pseudocolobomas. Pericentral retina with normal lamination showed a thinned (<30% of normal thickness) ganglion cell layer (GCL) that colocalized in 7 of 8 eyes with a normal photoreceptor layer. The inner nuclear layer was normal or had borderline thinning. The central retinal degeneration was similar to that of cblC deficiency. Conclusions and Relevance: Congenital Zika syndrome showed a central retinal degeneration with severe GCL loss, borderline inner nuclear layer thinning, and less prominent photoreceptor loss. The findings provide the first, to date, in vivo evidence in humans for possible retinal maldevelopment with a predilection for retinal GCL loss in CZS, consistent with a murine model of the disease and suggestive of in utero depletion of this neuronal population as a consequence of Zika virus infection.

Quantitative Assessment of Retinal Degeneration in Birdshot Chorioretinopathy Using Optical Coherence Tomography.

BACKGROUND AND OBJECTIVE: Retinal degeneration in birdshot chorioretinopathy (BSCR) has been assessed qualitatively using spectral-domain optical coherence tomography (SD-OCT). The purpose of this study was to determine whether these changes could be quantified. PATIENTS AND METHODS: The charts of 22 eyes of 11 patients with BSCR and 22 eyes of 22 controls were reviewed. SD-OCT was used to determine the photoreceptor outer segment (PROS) volume and choroidal thickness. RESULTS: PROS volume in patients with BSCR was lower than in controls (P < .003). Furthermore, the PROS volume in BSCR patients with abnormalities on electroretinography (ERG) was lower than the PROS volume in BSCR patients with normal ERGs (P < .02). There was no correlation between PROS volume and choroidal thickness (r = 0.27; P = .22). CONCLUSION: SD-OCT can be used to quantitate retinal degeneration in BSCR. The retinal and choroidal degeneration in BSCR are not correlated, suggesting that the inflammatory pathophysiology affecting these two structures may be different.

In vivo assessment of thickness and reflectivity in a rat outer retinal degeneration model with ultrahigh resolution optical coherence tomography.

PURPOSE: To provide in vivo quantitative assessment of sodium iodate-induced retinal damage in a rat model of outer retinal degeneration using ultrahigh resolution optical coherence tomography (UHR-OCT). METHODS: Outer retinal degeneration was induced in four female Long Evans rats via tail vein injection of sodium iodate (40 mg/kg). Changes in the thickness and optical reflectivity of individual retinal layers were extracted using a semi-automatic segmentation algorithm and were assessed in vivo at 6 hours, days 1, 3, and 7, and up to 3 months post injection with UHR-OCT. Hematoxylin and eosin (H&E) histology was used to confirm the morphologic changes observed in the UHR-OCT images. RESULTS: UHR-OCT tomograms showed progressive structural damage in the rat retina over time, such as swelling, thinning, complete disintegration of individual retinal layers, and clustering of highly reflective cellular debris. Photoreceptor swelling was observed 6 hours after injection of sodium iodate, followed by progressive structural decomposition of the outer retina. At 3 months post injection, the outer retina was completely disintegrated, and the inner nuclear layer (INL) was in direct contact with the choroid. Changes in the reflectivity of individual retinal layers were observed over time and correlated well with the morphologic changes. CONCLUSIONS: UHR-OCT permits in vivo, noninvasive, longitudinal, quantitative assessment of the progressive changes in retinal morphology and optical reflectivity in a sodium iodate rodent model of outer retinal degeneration.

Longitudinal assessment of retinal structure and function reveals a rod-cone degeneration in a guinea pig model initially presented as night blind.

We have previously reported a naturally occurring retinopathy in a population of guinea pigs, where the affected animals presented a defect of the rod-mediated vision. The purpose of this study was to investigate if the mutants were affected with a stationary or degenerative retinopathy and to identify the cellular origin of this unique disorder. Electroretinogram (ERG) [postnatal day 1 (P1) to P450], light (LM) and electron microscopy (EM) [P5, P150, P450], and immunohistochemistry [P30, P150, P450] were evaluated from normal and mutant animals. Irrespective of age, the scotopic ERGs of mutants could only be evoked by bright flashes, and the resulting ERGs were of photopic waveform. Interestingly, the amplitude of the cone and the rod/cone a-waves was always of smaller amplitude in mutants, but this difference tended to decrease with age. In contrast, the b-waves were of larger amplitude than normal in photopic ERGs obtained prior to age 25 (days) and prior to age 10 for rod/cone ERGs. LM revealed, in mutants, an absence of the outer segment layer (OSL) with a reduction in the outer nuclear layer (ONL) thickness. EM disclosed the presence of cone outer segment (OS) while no rod OS could be evidenced. Immunohistochemistry revealed the presence of rhodopsin, both cone opsins as well as normal synaptophysin immunoreactivity. Finally, neither the retinal structure nor the function in the mutants achieved normal development. Results suggest that mutant animals are suffering from a degenerative retinal disorder that affects the structure and function of rods and cones.

Flicker assessment of rod and cone function in a model of retinal degeneration.

Critical flicker frequency (CFF) is the lowest frequency for which a flickering light is indistinguishable from a non-flickering light of the same mean luminance. CFF is related to light intensity, with cone photoreceptors capable of achieving higher CFF than rods. A contemporaneous measure of rod and cone function can facilitate characterization of a retinal degeneration. We used sinusoidal flicker ERG to obtain CFF values, over a wide range of light intensities, in RCS dystrophic (RCS-p(+)) and wild type rats. Recordings were made at PN23, PN44, and PN64. The CFF curve in control animals increased in proportion to the log of stimulus intensity, with a gentle slope over the lowest 4 log-unit intensity range. The slope of the CFF curve dramatically increased for higher intensities, indicating a rod-cone break. In the RCS rats the rod driven CFF was significantly lower in amplitude compared to normal rats at the earliest age tested (PN23). By PN64 the rod driven CFF was immeasurable in the RCS rats. The amplitude of the cone driven CFF approached normal values at PN23, but was greatly reduced by PN44. By PN64 the entire CFF function was greatly depressed and there was no longer a discernable rod-cone break. These CFF/ERG data show that RCS rats exhibit significant early degeneration of the rods, followed soon after by degeneration of the cones. Using this approach, rod and cone function can be independently accessed using flicker ERG by testing at a few select intensities.

Functional assessment of the regional distribution of disease in a cat model of hereditary retinal degeneration.

PURPOSE: To establish a method for the recording of multifocal electroretinograms (MF-ERGs) in animals under fundus control using a scanning-laser ophthalmoscope (SLO) and to analyze the spatial distribution of disease in a strain of Abyssinian cats with a recessively inherited rod-cone degeneration (ARCD). METHODS: Four normal and 12 Abyssinian cats at four different clinical stages of ARCD were examined with the RETIscan MF-ERG system using 61 hexagonal elements within a visual field of approximately 30 degrees radius. The stimulus pattern was generated by the green laser beam (515 nm) of a Heidelberg Engineering HRA SLO, whose power was reduced with a Schott long-pass filter allowing for simultaneous infrared fundus imaging. RESULTS: Topographical recordings could be obtained in all animals except one in stage 4. Amplitudes were minimal at the optic disc and had a slight maximum at the area centralis. Implicit times had a tendency to lower values in the central region, most pronounced in progressed stages of ARCD. The clinical stages of ARCD correlated with a successive generalized loss of amplitude and a rise in implicit time. Without a decrease in retinal illuminance, topographical landmarks like the optic disc were no longer detectable, pointing to stray light as a possible cause. CONCLUSIONS: It was demonstrated that topographical MF-ERG recordings can be obtained in an animal model under fundus control using SLO stimulation. The appearance of retinal landmarks was found to be dependent on sufficient attenuation of laser power. Because the changes in ARCD are more patchy than in human retinitis pigmentosa (RP), a generalized loss of function was detected. However, like in RP, the central area was found to retain a better function than the periphery, especially in later stages of the disease. In summary, fundus controlled methods like the one presented will greatly improve the reliability of MF-ERG in future research on glaucoma, transplantation studies, and evaluation of gene therapy.