SGLT2 inhibitors and diabetic retinopathy progression.

PURPOSE: To evaluate whether sodium-glucose co-transporter 2 (SGLT2) inhibitors affect progression of non-proliferative diabetic retinopathy (NPDR) compared to standard of care. METHODS: A retrospective cohort study compared subjects enrolled in a commercial and Medicare Advantage medical claims database who filled a prescription for a SGLT2 inhibitor between 2013 and 2020 to unexposed controls, matched up to a 1:3 ratio. Patients were excluded if they were enrolled for less than 2 years in the plan, had no prior ophthalmologic exam, had no diagnosis of NPDR, had a diagnosis of diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR), had received treatment for vision-threatening diabetic retinopathy (VTDR), or were younger than 18 years. To balance covariates of interest between the cohorts, an inverse probability treatment weighting (IPTW) propensity score for SGLT2 inhibitor exposure was used. Multivariate Cox proportional hazard regression modeling was employed to assess the hazard ratio (HR) for VTDR, PDR, or DME relative to SGLT2 exposure. RESULTS: A total of 6065 patients who initiated an SGLT2 inhibitor were matched to 12,890 controls. There were 734 (12%), 657 (10.8%), and 72 (1.18%) cases of VTDR, DME, and PDR, respectively, in the SGLT2 inhibitor cohort. Conversely, there were 1479 (11.4%), 1331 (10.3%), and 128 (0.99%) cases of VTDR, DME, and PDR, respectively, among controls. After IPTW, Cox regression analysis showed no difference in hazard for VTDR, PDR, or DME in the SGLT2 inhibitor-exposed cohort relative to the unexposed group [HR = 1.04, 95% CI 0.94 to 1.15 for VTDR; HR = 1.03, 95% CI 0.93 to 1.14 for DME; HR = 1.22, 95% CI 0.89 to 1.67 for PDR]. CONCLUSION: Exposure to SGLT2 inhibitor therapy was not associated with progression of NPDR compared to patients receiving other diabetic therapies.

Optimization and Validation of a Virtual Reality Orientation and Mobility Test for Inherited Retinal Degenerations.

Purpose: To optimize a virtual reality (VR) orientation and mobility (O&M) test of functional vision in patients with inherited retinal degenerations (IRDs). Methods: We developed an O&M test using commercially available VR hardware and custom-generated software. Normally sighted subjects (n = 20, ages = 14-67 years) and patients with IRDs (n = 29, ages = 15-63 years) participated. Individuals followed a dim red arrow path to a "course exit," while trying to identify nine obstacles adjacent to, or directly in their path. Dark-adapted subjects completed 35 randomly selected VR courses at increasing luminances, twice per luminance step, binocularly, and uni-ocularly. Performance was graded automatically by the software. Patients with IRD completed a modified Visual Function Questionnaire (VFQ). Results: Normally sighted subjects identified approximately 50% of the obstacles at the dimmest course luminance. Except for two patients with IRD with poor vision, all patients were able to complete the test, although they required brighter (by >2 log units) luminances to identify 50% of the obstacles. In a single-luminance screening test in which normal subjects detected at least eight of nine objects, most patients with IRD underperformed; their performance related to disease severity, as measured by visual acuity, kinetic visual field extent, and VFQ scores. Test-retest differences in object detection were similar to the differences between the two eyes (±2 SD = ±2 objects). Conclusions: This VR-O&M test was able to distinguish subjects with IRDs from normal subjects reliably and reproducibly. Translational Relevance: This easily implemented, flexible, and objectively scored VR-O&M test promises to become a useful tool to assess the impact that IRDs and their treatments have on functional vision.

Systemic disease associations with angioid streaks in a large healthcare claims database.

BACKGROUND/OBJECTIVES: To assess systemic associations of angioid streaks (AS) using a large US healthcare database. SUBJECTS/METHODS: A retrospective cross-sectional study was conducted of patients diagnosed with AS in a large, national US insurer from 2000-2019. Cases were matched 1:5 to controls. The prevalence rates of established associated disease states and other systemic diseases were calculated and compared using logistic regression. Additionally, the rate of anti-VEGF treatment was assessed as a proxy for the incidence of choroidal neovascularization (CNV). RESULTS: One thousand eight hundred fifty-two cases of AS and 9028 matched controls were included. The rates of association between AS and the well-characterized conditions included: Pseudoxanthoma elasticum (PXE)-228 patients (12.3%), Ehlers-Danlos syndrome-18 patients (1.0%), Paget's disease-6 patients (0.3%), hemoglobinopathies-30 patients (1.6%), and idiopathic-1573 patients (84.9%). There was a statistically higher prevalence of the following less classically associated diseases among patients with AS compared to controls: hereditary spherocytosis (1.7% vs. 0.6%, p < 0.001), connective tissue disease (1.0% vs 0.3%, p < 0.001) and non-exudative age-related macular degeneration (33.9% vs 10.6%, p < 0.001). Among 1442 eligible cases analyzed, 427 (29.6%) received at least 1 anti-VEGF injection with 338 (23.4%) patients having the injection after their AS diagnosis. CONCLUSIONS: In the largest collection of AS patients to date, the classical teaching of systemic disease associations occur at rates far, far lower than previously reported. The association of AS with other less reported diseases highlights new potential associations and may contribute to the understanding of AS formation.

Effect of Autologous Platelet-Rich Plasma Drops in the Treatment of Ocular Surface Disease.

Purpose: Platelet rich plasma (PRP) is an autologous preparation that concentrates platelets in a small volume of plasma. The purpose of this study was to determine if PRP eye drops improved the symptoms and signs of ocular surface disease. Patients and Methods: A retrospective case series was conducted of patients who were prescribed PRP eye drops. Subjects were excluded if they did not have follow-up, underwent intraocular surgery prior to follow-up, received nerve growth factor treatments, or did not have a baseline examination with photography. Symptoms were assessed using the Ocular Surface Disease Index (OSDI). Patients also underwent a slit lamp exam, ocular surface staining with fluorescein and lissamine green, and Schirmer testing. Results: The charts of 47 patients treated with PRP drops for ocular surface disease were reviewed. Sixty-four eyes of 32 patients were included in the study who had photographs of lissamine green staining taken at baseline and at follow-up. Thirteen patients (28%) had ocular graft-versus-host disease, 16 patients (34%) had Sjögren's syndrome, and 4 patients (8.5%) had rheumatoid arthritis. There was a statistically significant decrease in OSDI score from baseline to follow-up (39.5 vs 30.8 points, p = 0.02). Among the 64 eyes included, 9 (14%) had an improvement in conjunctival lissamine green staining, while 6 (9%) had an increase in staining at follow-up. Among the 20 eyes with Schirmer testing, there was a borderline significant increase in score from baseline to follow-up (5.9 vs 9.7, p = 0.06). Among the 44 eyes that had corneal fluorescein staining (CFS) reported, 8 (18.2%) had decreased staining and 2 (4.5%) had increased staining at follow-up. Conclusion: Treatment with PRP drops was associated with a significant improvement in symptoms in patients with ocular surface disease. Future larger prospective studies are needed to further evaluate the efficacy of PRP drops for treating ocular surface disease.

Evaluation of intravitreal topotecan dose levels, toxicity and efficacy for retinoblastoma vitreous seeds: a preclinical and clinical study.

BACKGROUND: Current melphalan-based intravitreal regimens for retinoblastoma (RB) vitreous seeds cause retinal toxicity. We assessed the efficacy and toxicity of topotecan monotherapy compared with melphalan in our rabbit model and patient cohort. METHODS: Rabbit experiments: empiric pharmacokinetics were determined following topotecan injection. For topotecan (15 µg or 30 µg), melphalan (12.5 µg) or saline, toxicity was evaluated by serial electroretinography (ERG) and histopathology, and efficacy against vitreous seed xenografts was measured by tumour cell reduction and apoptosis induction. PATIENTS: retrospective cohort study of 235 patients receiving 990 intravitreal injections of topotecan or melphalan. RESULTS: Intravitreal topotecan 30 µg (equals 60 µg in humans) achieved the IC90 across the rabbit vitreous. Three weekly topotecan injections (either 15 µg or 30 µg) caused no retinal toxicity in rabbits, whereas melphalan 12.5 µg (equals 25 µg in humans) reduced ERG amplitudes 42%-79%. Intravitreal topotecan 15 µg was equally effective to melphalan to treat WERI-Rb1 cell xenografts in rabbits (96% reduction for topotecan vs saline (p=0.004), 88% reduction for melphalan vs saline (p=0.004), topotecan vs melphalan, p=0.15). In our clinical study, patients received 881 monotherapy injections (48 topotecan, 833 melphalan). Patients receiving 20 µg or 30 µg topotecan demonstrated no significant ERG reductions; melphalan caused ERG reductions of 7.6 µV for every injection of 25 µg (p=0.03) or 30 µg (p<0.001). Most patients treated with intravitreal topotecan also received intravitreal melphalan at some point during their treatment course. Among those eyes treated exclusively with topotecan monotherapy, all eyes were salvaged. CONCLUSIONS: Taken together, these experiments suggest that intravitreal topotecan monotherapy for the treatment of RB vitreous seeds is non-toxic and effective.

Compound Heterozygous Mutations in ZNF408 in a Patient with a Late Onset Pigmentary Retinopathy and Relatively Preserved Central Retina.

PURPOSE: To describe in detail the phenotype of a patient with compound heterozygous mutations in ZNF408 and an adult-onset pigmentary retinopathy rather than familial exudative vitreoretinopathy as expected with heterozygous mutations in this gene. METHODS: A 70-year-old male presented with a pigmentary retinopathy, which prompted a genetic evaluation that revealed two variants in trans in the ZNF408 gene. He underwent an ophthalmic examination, kinetic fields, electroretinography (ERG), spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence, wide-angle fluorescein angiography and near-infrared imaging. RESULTS: Visual acuity was 20/20 for both eyes. Fundus examination showed epiretinal membrane, vascular attenuation and peripheral bone spicule pigmentation in both eyes. Fluorescein angiography showed no vascular anomalies in both eyes. Fundus autofluorescence showed a preserved island of fundus autofluorescence centrally. Visual field by kinetic perimetry (V-4e stimulus) showed generalized constriction to 40 degrees of eccentricity and by an I-4e target showed generalized constriction to 10 degrees of eccentricity. ERG showed detectable but reduced cone-mediated responses. SD-OCT demonstrated preserved outer nuclear layer thickness centrally, which decreased with eccentricity. Static perimetry showed substantial rod and cone sensitivities centrally that declined with eccentricity. A next-generation sequencing panel revealed bi-allelic variants (p.Arg567Ter; c.1699C > T and p.Leu566His; c.1697 T > A) in the ZNF408 gene. CONCLUSIONS: ZNF408-associated retinal dystrophies can present with predominantly retinal findings and should be considered in the differential diagnosis of retinitis pigmentosa. Our study revealed a novel variant p.L566H, which to our knowledge has not previously been reported.

ROLE OF OPTICAL COHERENCE TOMOGRAPHY FOR PREDICTING POSTOPERATIVE VISUAL OUTCOMES AFTER REPAIR OF MACULA-OFF RHEGMATOGENOUS RETINAL DETACHMENT.

PURPOSE: To identify any prognostic associations between preoperative optical coherence tomography findings and postoperative visual outcomes in patients with macula-off rhegmatogenous retinal detachment. METHODS: A retrospective, single-center study of patients diagnosed with macula-off rhegmatogenous retinal detachment whom underwent surgical reattachment from 2012 to 2017. Optical coherence tomography images were analyzed by two retina surgeons. Outcome measures included "good" final vision (best-corrected visual acuity of 20/40 or better), "poor" final vision (best-corrected visual acuity of 20/200 or worse), and change in vision (worsened, improved, and improved ≥15 letters) at most recent follow-up. P values were calculated using t tests, analysis of variance, Wilcoxon rank-sum, or Kruskall-Wallis test. RESULTS: A total of 49 eyes were included. There was a significant difference in the mean preoperative central retinal thickness between patients who had good final vision and patients who did not (96 µm vs. 161 µm, P = 0.048). In addition, a worse preoperative best-corrected visual acuity and greater subretinal fluid height were associated with vision improvement (P < 0.001). Those with persistent ellipsoid zone disruption postoperatively were less likely to have good final vision (odds ratio = 0.217, 95% confidence interval: 0.057-0.828). CONCLUSION: A lower mean preoperative central retinal thickness is associated with good visual prognosis. Eyes with ellipsoid zone disruption postoperatively were less likely to have good final vision. Future studies should include a larger cohort of patients and more optical coherence tomography variables to address the inconsistencies in the current literature.

Is intravitreal topotecan toxic to retinal function?

BACKGROUND: Intravitreal injections of topotecan are used in the management of retinoblastoma with vitreous seeds. This study evaluated whether intravitreal topotecan was associated with retinal toxicity. METHODS: Retrospective cohort study of patients with retinoblastoma who were treated with intravitreal topotecan at Memorial Sloan Kettering Cancer Center between December 2014 and May 2019. Electroretinogram (ERG) responses under anaesthesia were measured immediately before treatment with intravitreal topotecan and at the next visitor approximately one-month. Ocular toxicity was defined by a decrease in the ERG response at 30 Hz at follow-up. RESULTS: Ocular toxicity was evaluated by ERG on 50 evaluable injections administered to 28 eyes. 22 (44.0%) injections were performed with concurrent intravitreal melphalan. The median time to ERG measurement following an injection was 27 days. By using a paired t-test, intravitreal topotecan combined with melphalan (n=22) at a dose of 25 µg or 30 µg was associated with a significant decrease in ERG amplitude at follow-up (p=0.046, 95% CI -20.4 µV to -0.2 µV). Among eyes that only received topotecan (n=28) at doses of 20 µg or 30 µg, there was not a significant difference in ERG amplitude measured (p=0.85, 95% CI -7.0 µV to 5.8 µV). CONCLUSION: Intravitreal topotecan combined with intravitreal melphalan was associated with a decrease in ERG amplitude; there was not a significant decrease in ERG amplitude observed in patients who received topotecan alone. These findings suggest that intravitreal topotecan injections at doses of 20 µg or 30 µg are not associated with retinal toxicity in patients with retinoblastoma.

Association of Retinal Vascular Occlusion With Women Filling a Prescription for Female Hormone Therapy.

Importance: Oral contraceptives have been associated with cardiovascular disease, ischemic stroke, venous thromboembolic disease, and breast cancer. Retinal vascular occlusions share the same risk factors as cardiovascular and cerebrovascular disease. Objective: To determine whether filling a prescription of female hormone therapy (FHT) is associated with an increased risk of retinal artery occlusion (RAO) or retinal vein occlusions (RVO). Design, Setting, and Participants: A multiple-cohort study was conducted using an administrative claims insurance database comparing women who filled a prescription for FHT with matched control individuals. Exclusion occurred for those enrolled for less than 2 years in the plan, with no prior ophthalmologic examination, with a history of a RAO/RVO, with systemic diseases/medications that affected estrogen levels, or a disease associated with an increased risk for thromboembolism. Main Outcomes and Measures: The primary outcome was the incidence of a new diagnosis of RAO or RVO. Cox proportional hazard regression modeling with inverse probability of treatment weight was used to assess the hazard ratio (HR) for a new diagnosis of RAO or RVO relative to filling prescription for FHT. Subanalyses were conducted to stratify by age, race/ethnicity, diabetes, and hypertension. Results: A total of 205 304 women who filled a prescription for FHT were matched to 755 462 control individuals. After inverse probability of treatment weight, the study cohort was a mean age of 47.2 years, 71% were White, 7% were Black, 6% were Hispanic, 3% were Asian, and 3% were unknown. There were 41 cases (0.01%) of RAO and 68 cases of RVO (0.02%) in the FHT cohort. In comparison, there were 373 cases of RAO (0.05%) and 617 cases of RVO (0.08%) in the control cohort. After inverse probability of treatment weight, Cox regression analysis showed no difference in hazard for RAO, RVO, or combined outcomes in the FHT cohort relative to the control cohort (RAO HR, 1.17; 95% CI, 0.83-1.65; P = .36; RVO HR, 1.07; 95% CI, 0.82-1.39; P = .65; combined HR, 1.10; 95% CI, 0.89-1.36; P = .37). Subanalyses that stratified by age, diabetes, and hypertension similarly showed no significant associations between the FHT prescription cohort and all outcomes. Conclusions and Relevance: These findings suggest that filling a prescription for FHT, and presumably taking FHT, does not increase the risk of RAO or RVO. Such history may not be relevant in the evaluation of an individual with an RAO or RVO nor do our results support stopping FHT in an individual who develops an RAO or RVO.

Ultra-Widefield Autofluorescence Imaging of Retinal Detachment Compared to Retinoschisis.

BACKGROUND AND OBJECTIVE: Localized retinal detachment can appear similar to peripheral retinoschisis (RS) based on clinical exam alone. This study utilized ultra-widefield autofluorescence (UAF) to characterize retinal changes in patients with rhegmatogenous retinal detachment (RRD) compared to RS and to help differentiate these two entities in the era of multimodal imaging. PATIENTS AND METHODS: A retrospective review of 282 eyes undergoing diagnostic UAF. Eyes were excluded if the quality of the color photograph or UAF prevented reliable evaluation, or if they contained significant peripheral retinal pathology such as diabetic retinopathy or retinal vein occlusions. Eyes were determined to have RRD or RS based on dilated fundus examination, ultrasound, and optical coherence tomography imaging consistent with the diagnosis. RESULTS: Fifty-three eyes were included; 38 had retinal detachment, and 25 had RS. Eyes were determined to be bullous or not from the color photographs. Based on all UAFs reviewed, images were determined to have granular, normal, hypo-, hyper-, or mixed autofluorescence patterns. The posterior border of the RRD and RS was evaluated separately and determined to have hyper-, hypo-, granular, mixed, or normal autofluorescence. Thirty-three eyes with RRD (86.8%) appeared bullous compared to 12 eyes with RS (48%; P = .002). UAF was considered granular in zero (0%) of RRD eyes and one (4%) RS eye, normal in one RRD eye (2.63%) and 17 (68%) RS eyes, hypoautofluorescent in 27 (71.1%) RRD eyes and four (16%) RS eyes, hyperautofluorescent in one (2.63%) RRD eye and one (4%) RS eye, and mixed in nine (4%) RRD eyes and two (8%) RS eyes (P < .001). When evaluating the posterior leading edge on UAF, 84.2% (n = 32) of patients with RRD had a hyperautofluorescent leading edge compared to 25% (n = 6) of patients with RS (P < .001). UAF was homogenous in 65.8% (n = 25) of cases of RRD versus in 92% (n = 23) of cases of RS (P = .037). CONCLUSIONS: To the authors' knowledge, this is the first study to utilize UAF imaging to differentiate RRD and RS. Findings suggest there are differences between RRD and RS with regards to UAF, UAF of the posterior border, and homogeneity of the area affected. UAF should be considered in the era of multimodal imaging, particularly when clinical exam alone is inadequate to differentiate these two entities. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:550-556.].

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY FINDINGS IN MACULA-INVOLVING CYTOMEGALOVIRUS RETINITIS.

PURPOSE: To evaluate the microstructural features of cytomegalovirus (CMV) retinitis by spectral domain optical coherence tomography (OCT). METHODS: Subjects were patients with macula-involving CMV retinitis with OCT imaging. The leading edge of retinitis in the macula was identified based on fundus imaging, and OCT findings were longitudinally evaluated in three areas: within the area of active retinitis, at the leading edge of retinitis, and just beyond the leading edge of retinitis. RESULTS: Optical coherence tomography imaging of macular CMV retinitis identified vitreous cells in 10 eyes (100%), posterior vitreous detachment in four eyes (40%), broad-based vitreomacular traction in one eye (10%), epiretinal membrane in eight eyes (80%), and lamellar hole-associated epiretinal proliferation associated with an atrophic hole in one eye (10%). Retinal architectural disruption, disruption of inner retinal layers, disruption of the external limiting membrane, and ellipsoid zone abnormalities were noted within the area of retinitis in all eyes and decreased in frequency and severity at and beyond the leading edge of retinitis, although all 10 eyes (100%) exhibited one of these abnormalities, especially outer retinal microabnormalities, beyond the leading edge of retinitis. CONCLUSION: Microstructural abnormalities were frequently noted on OCT of CMV retinitis, including within the retina beyond the leading edge of retinitis identified by corresponding fundus imaging. Outer retinal abnormalities were noted more frequently than inner retinal abnormalities beyond the leading edge of retinitis. These findings provide insight into the effects of CMV retinitis on retinal microstructure and potentially on vision and highlight the potential utility of OCT for monitoring microprogression of macula-involving CMV retinitis.

Cortical ß-amyloid burden, gray matter, and memory in adults at varying APOE ε4 risk for Alzheimer's disease.

Models of preclinical Alzheimer's disease (AD) propose that cerebral amyloidosis leads to neurodegeneration and subsequent cognitive decline. This study investigated whether APOE genotype is related to ß-amyloid (Aß) burden in brain regions preferentially affected by AD and whether Aß burden is associated with gray-matter (GM) fraction (as a marker of neurodegeneration) and episodic memory performance in cognitively normal middle-aged individuals at varying genetic risk for AD. Three groups of cognitively normal participants aged 50-65 years with a first-degree family history of AD (APOE genotype ε4ε4 [n = 15], ε3ε4 [n = 15], and ε3ε3 [n = 15]) underwent [11C]PiB positron emission tomography scans to quantify cortical Aß, brain magnetic resonance imaging, and neuropsychological testing. APOE ε4ε4 participants demonstrated significantly higher cortical Aß burden than APOE ε3ε3 (p < 0.001). Furthermore, cortical Aß burden was inversely associated with cortical GM fraction (p = 0.017) but not episodic memory performance. In cognitively normal, middle-aged individuals, Aß burden is significantly associated with GM fraction but not episodic memory performance. These findings are consistent with models of preclinical AD in which neurodegeneration occurs before manifest cognitive decline.