Risk Factors for Meeting Criteria for Switching from Bevacizumab to Aflibercept When Treating Eyes with Diabetic Macular Edema and Visual Acuity of < 20/40.

PURPOSE: To identify factors for meeting prespecified criteria for switching from bevacizumab to aflibercept in eyes with center-involved diabetic macular edema (CI-DME) and moderate vision loss initially treated with bevacizumab in DRCR Retina Network protocol AC. DESIGN: Post hoc analysis of data from a randomized clinical trial. PARTICIPANTS: Two hundred seventy participants with one or both eyes harboring CI-DME with visual acuity (VA) letter score of 69 to 24 (Snellen equivalent, 20/50-20/320). METHODS: Eligible eyes were assigned to receive intravitreal aflibercept monotherapy (n = 158) or bevacizumab followed by aflibercept if prespecified criteria for switching were met between 12 weeks and 2 years (n = 154). MAIN OUTCOME MEASURES: Meeting switching criteria: (1) at any time, (2) at 12 weeks, and (3) after 12 weeks. Associations between meeting the criteria for switching and factors measured at baseline and 12 weeks were evaluated in univariable analyses. Stepwise procedures were used to select variables for multivariable models. RESULTS: In the group receiving bevacizumab first, older participants showed a higher risk of meeting the switching criteria at any time, with a hazard ratio (HR) for a 10-year increase in age of 1.32 (95% confidence interval [CI], 1.11-1.58). Male participants or eyes with worse baseline VA were more likely to switch at 12 weeks (for male vs. female: odds ratio [OR], 4.84 [95% CI, 1.32-17.81]; 5-letter lower baseline VA: OR, 1.30 [95% CI, 1.03-1.63]). Worse 12-week central subfield thickness (CST; 10-µm greater: HR, 1.06 [95% CI, 1.04-1.07]) was associated with increased risk of switching after 12 weeks. The mean ± standard deviation improvement in visual acuity after completing the switch to aflibercept was 3.7 ± 4.9 letters compared with the day of switching. CONCLUSIONS: The identified factors can be used to refine expectations regarding the likelihood that an eye will meet protocol criteria to switch to aflibercept when treatment is initiated with bevacizumab. Older patients are more likely to be switched. At 12 weeks, thicker CST was predictive of eyes most likely to be switched in the future. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The effect of ocular rinse volume on surface irritation after povidone-iodine preparation for intravitreal injections: a randomized controlled trial.

PURPOSE: To evaluate whether the volume of wash out rinse after povidone iodine (PI) application for intravitreal injections (IVI) affects patients' ocular surface irritation. METHODS: This was a prospective, single-masked, randomized-controlled trial consisting of 142 subjects. A total of 51, 45, and 46 patients received 3-mL, 10-mL, and 15-mL of ocular rinse respectively. Reductions in the Ocular Surface Disease Index (OSDI) and the Standardized Patient Evaluation of Eye Dryness II (SPEED II) surveys, conducted before and at 24-72 h post-injection, were analyzed. RESULTS: There was no statistical difference in objective dry eye findings of Schirmer test (p-value = 0.788), tear break-up time (p-value = 0.403), Oxford fluorescein grade (p-value = 0.424) between the study groups prior to injections. Dry eye symptoms as measured by reductions in the OSDI and SPEEDII scores were not different between the study groups (p-value = 0.0690 and 0.6227, respectively). CONCLUSION: There is no difference in patients' ocular surface irritation between 3-mL, 10-mL, and 15-mL post injection rinse. Given the large number of IVIs performed, modification of practice patterns based on these findings could lead to significant reduction in global cost burden for IVIs.

Utility of No-Charge Panel Genetic Testing for Inherited Retinal Diseases in a Real-World Clinical Setting.

Purpose: To show the utility of genetic testing in inherited retinal disease (IRD) patients. Methods: This retrospective cohort study was performed at a single academic center and comprised 59 patients clinically diagnosed with IRD who had testing via the Invitae IRD Panel (Invitae Corp). Samples were collected from August 2019 to April 2021. The rates of genetic diagnosis and disease-category specific results (ie, positive, undetermined, negative) were assessed. Results: Testing results were returned a mean of 20 days (range, 14-28 days) after submission. Of the samples, 50.8% (30/59) had a diagnostic yield. By disease category, the yield was 46.4% (13/28) nonsyndromic retinitis pigmentosa (RP), 50.0% (4/8) syndromic RP, 46.2% (6/13) macular dystrophies, 75.0% (3/4) cone or cone-rod dystrophies, and 80.0% (4/5) other retinopathies; there were no cases of rod dystrophies. The results were undetermined in 47.5% of patients (28/59) because of identification of only 1 recessive mutation (5.1%; 3/59), 1 recessive mutation and at least 1 variant of uncertain significance (VUS) (13.6%; 8/59), or VUS only (28.8%; 17/59). One patient (1.7%) received negative testing results with no mutations or VUS identified. Conclusions: Open-access, no-charge panel testing offers a reasonable diagnostic yield. Accurate clinical diagnosis of IRD before testing and acknowledgment of the limitations of panel testing are critical. The results add to the current estimates of the value of genetic testing for retina specialists in the management of IRD.

ASSESSMENT OF FLUORESCEIN ANGIOGRAPHY NONPERFUSION IN EYES WITH DIABETIC RETINOPATHY USING ULTRAWIDE FIELD RETINAL IMAGING.

PURPOSE: Evaluate association of retinal nonperfusion (NP) on ultrawide field (UWF) fluorescein angiography (FA) with diabetic retinopathy (DR) severity and predominantly peripheral lesions (PPL). METHODS: Multicenter observational study, 652 eyes (361 participants) having nonproliferative DR (NPDR) without center-involved diabetic macular edema in at least one eye. Baseline 200° UWF-color and UWF-FA images were graded by a central reading center for color-PPL and FA-PPL, respectively. UWF-FA was graded for NP index within concentric zones: posterior pole (<10 mm from fovea), midperiphery (10-15 mm), and far periphery (>15 mm). RESULTS: Baseline Early Treatment Diabetic Retinopathy Study DR severity was 31.7% no DR/mild NPDR, 24.1% moderate NPDR, 14.0% moderately severe NPDR, 25.6% severe/very severe NPDR, and 4.6% proliferative DR. Worse DR severity was associated with increased NP index overall (P = 0.002), in the posterior pole (P < 0.001), midperiphery (P < 0.001), and far periphery (P = 0.03). On average, 29.6% of imaged retinal NP was in the posterior pole, 33.7% in midperiphery, and 36.7% in far periphery. Increased NP index was associated with FA-PPL (P < 0.001) but not with color-PPL (P = 0.65). CONCLUSION: Approximately, 70% of NP in diabetic eyes is located outside the posterior pole. Increased NP is associated with the presence of FA-PPL, suggesting UWF-FA may better predict future DR worsening than UWF-color alone.

The effect of punctal plugs in reducing ocular surface irritation after povidone-iodine preparation of intravitreal injection-a randomized trial.

PURPOSE: To evaluate the utility of dissolvable collagen punctal plugs (CPP) in reducing ocular surface irritation after intravitreal injections (IVI). METHODS: Sixty-four subjects in the experimental group received CPP after intravitreal injections. Sixty-two controls did not receive CPP. Reductions in the Ocular Surface Disease Index© (OSDI) and Standardized Patient Evaluation of Eye Dryness II (SPEED II) scores were analysed. RESULTS: Dry eye symptoms, as measured by reductions from the pre- to post-injection OSDI (p = 0.137) and SPEED II (p = 0.381) scores, did not significantly differ between the two groups. In sub-group analysis, patients with objective findings of dry eyes had significant improvement in their symptoms (p = 0.046) with CPP. The effect of CPP is not significant in those without dry eyes (p = 0.27). CONCLUSION: CPPs were not effective in reducing post-injection ocular irritation in patients with no or only mild dry eye symptoms. CPPs improved patients' post-injection comfort levels in those who had moderate-to-severe symptoms and objective findings of dry eye. Though costly CPP could be considered in selective patients. A standardized eye rinse could be a simple, efficacious, and cost-effective way to reduce post-injection ocular irritation; however, more studies are needed.

Genetic Diagnosis for 64 Patients with Inherited Retinal Disease.

The overlapping genetic and clinical spectrum in inherited retinal degeneration (IRD) creates challenges for accurate diagnoses. The goal of this work was to determine the genetic diagnosis and clinical features for patients diagnosed with an IRD. After signing informed consent, peripheral blood or saliva was collected from 64 patients diagnosed with an IRD. Genetic testing was performed on each patient in a Clinical Laboratory Improvement Amendments of 1988 (CLIA) certified laboratory. Mutations were verified with Sanger sequencing and segregation analysis when possible. Visual acuity was measured with a traditional Snellen chart and converted to a logarithm of minimal angle of resolution (logMAR). Fundus images of dilated eyes were acquired with the Optos® camera (Dunfermline, UK). Horizontal line scans were obtained with spectral-domain optical coherence tomography (SDOCT; Spectralis, Heidelberg, Germany). Genetic testing combined with segregation analysis resolved molecular and clinical diagnoses for 75% of patients. Ten novel mutations were found and unique genotype phenotype associations were made for the genes RP2 and CEP83. Collective knowledge is thereby expanded of the genetic basis and phenotypic correlation in IRD.

Variable expressivity in patients with autosomal recessive retinitis pigmentosa associated with the gene CNGB1.

PURPOSE: In a cohort of eight families (11 patients) with autosomal recessive retinitis pigmentosa (arRP), we clinically characterized disease associated with mutations in CNGB1. METHODS: Visual function was determined by measuring the patients' visual acuity, dark- and light-adapted perimetry, and by full-field electroretinography. Retinal structure was evaluated with spectral-domain optical coherence tomography, fundus imaging, and autofluorescence imaging. RESULTS: Age of onset ranged from 4 to 49 years (mean [SD] 26 [17], median 27 years). The age at visit was 27-54 years, mean 37 (17). The range of visual acuity was logMAR -0.1 to 1.3 (Snellen 20/16 to 20/400) in the right eye and -0.1 to 0.9 (Snellen 20/16 to 20/160) in the left eye. Electrophysiological testing in five patients showed an absence of the rod response. Cone responses ranged from normal to severely reduced. The patients exhibited loss of rod vision more severe than cone vision. Funduscopic images showed widespread retinal degeneration with pigment clumping, optic disk pallor, arteriole attenuation, and a peri-foveal ring of hyper autofluorescence. Three families were tested for olfactory dysfunction and results indicated mild to complete anosmia in individuals with mutations in CNGB1. Genetic analysis revealed 6 novel variants, c.2127 C > G, p.Phe709Leu; c.1431 C > A, p.Cys477*; c.2034 G > A, p.Trp678*; c.2092 T > C, p.Cys698Arg; and c.583 + 2 T > C, c.2305-34 G > A and 3 variants that have been previously described, c.2957A>T, p.Asn986Ile; c.2544dup, p.Leu849Alafs*3; and c.2492 + 1 G > A. DISCUSSION: This is the first report for six novel CNGB1 variants associated with arRP. Two families had olfactory dysfunction in patients with arRP and family members who were heterozygous for a CNGB1 mutation. Additionally, findings demonstrated variable penetrance and expressivity of disease in these patients.

Prevalence and risks factors of age-related macular degeneration in Oklahoma Indians: the Vision Keepers Study.

OBJECTIVE: To determine the prevalence of age-related macular degeneration (AMD) and to identify its risk factors in an Oklahoma Indian population. DESIGN: Cross-sectional study design. PARTICIPANTS: Included 1019 Oklahoma Indians who participated in baseline and second examinations of the Strong Heart Study. METHODS: Retinal photographs of at least 1 eye were obtained and graded for AMD by the University of Wisconsin Ocular Epidemiology Reading Center. Retinal photographs of 986 participants were considered gradable and were included in the study. MAIN OUTCOME MEASURES: Age-related macular degeneration (early and late). RESULTS: The overall prevalence of AMD in the study was 35.2%, including a prevalence of 0.81% for late AMD. The prevalence of early AMD increased from 30.6% in those aged 48 to 59 years to 46.1% in those 70 to 82 years of age. When potential risk factors were analyzed individually (univariate analyses), men with hypertension had a significantly higher prevalence of AMD (P = 0.02) than those without hypertension. In women, high-density lipoprotein cholesterol and sun exposure were associated positively with the prevalence of AMD (P = 0.01), whereas a history of using multivitamins was associated with lower AMD prevalence (P = 0.005). When multiple risk factors were analyzed simultaneously using logistic regression, only age showed significant association with AMD in both men (P = 0.02) and women (P<0.0001) and was the only significant risk factor in men. In women, multivitamin use and total cholesterol had a significant inverse association with AMD, whereas sun exposure and high-density lipoprotein cholesterol had a positive association. When men and women were combined, age and high-density lipoprotein cholesterol had significant positive associations, whereas total cholesterol, multivitamin use, and current alcohol use showed a significant inverse association with AMD. CONCLUSIONS: This study was the first to report a detailed prevalence of AMD in Oklahoma Indians and its risk factors. The prevalence seemed to be relatively high compared with that in other ethnic groups. Some of the modifiable risk factors identified confirmed previous findings and can be used to design preventive programs to reduce the burden of AMD, although longitudinal data are still needed.

Biochemical alterations in the retinas of very low-density lipoprotein receptor knockout mice: an animal model of retinal angiomatous proliferation.

OBJECTIVE: To identify and characterize biochemical alterations in the retinas of very low-density lipoprotein receptor (VLDLr) knockout mice in an animal model of retinal angiomatous proliferation. METHODS: Immunohistochemical analysis, Western blot analysis, reverse transcriptase-polymerase chain reaction, and electrophoretic mobility shift assay were used to identify and characterize the altered gene and protein expression as well as signal cascades involved in the pathogenesis of neovascularization in the retinas of VLDLr mice. RESULTS: Expression of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor was significantly greater in the lesion area, and Müller cells around the lesion area were activated, as indicated by increased expression of glial fibrillary acidic protein. Expression of the proinflammatory cytokine IL-18 (interleukin 18) and the inflammation mediator intercellular adhesion molecule-1 was increased before significant intraretinal neovascularization. Furthermore, phosphorylation of Akt and mitogen-activated protein kinase and translocalization of nuclear factor kappa B were greater in VLDLr knockout mouse retinas. CONCLUSION: An inflammatory process is involved in the development of neovascularization in the VLDLr knockout mouse retina. CLINICAL RELEVANCE: Understanding the molecular mechanisms underlying these biochemical alterations in the retinas of VLDLr knockout mice will provide a foundation for developing novel therapeutic approaches to retinal angiomatous proliferation.

Visual impairment and eye abnormalities in Oklahoma Indians.

OBJECTIVE: To determine the prevalence of visual impairment and eye abnormalities in Oklahoma Indians. METHODS: The cross-sectional study included 1019 Oklahoma Indians, aged 48 to 82 years; 60.2% were women. All participants gave a personal interview, and all underwent an eye examination, including the determination of best-corrected visual acuity and an ophthalmoscopic examination. In addition, two 45 degrees fundus photographs were taken of each eye, and these photographs were graded by the Fundus Photography Reading Center at the University of Wisconsin, Madison. RESULTS: Among the 1019 participants, 77.4% had a visual acuity of 20/20 or better, 19.5% and 2.5% had visual acuities of between 20/25 and 20/40 and between 20/50 and 20/190, respectively; and 0.6% were legally blind, all in the better eye. Cataract was the most frequent contributing cause and age-related macular degeneration the second most frequent contributing cause of visual impairment. The overall prevalence proportions of age-related macular degeneration, cataract, diabetic retinopathy, and definite glaucoma were 33.6%, 39.6%, 20.1%, and 5.6%, respectively. Most of the other eye abnormalities were rare in the study participants, except for pinguecula (42.4%) and dermatochalasis (30.1%). CONCLUSIONS: Oklahoma Indians have a higher prevalence of visual impairment, age-related macular degeneration, and diabetic retinopathy than other ethnic groups. The implementation of adequate treatment and prevention programs for eye diseases is indicated.

Computer classification of nonproliferative diabetic retinopathy.

OBJECTIVE: To propose methods for computer grading of the severity of 3 early lesions, namely, hemorrhages and microaneurysms, hard exudates, and cotton-wool spots, and classification of nonproliferative diabetic retinopathy (NPDR) based on these 3 types of lesions. METHODS: Using a computer diagnostic system developed earlier, the number of each of the 3 early lesions and the size of each lesion in the standard photographs were determined. Computer classification criteria were developed for the levels of individual lesions and for NPDR. Evaluation of the criteria was performed using 430 fundus images with normal retinas or any degree of retinopathy and 361 fundus images with no retinopathy or the 3 early lesions only. The results were compared with those of the graders at the University of Wisconsin Ocular Epidemiology Reading Center and an ophthalmologist. MAIN OUTCOME MEASURES: Agreement rates in the classification of NPDR between the computer system and human experts. RESULTS: In determining the severity levels of individual lesions, the agreement rates between the computer system and the reading center were 82.6%, 82.6%, and 88.3% using the 430 images and 85.3%, 87.5%, and 93.1% using the 361 images, respectively, for hemorrhages and microaneurysms, hard exudates, and cotton-wool spots. When the "questionable" category was excluded, the corresponding agreement rates were 86.5%, 92.3%, and 91.0% using the 430 images and 89.7%, 96.3%, and 97.4% using the 361 images. In classifying NPDR, the agreement rates between the computer system and the ophthalmologist were 81.7% using the 430 images and 83.5% using the 361 images. CONCLUSIONS: The proposed criteria for computer classification produced results that are comparable with those provided by human experts. With additional research, this computer system could become a useful clinical aid to physicians and a tool for screening, diagnosing, and classifying NPDR.

Novel mutation in the TIMP3 gene causes Sorsby fundus dystrophy.

OBJECTIVE: To determine the molecular basis of a retinopathy previously described as dominant macular subretinal neovascularization with peripheral retinal degeneration. METHODS: The TIMP3 gene was analyzed in family members, and 4 mutation-positive patients were studied using psychophysics and electroretinography. RESULTS: Cosegregating with disease in the family was a single base pair change in the TIMP3 gene, altering a conserved tyrosine to cysteine at amino acid position 172 (Y172C). There was psychophysical and electroretinographic evidence of rod dysfunction greater than cone dysfunction. Dark adaptometry showed abnormalities with regional retinal variation in degree. CONCLUSIONS: The Y172C mutation in the TIMP3 gene is another cause of Sorsby fundus dystrophy. The expression of this form of the disease, as in other C-terminal TIMP3 mutations, is speculated to be secondary to mutant TIMP-3, causing a decreased turnover of the extracellular matrix. CLINICAL RELEVANCE: The molecular clarification of inherited retinal degeneration involving abnormal extracellular matrix turnover in and around Bruch's membrane should provide clues to the pathogenesis of not only these particular diseases but also forms of age-related macular degeneration.