Diabetic Eye Disease

Diabetic Eye Disease Publications

Lin LY, Lee NG, Yoon MK, Stagner AM. Clear Cell Syringoma of the Eyelids, a Distinctive Histopathologic Variant Associated with Diabetes Mellitus. Ophthalmic Plast Reconstr Surg 2022;Abstract
The authors describe the clinical and histologic findings of the clear cell variant of syringoma. Three adult female patients (age range 39-76 years old) were found to have multiple, flesh-colored lower eyelid papules, clinically consistent with syringomas, but histologically displaying abundant clear cell change. Two patients had known diagnoses of uncontrolled diabetes.
Susarla G, Rizza A, Li A, Han S, Khan R, Chan W, Lains I, Apivatthakakul A, Brustoski K, Khetan V, Raman R, Igo RP, Iyengar SK, Mathavan S, Sobrin L. Younger age and albuminuria are associated with proliferative diabetic retinopathy and diabetic macular edema in the South Indian GeNetics of DiAbeTic Retinopathy (SIGNATR) Study. Curr Eye Res 2022;:1-27.Abstract
PURPOSE: The purpose of the South Indian GeNetics of DiAbeTic Retinopathy (SIGNATR) Study is to identify non-genetic and genetic risk factors associated with diabetic retinopathy (DR). This report examines the non-genetic risk factors for DR in South Indian patients. MATERIALS AND METHODS: Participants with South Indian ancestry and type 2 diabetes (T2D) were included from two sources: the Sankara Nethralaya Diabetic Retinopathy and Molecular Genetics Study (SN-DREAMS) and prospective recruitment at Sankara Nethralaya affiliates. Fundus photography and optical coherence tomography (OCT) were obtained on participants. Fundus images were graded for DR severity and OCTs were graded for center-involved diabetic macular edema (ciDME). Multivariate analyses were performed using stepwise logistic regression to assess effects of the demographic and clinical factors on proliferative DR (PDR) and DME. RESULTS: Among the 2941 participants with DR grading, participants with PDR were more likely to be younger [odds ratio (OR)=0.95], men (OR =1.83), have a longer duration of diabetes (OR =1.10), have a higher hemoglobin A1c (OR =1.12), have albuminuria (OR =5.83), have hypertension (OR =1.69), have a higher HDL (OR =1.02) and a lower total cholesterol (OR =0.99) (all P < 0.05). Among the 483 participants with gradable OCT scans, participants who had ciDME were more likely to be younger (OR =0.97), men (OR =2.80), have a longer duration of diabetes (OR =1.06), have lower triglycerides (OR =0.99), and have albuminuria (OR =3.12) (all P < 0.05). CONCLUSIONS: Younger age, male sex, longer duration of diabetes, higher HbA1c, and presence of albuminuria were identified as risk factors for PDR and DME in a South Indian population with T2D.
Singhal S, Patel G, Singh RB, Goyal A, Avgush K, Koka J. Atezolizumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis and Takotsubo cardiomyopathy. BMJ Case Rep 2022;15(7)Abstract
Atezolizumab is a humanised monoclonal IgG1 antibody that is used in treating many solid malignancies. Endocrinopathies are known but a rare adverse event of these immunotherapeutic drugs. Autoimmune diabetes induced by atezolizumab has been rarely reported in the literature. We report the case of a woman in her eighth decade with no known history of diabetes who developed new-onset autoimmune diabetes and Takotsubo cardiomyopathy due to the adverse effects of atezolizumab therapy for hepatocellular carcinoma. We also review the characteristics and outcomes of cases previously reported in the literature.
Fickweiler W, Park H, Park K, Mitzner MG, Chokshi T, Boumenna T, Gautier J, Zaitsu Y, Wu I-H, Cavallerano J, Aiello LP, Sun JK, King GL. Elevated Retinol Binding Protein 3 Concentrations Are Associated With Decreased Vitreous Inflammatory Cytokines, VEGF, and Progression of Diabetic Retinopathy. Diabetes Care 2022;45(9):2159-2162.Abstract
OBJECTIVE: To correlate inflammatory cytokines and vascular endothelial growth factor (VEGF) in vitreous and plasma with vitreous retinol binding protein 3 (RBP3), diabetic retinopathy (DR) severity, and DR worsening in a population with type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: RBP3, VEGF, and inflammatory cytokines were measured in plasma and vitreous samples (n = 205) from subjects of the Joslin Medalist Study and Beetham Eye Institute. RESULTS: Higher vitreous RBP3 concentrations were associated with less severe DR (P < 0.0001) and a reduced risk of developing proliferative DR (PDR) (P < 0.0001). Higher RBP3 correlated with increased photoreceptor segment thickness and lower vitreous interleukin-12 (IL-12), tumor necrosis factor-α (TNF-α), and TNF-β (P < 0.05). PDR was associated with lower vitreous interferon-γ and IL-10 and higher VEGF, IL-6, and IL-15 (P < 0.05), but was not associated with their plasma concentrations. CONCLUSIONS: Higher vitreous RBP3 concentrations are associated with less severe DR and slower rates of progression to PDR, supporting its potential as a biomarker and therapeutic agent for preventing DR worsening, possibly by lowering retinal VEGF and inflammatory cytokines.
Joseph S, Rajan RP, Sundar B, Venkatachalam S, Kempen JH, Kim R. Validation of diagnostic accuracy of retinal image grading by trained non-ophthalmologist grader for detecting diabetic retinopathy and diabetic macular edema. Eye (Lond) 2022;Abstract
PURPOSE: To validate the fundus image grading results by a trained grader (Non-ophthalmologist) and an ophthalmologist grader for detecting diabetic retinopathy (DR) and diabetic macular oedema (DMO) against fundus examination by a retina specialist (gold standard). METHODS: A prospective diagnostic accuracy study was conducted using 2002 non-mydriatic colour fundus images from 1001 patients aged ≥40 years. Using the Aravind Diabetic Retinopathy Evaluation Software (ADRES) images were graded by both a trained non-ophthalmologist grader (grader-1) and an ophthalmologist (grader-2). Sensitivity, specificity, positive predictive value and negative predictive value were calculated for grader-1 and grader-2 against the grading results by an independent retina specialist who performed dilated fundus examination for every study participant. RESULTS: Out of 1001 patients included, 42% were women and the mean ± (SD) age was 55.8 (8.39) years. For moderate or worse DR, the sensitivity and specificity for grading by grader-1 with respect to the gold standard was 66.9% and 91.0% respectively and the same for the ophthalmologist was 83.6% and 80.3% respectively. For referable DMO, grader-1 and grader-2 had a sensitivity of 74.6% and 85.6% respectively and a specificity of 83.7% and 79.8% respectively. CONCLUSIONS: Our results demonstrate good level of accuracy for the fundus image grading performed by a trained non-ophthalmologist which was comparable with the grading by an ophthalmologist. Engaging trained non-ophthalmologists potentially can enhance the efficiency of DR diagnosis using fundus images. Further study with multiple non-ophthalmologist graders is needed to verify the results and strategies to improve agreement for DMO diagnosis are needed.
Jhaveri CD, Glassman AR, Ferris FL, Liu D, Maguire MG, Allen JB, Baker CW, Browning D, Cunningham MA, Friedman SM, Jampol LM, Marcus DM, Martin DF, Preston CM, Stockdale CR, Sun JK, Sun JK. Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema. N Engl J Med 2022;Abstract
BACKGROUND: In eyes with diabetic macular edema, the relative efficacy of administering aflibercept monotherapy as compared with bevacizumab first with a switch to aflibercept if the eye condition does not improve sufficiently (a form of step therapy) is unclear. METHODS: At 54 clinical sites, we randomly assigned eyes in adults who had diabetic macular edema involving the macular center and a visual-acuity letter score of 24 to 69 (on a scale from 0 to 100, with higher scores indicating better visual acuity; Snellen equivalent, 20/320 to 20/50) to receive either 2.0 mg of intravitreous aflibercept or 1.25 mg of intravitreous bevacizumab. The drug was administered at randomization and thereafter according to the prespecified retreatment protocol. Beginning at 12 weeks, eyes in the bevacizumab-first group were switched to aflibercept therapy if protocol-specified criteria were met. The primary outcome was the mean change in visual acuity over the 2-year trial period. Retinal central subfield thickness and visual acuity at 2 years and safety were also assessed. RESULTS: A total of 312 eyes (in 270 adults) underwent randomization; 158 eyes were assigned to receive aflibercept monotherapy and 154 to receive bevacizumab first. Over the 2-year period, 70% of the eyes in the bevacizumab-first group were switched to aflibercept therapy. The mean improvement in visual acuity was 15.0 letters in the aflibercept-monotherapy group and 14.0 letters in the bevacizumab-first group (adjusted difference, 0.8 letters; 95% confidence interval, -0.9 to 2.5; P = 0.37). At 2 years, the mean changes in visual acuity and retinal central subfield thickness were similar in the two groups. Serious adverse events (in 52% of the patients in the aflibercept-monotherapy group and in 36% of those in the bevacizumab-first group) and hospitalizations for adverse events (in 48% and 32%, respectively) were more common in the aflibercept-monotherapy group. CONCLUSIONS: In this trial of treatment of moderate vision loss due to diabetic macular edema involving the center of the macula, we found no evidence of a significant difference in visual outcomes over a 2-year period between aflibercept monotherapy and treatment with bevacizumab first with a switch to aflibercept in the case of suboptimal response. (Funded by the National Institutes of Health; Protocol AC ClinicalTrials.gov number, NCT03321513.).
Garg I, Uwakwe C, Le R, Lu ES, Cui Y, Wai KM, Katz R, Zhu Y, Moon JY, Li CY, Laíns I, Eliott D, Elze T, Kim LA, Wu DM, Miller JW, Husain D, Vavvas DG, Miller JB. Nonperfusion Area and Other Vascular Metrics by Wider Field Swept-Source OCT Angiography as Biomarkers of Diabetic Retinopathy Severity. Ophthalmol Sci 2022;2(2)Abstract
Purpose: To study the wider field swept-source optical coherence tomography angiography (WF SS-OCTA) metrics, especially non-perfusion area (NPA), in the diagnosing and staging of DR. Design: Cross-sectional observational study (November 2018-September 2020). Participants: 473 eyes of 286 patients (69 eyes of 49 control patients and 404 eyes of 237 diabetic patients). Methods: We imaged using 6mm×6mm and 12mm×12mm angiograms on WF SS-OCTA. Images were analyzed using the ARI Network and FIJI ImageJ. Mixed effects multiple regression models and receiver operator characteristic analysis was used for statistical analyses. Main Outcome Measures: Quantitative metrics such as vessel density (VD); vessel skeletonized density (VSD); foveal avascular zone (FAZ) area, circularity, and perimeter; and NPA in DR and their relative performance for its diagnosis and grading. Results: Among patients with diabetes (median age 59 years), 51 eyes had no DR, 185 eyes (88 mild, 97 moderate-severe) had non-proliferative DR (NPDR); and 168 eyes had proliferative DR (PDR). Trend analysis revealed a progressive decline in superficial capillary plexus (SCP) VD and VSD, and increased NPA with increasing DR severity. Additionally, there was a significant reduction in deep capillary plexus (DCP) VD and VSD in early DR (mild NPDR), but the progressive reduction in advanced DR stages was not significant. NPA was the best parameter to diagnose DR (AUC:0.96), whereas all parameters combined on both angiograms efficiently diagnosed (AUC:0.97) and differentiated between DR stages (AUC range:0.83-0.97). The presence of diabetic macular edema was associated with reduced SCP and DCP VD and VSD within mild NPDR eyes, whereas an increased VD and VSD in SCP among moderate-severe NPDR group. Conclusions: Our work highlights the importance of NPA, which can be more readily and easily measured with WF SS-OCTA compared to fluorescein angiography. It is additionally quick and non-invasive, and hence can be an important adjunct for DR diagnosis and management. In our study, a combination of all OCTA metrics on both 6mm×6mm and 12mm×12mm angiograms had the best diagnostic accuracy for DR and its severity. Further longitudinal studies are needed to assess NPA as a biomarker for progression or regression of DR severity.
PURPOSE: The purpose of this study was to evaluate the prognostic utility of the degree of vitreous attachment for predicting outcomes of vitrectomy for nonclearing vitreous hemorrhage associated with proliferative diabetic retinopathy. METHODS: Medical records of patients who underwent primary vitrectomy for dense nonclearing vitreous hemorrhage secondary to proliferative diabetic retinopathy were examined retrospectively. Eyes were divided into four groups based on the intraoperatively assessed stage of posterior vitreous detachment (PVD), ranging from Stage 0/1 (complete or near-complete vitreoretinal adhesion) to Stage 4 (complete PVD). RESULTS: Overall, 136 eyes (117 patients) were included. In comparison with eyes with a partial or complete PVD (Stages 2-4), eyes with no PVD (Stage 0/1) had a higher incidence of postoperative hypotony (8%, P = 0.03) and traction retinal detachment (27%, P = 0.002), an increased rate of repeat vitrectomy (49%, P = 0.04), and poorer best-corrected visual acuity at 6 months and 1 year postoperatively (P = 0.04 and P = 0.01, respectively). Presence of a complete PVD at baseline was independently associated with improved postoperative vision at 6 months (P = 0.04). CONCLUSION: More extensive vitreoretinal adhesion is associated with higher rates of reoperation and poorer visual outcomes after vitrectomy for dense nonclearing vitreous hemorrhage associated with proliferative diabetic retinopathy. Preoperative determination of PVD status using B-scan ultrasonography may be useful for predicting anatomical and functional outcomes after vitrectomy in these patients.
Song S, Lemire CA, Seto B, Arroyo JG. Nocturnal normobaric hyperoxia treatment in a case of chronic diabetic macular edema. Eur J Ophthalmol 2022;:11206721221101365.Abstract
PURPOSE: To study the long-term anatomic and physiologic effects of nocturnal normobaric hyperoxia (NNBH) in a patient with treatment-resistant diabetic macular edema (DME). METHODS: A 64-year-old diabetic man with bilateral DME requiring regular anti-VEGF treatments in both eyes was started on 5 LPM (40% FiO2) NNBH treatment 6-h per night. Visual acuity, OCT measurements of retinal thickness and volume, as well as the number of injections given in each eye were retrospectively examined one year prior and prospectively after initiation of NNBH, as well as before and after a planned 1-month discontinuation of NNBH. RESULTS: The patient received 12 anti-VEGF injections in the year prior to beginning NNBH treatment (4 OD; 8 OS) and did not require any injections after commencing NNBH treatment. Visual acuity improved and stabilized to 20/20 and macular edema rapidly resolved in both eyes following initiation of NNBH. After a planned 1-month NNBH vacation, DME recurred but quickly resolved once NNBH treatment was restarted. CONCLUSION: This model case demonstrates that a 6-h NNBH regimen can be successful in treating DME and improving vision, without the need for intravitreal injections. NNBH is a more acceptable treatment regimen compared to 24-h continuous oxygen delivery and may provide a less invasive alternate method for treating DME in patients with diabetes. Further study is warranted.
Wu M, Yu Z, Matar DY, Karvar M, Chen Z, Ng B, Aoki S, Haug V, Orgill DP, Panayi AC. Human Amniotic Membrane Promotes Angiogenesis in an Oxidative Stress Chronic Diabetic Murine Wound Model. Adv Wound Care (New Rochelle) 2022;Abstract
Objective: The development of animal models, which adequately replicate the pathophysiology of chronic wounds, has been challenging. In this study, we utilized an oxidative stress (OS) murine model, which was previously developed by our group, to study the effect of a human amniotic membrane (AM) on chronic wound healing. Approach: Forty-five diabetic (genetically obese leptin receptor-deficient mice [db/db]) mice were separated into three groups. Thirty mice received an OS regimen and a 1 - × 1 cm2 full-thickness excisional dorsal wound. The wounds were either covered with AM and occlusive dressing (db/dbOS-AM) or occlusive dressing only (db/dbOS). Fifteen mice did not receive the OS regimen, and were covered with AM and occlusive dressing (db/db-AM). The wounds were photographed, and tissue was harvested at various time points. Results: Vascular density was higher in the AM-treated groups (db/dbOS-AM: 34 ± 12; db/db-AM: 37 ± 14; vs. db/dbOS: 19 ± 9 cluster of differentiation 31 [CD31+]/high power field [HPF] photograph; p = 0.04 and p = 0.003). Vessel maturity was lowest in the db/dbOS group (21% ± 4%; vs. db/dbOS-AM: 38% ± 10%, p = 0.004; db/db-AM: 40% ± 11%, p = 0.0005). Leukocyte infiltration was higher in the AM groups (db/dbOS-AM: 15 ± 4; db/db-AM: 16 ± 4 vs. db/dbOS: 8 ± 3 lymphocyte common antigen [CD45+]/HPF; p = 0.005 and p = 0.06). AM upregulated various proangiogenic factors, including vascular endothelial growth factor (VEGF), and downregulated genes involved in chronicity, such as osteopontin, as visualized through proteome analysis and western blotting. Cell death was lower in the AM groups (db/dbOS-AM: 28 ± 10, db/db-AM: 7 ± 5 vs. db/dbOS: 17% ± 9% Terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling [TUNEL+]; p = 0.03 and p < 0.0001). Innovation: This study offers new insight on the mechanisms of action of human AM in chronic wound healing. Conclusion: AM treatment promoted healing in mice with complex chronic wounds. The AM stimulated angiogenesis through upregulation of proangiogenic factors, improving the wound milieu by increasing leukocyte and growth factor delivery and decreasing cell death.
Ofuji Y, Katada Y, Tomita Y, Nagai N, Sonobe H, Watanabe K, Shinoda H, Ozawa Y, Negishi K, Tsubota K, Kurihara T. Non-Perfusion Area Index for Prognostic Prediction in Diabetic Retinopathy. Life (Basel) 2022;12(4)Abstract
Fundus fluorescent angiography is a standard examination in Japan that can directly visualize the circulatory failure in diabetic retinopathy but is not used in Western countries. In this study, we examine the relationship between the non-perfusion area in fundus fluorescent angiography and the progression of diabetic retinopathy. We evaluated 22 eyes between 22 patients who had their first fundus fluorescent angiography during a clinical episode at Keio University Hospital from January 2012 to May 2015, were diagnosed as having preproliferative diabetic retinopathy, and could be followed for at least three years. The non-perfusion area index (%) in nine segmented fundi in the initial fundus fluorescent angiography was calculated, and the progression to proliferative diabetic retinopathy over three years was evaluated. Three out of the 22 eyes (13.6%) developed proliferative diabetic retinopathy over three years. The non-perfusion area index for the initial fundus fluorescent angiography was significantly associated with progression to proliferative diabetic retinopathy. The non-perfusion area index in the posterior pole was most strongly correlated with the progression to proliferative diabetic retinopathy. Thus, the non-perfusion area index in the posterior pole among those with preproliferative diabetic retinopathy may predict the progression to proliferative diabetic retinopathy in the subsequent three years.
Salongcay RP, Aquino LAC, Salva CMG, Saunar AV, Alog GP, Sun JK, Peto T, Silva PS. Comparison of Handheld Retinal Imaging with ETDRS 7-Standard Field Photography for Diabetic Retinopathy and Diabetic Macular Edema. Ophthalmol Retina 2022;6(7):548-556.Abstract
PURPOSE: To compare nonmydriatic (NM) and mydriatic (MD) handheld retinal imaging with standard ETDRS 7-field color fundus photography (ETDRS photographs) for the assessment of diabetic retinopathy (DR) and diabetic macular edema (DME). DESIGN: Prospective, comparative, instrument validation study. SUBJECTS: A total of 225 eyes from 116 patients with diabetes mellitus. METHODS: Following a standardized protocol, NM and MD images were acquired using handheld retinal cameras (NM images: Aurora, Smartscope, and RetinaVue-700; MD images: Aurora, Smartscope, RetinaVue-700, and iNview) and dilated ETDRS photographs. Grading was performed at a centralized reading center using the International Clinical Classification for DR and DME. Kappa statistics (simple [K], weighted [Kw]) assessed the level of agreement for DR and DME. Sensitivity and specificity were calculated for any DR, referable DR (refDR), and vision-threatening DR (vtDR). MAIN OUTCOME MEASURES: Agreement for DR and DME; sensitivity and specificity for any DR, refDR, and vtDR; ungradable rates. RESULTS: Severity by ETDRS photographs: no DR, 33.3%; mild nonproliferative DR, 20.4%; moderate DR, 14.2%; severe DR, 11.6%; proliferative DR, 20.4%; no DME, 68.0%; DME, 9.3%; non-center involving clinically significant DME, 4.9%; center-involving clinically significant DME, 12.4%; and ungradable, 5.3%. For NM handheld retinal imaging, Kw was 0.70 to 0.73 for DR and 0.76 to 0.83 for DME. For MD handheld retinal imaging, Kw was 0.68 to 0.75 for DR and 0.77 to 0.91 for DME. Thresholds for sensitivity (0.80) and specificity (0.95) were met by NM images acquired using Smartscope and MD images acquired using Aurora and RetinaVue-700 cameras for any DR and by MD images acquired using Aurora and RetinaVue-700 cameras for refDR. Thresholds for sensitivity and specificity were met by MD images acquired using Aurora and RetinaVue-700 for DME. Nonmydriatic and MD ungradable rates for DR were 15.1% to 38.3% and 0% to 33.8%, respectively. CONCLUSIONS: Following standardized protocols, NM and MD handheld retinal imaging devices have substantial agreement levels for DR and DME. With mydriasis, not all handheld retinal imaging devices meet standards for sensitivity and specificity in identifying any DR and refDR. None of the handheld devices met the established 95% specificity for vtDR, suggesting that lower referral thresholds should be used if handheld devices must be utilized. When using handheld devices, the ungradable rate is significantly reduced with mydriasis and DME sensitivity thresholds are only achieved following dilation.