Standardization of Optical Coherence Tomography Angiography Imaging Biomarkers in Diabetic Retinal Disease.

Optical coherence tomography Angiography (OCT-A) represents a revolution in the noninvasive evaluation of retinal and choroidal circulation especially in detecting early clinical signs of diabetic retinal disease (DRD). With appropriate use, OCT-A characteristics and measurements have the potential to become new imaging biomarkers in managing and treating DRD. Major challenges include (a) provision of standardized outputs from different OCT-A instruments providing standardized terminology to correctly interpret data; (b) the presence of artifacts; (c) the absence of standardized grading or interpretation method in the evaluation of DRD, similar to that already established in fundus photography; and (d) establishing how OCT-A might be able to provide surrogate markers to demonstrate blood retinal barrier breakdown and vascular leakage, commonly associated with DRD. In fact, OCT-A guidelines for DRD are still evolving. The outputs of quantitative OCT-A data offer a unique opportunity to develop tools based on artificial intelligence to assist the clinicians in diagnosing, monitoring, and managing patients with diabetes. In addition, OCT-A has the potential to become a useful tool for the evaluation of cardiovascular diseases and different neurological diseases including cognitive impairment. This article written by the members of Diabetic Retinopathy expert committee of the European Vision Clinical Research network will review the available evidence on the use of OCT-A as an imaging biomarker in DRD and discuss the limits and the current application as well as future developments for its use in both clinical practice and research trials of DRD.

State-of-the art pharmacotherapy for non-neovascular age-related macular degeneration.

INTRODUCTION: Age-related macular degeneration (AMD) is the most common cause of blindness among the elderly in the industrialized world. While effective treatment is available for neovascular AMD, no therapy is successful for the non-neovascular form. Herein, the authors report the current knowledge on non-neovascular AMD pathogenesis and the promising research on treatments. AREAS COVERED: In the present review, the authors summarize the most recent advances in the treatment of non-neovascular AMD and provide an update on current treatment strategies. Evidence available from preclinical and clinical studies and from a selective literature search is reported. EXPERT OPINION: When investigating AMD, numerous pathological cascades and alterations of physiological processes have been investigated. It is well-known that AMD is a multifactorial disease, with environmental causes and genetics playing a role. Perturbations in multiple pathogenic pathways have been identified and this led to the development of several molecules directed at specific therapeutic targets. However, despite the huge research effort, the only proven approach so far is oral antioxidant supplementation. We believe that, in addition to successful advancement of promising drugs, further research should be directed at tailoring therapy to specific patient groups, eventually employing a combinational therapy strategy.

An optical coherence tomography-based grading of diabetic maculopathy proposed by an international expert panel: The European School for Advanced Studies in Ophthalmology classification.

AIMS: To present an authoritative, universal, easy-to-use morphologic classification of diabetic maculopathy based on spectral domain optical coherence tomography. METHODS: The first draft of the project was developed based on previously published classifications and a literature search regarding the spectral domain optical coherence tomography quantitative and qualitative features of diabetic maculopathy. This draft was sent to an international panel of retina experts for a first revision. The panel met at the European School for Advanced Studies in Ophthalmology headquarters in Lugano, Switzerland, and elaborated the final document. RESULTS: Seven tomographic qualitative and quantitative features are taken into account and scored according to a grading protocol termed TCED-HFV, which includes foveal thickness (T), corresponding to either central subfoveal thickness or macular volume, intraretinal cysts (C), the ellipsoid zone (EZ) and/or external limiting membrane (ELM) status (E), presence of disorganization of the inner retinal layers (D), number of hyperreflective foci (H), subfoveal fluid (F), and vitreoretinal relationship (V). Four different stages of the disease, that is, early diabetic maculopathy, advanced diabetic maculopathy, severe diabetic maculopathy, and atrophic maculopathy, are based on the first four variables, namely the T, C, E, and D. The different stages reflect progressive severity of the disease. CONCLUSION: A novel grading system of diabetic maculopathy is hereby proposed. The classification is aimed at providing a simple, direct, objective tool to classify diabetic maculopathy (irrespective to the treatment status) even for non-retinal experts and can be used for therapeutic and prognostic purposes, as well as for correct evaluation and reproducibility of clinical investigations.

Biosimilars in ophthalmology: "Is there a big change on the horizon?"

Retinal disease management has witnessed remarkable advances in posterior segment pharmacotherapy with the development of anti-VEGF molecules such as Lucentis® (ranibizumab), Eylea® (aflibercept), and off-label bevacizumab (Avastin). The US patents for ranibizumab and aflibercept will expire in 2020 (though Regeneron has indicated that it might attempt to extend its US patent to June 2023 with additional patent claims), and their European patents will expire in 2022 and 2025. Aflibercept comes off patent in 2022 in People's Republic of China and Japan. As soon as each patent expires, biosimilar molecules could potentially come in the mainstream clinical practice as a more cost-efficient choice in the form of generic biosimilars. It is difficult to predict how significant this shift would be in terms of more cost-effective clinical management and how it will impact the care in developed and developing world. It is important for clinicians to have a clear understanding about ophthalmic biosimilars before the industry brings these molecules to the mainstream clinical use globally.

The correlation between retinal blood flow velocity measured by the retinal function imager and various physiological parameters.

BACKGROUND AND OBJECTIVE: The retinal function imager (RFI) (Optical Imaging Ltd., Rehovot, Israel) measures retinal blood flow velocity non-invasively. The authors studied the reproducibility of these measurements and assessed the effect of physiological components on them. PATIENTS AND METHODS: Sixty-seven individuals with no retinal pathology were recruited. Velocity reproducibility was verified by comparing repeated RFI measurements. The correlation of the velocity with physiological parameters was assessed by mixed linear and Gaussian models. RESULTS: The average velocity was 4.2 ± 0.9 mm/sec arterial and 3.3 ± 0.8 mm/sec venous. Variability was 7.5% ± 3.7% and interclass correlation coefficient was r = 0.744. Venous velocity decreased after 40 years of age (0.32 mm/sec per decade, P < .01). Arterial velocity increased as mean arterial pressure increased (0.25 mm/sec per 10 mm Hg, P < .01). There was also a positive association between velocities and heart rate (arteries: 0.21 mm/sec per 10 bpm, P < .05; veins: 0.22 mm/sec per 10 bpm, P < .01). CONCLUSION: The RFI provides a reproducible, non-invasive technique to assess retinal velocities.

Increased retinal blood flow velocity in patients with early diabetes mellitus.

PURPOSE: To compare retinal blood flow velocity in small vessels of patients with early diabetes mellitus (DM), without any morphologic changes related to diabetic retinopathy, with that in a control group. METHODS: The authors used the retinal function imager to measure blood flow velocities, from many small vessels, simultaneously. Twenty-three eyes of 14 patients with early DM and 51 eyes of 31 healthy subjects were enrolled. Differences between the patients and the control group were assessed by mixed linear models. RESULTS: Venous average velocity significantly increased in the DM group (3.8 ± 1.2 vs. 2.9 ± 0.5 mm/second, P < 0.0001) than in the healthy subjects. Arterial velocity of DM patients was also significantly higher (4.7 ± 1.7 vs. 4.1 ± 0.9 mm/second, P = 0.03). There was no statistically significant difference between groups in age, gender, heart rate, and systolic blood pressure. The diastolic blood pressure in the DM patients was lower than that in the healthy group (P = 0.03). CONCLUSION: There was an increase in arterial and venous retinal blood flow velocities of patients with early DM with no diabetic retinopathy. These findings support the notion that abnormalities in vessel function exist in diabetic eyes before the development of structural changes. This noninvasive approach facilitated the assessment of early hemodynamic abnormalities and may assist in screening and monitoring.

Influence of non-toxic doses of bevacizumab and ranibizumab on endothelial functions and inhibition of angiogenesis.

PURPOSE: Ranibizumab (Lucentis) is an antibody fragment developed against all fragments of vascular endothelial growth factor (VEGF) that was approved by the FDA for treating age-related macular degeneration (AMD). Bevacizumab, a full-length anti-VEGF antibody approved for use in colon cancer, is non-FDA approved at this time but it is widely used for treating AMD. The purpose of this study was to compare the influence of Bevacizumab and Ranibizumab on angiogenesis in an in vitro model. METHODS: A model consisting of H5V cells derived from murine hearts capillary endothelial cells (ECs) was used. The H5V cells were treated with three concentrations of Bevacizumab and Ranibizumab (0.125 mg/mL, 0.25 mg/mL, and 0.50 mg/mL) for 24 hr before all experiments. The effects of Bevacizumab and Ranibizumab on EC proliferation were compared by 3H-thymidine incorporation essay. Toxic effects and the safety of each drug in clinical concentrations were assessed by annexin 5 staining. The effects of the drugs on ECs functions were assessed by their ability to adhere to fibronectin and by evaluation of the cells' tube formation capacity on matrigel. RESULTS: Both Bevacizumab and Ranibizumab equally suppressed the adhesive properties of ECs to fibronectin, and similarly inhibited ECs' proliferation capacity in a dose-dependent manner. Both Bevacizumab and Ranibizumab inhibited the ECs' tube formation capacity on matrigel, and were equally safe. CONCLUSIONS: Ranibizumab and Bevacizumab at low, non-toxic doses similarly inhibit several properties of the angiogenesis process. Inhibition of ECs adhesion to fibronectin and tube formation capacity does not seem to be directly related to the anti-angiogenic effects as indicated by inhibition of VEGF. Further studies for delineating the exact mechanism of action of Ranibizumab and Bevacizumab in angiogenesis are warranted.

Reduced retinal blood flow velocity in diabetic retinopathy.

PURPOSE: The purpose of this study was to compare the retinal blood flow velocities of patients with diabetes and healthy control subjects. We used a novel device offering a noninvasive diagnostic of retinal function. METHODS: Flow velocities in retinal arterioles and venules were quantitatively analyzed by retinal function imager scanning in 58 eyes of 42 patients with nonproliferative diabetic retinopathy and 51 eyes of 32 normal subjects. Group differences were assessed by the mixed-model effect. RESULTS: Average velocity in arterial compartments (in mm/s) was 3.74 +/- 1.09 for the diabetic group and 4.19 +/- 0.99 for the control subjects. The average velocity of all segments, taking associated heart rate and individual segment widths into account, was 17% slower in the diabetic group (P < 0.0001). In both groups, average venous compartment velocity was lower than the arterial velocity (2.61 +/- 0.65 for the diabetic group; 3.03 +/- 0.59 for the control subjects). Individual vein velocities, taking heart rate and segment widths into account, was 17% slower, on average, in the diabetic group (P < 0.0001). CONCLUSION: Our measurement showed significantly decreased flow velocities in the retinal arterioles and venules of patients with diabetes compared with healthy control subjects, supporting the view of abnormal vessel function in eyes with nonproliferative diabetic retinopathy.

Ophthalmologists, suicide bombings and getting it right in the emergency department.

BACKGROUND: The number and extent of worldwide suicide attacks has risen sharply in recent years. The objectives of this retrospective study are: to determine the prevalence and outcome of the victims who sustained ocular injury, to describe the activities of ophthalmologists in the setting of an emergency department (ED) receiving mass casualties of a suicide bombing attack and to illustrate some of the treatment obstacles that they encountered and the protocol. METHODS: A single-centre, retrospective, interventional case series. PARTICIPANTS: Participants were the victims of 13 suicide bombing attacks (2000-2004), treated at a level I trauma center of an Israeli tertiary care, municipal medical center. MAIN OUTCOME MEASURES: The study includes a description of the ophthalmologist's role in the setting of mass evacuation to emergency facilities, prevalence and outcome of patients managed according to the recommended guidelines, and reemphasis of logistic and therapeutic guidelines for management of ocular injuries. RESULTS: The trauma center database yielded information on a total of 352 casualties from 13 suicide bombing attacks, including 17 surviving patients with any ocular/periocular trauma resulting from suicide bombing attacks. Six eyes required and underwent urgent primary closure of laceration for primary repair of open globe, one unsalvageable eye underwent primary enucleation, and two eyes underwent exploration of subconjunctival hemorrhage. Four eyes required additional surgical intervention, which was performed within 7 days (large intravitreal foreign bodies were extracted from three eyes whose final visual acuity was poor, and an intra-lenticular foreign body was extracted from the fourth eye whose final visual acuity was 6/12). The remaining eight patients received medical treatment as indicated and were continued to be followed up. DISCUSSION: Ocular trauma management under conditions of mass injuries requires special utilization of manpower and resources. Guidelines for efficacious patient management, description of the ophthalmologist's role, and the experience of one emergency facility are presented.

ICG angiography-guided photodynamic therapy for large pigment epithelial detachments in age-related macular degeneration.

BACKGROUND AND OBJECTIVE: To evaluate the role of photodynamic therapy (PDT) in the management of vascularized pigment epithelial detachment in age-related macular degeneration (AMD) when the pigment epithelial detachment is the predominant component of the neovascular complex. PATIENTS AND METHODS: Seventeen eyes of 17 patients underwent indocyanine green angiography-guided PDT and had at least 6 months of follow-up. Data retrieved included visual acuity and angiographic features prior to the treatment, number of PDT sessions, visual acuity, angiographic outcomes at the end of the follow-up, length of follow-up, and status of the fellow eye. in the series, with an average age of 77 years and a mean follow-up time of 11 months. Six (35%) of the patients lost less than 3 lines of visual acuity, 6 (35%) lost between 3 and 6 lines, and 5 (30%) lost 6 or more lines. Angiographic outcomes were categorized as failures in 14 (82%) of the treated eyes and successful in 3 (17%) eyes. CONCLUSIONS: In 82% of the eyes, PDT failed to flatten the pigment epithelial detachment or prevent growth of the choroidal neovascular membrane. Visual acuity outcomes correlated poorly with angiographic outcomes. PDT does not seem to improve the prognosis of eyes with large pigment epithelial detachments in AMD.