Chronic in ﬂ ammation contributes to the pathophysiology of both DR and DME. To that end, several novel thera- peutic targets have been identi ﬁ ed for this disease target- ing those processes that release cytokines and chemokines. These include direct and indirect antagonism of interleu- kins, proteases, chemokines, tumor necrosis factor (TNF), angiopoietin-2 (ANGPT-2) and kallikrein. Currently, there are no active clinical trials for DR and DME involving interleukins or proteases. One of the potent mediators of both in ﬂ ammation and breakdown of the blood retinal barrier is the chemokine ligand, CCL2. 279 A CCR2/5 receptor antagonist (Pf-04634817) (P ﬁ zer) was recently tested in patients with DME. 280 Another compound impli- cated in many systemic in ﬂ ammatory diseases as well as DR is TNF. A clinical trial with in ﬂ iximab, the monoclo- nal antibody antagonist of alpha (TNF- α ), in patients with persistent DME demonstrated signi ﬁ cant improvement in both VA and overall reduction in retinal thickening. 281,282 Angiopoietin-2 is another potent mediator of increased vascular permeability in DR. This growth factor achieves most of its biological effect by binding to the endothelial cell receptor tyrosine kinase Tie-2. A Phase I investigation of a competitive inhibitor of vascular endothelial-protein tyrosine phosphatase that promotes Tie2 activation and reduces vascular leakage in animal models showed no safety signal of concern and led to reduction in DME in a few cases. 283 A Phase II trial is planned. A recent study
Imai and Iijima 19,20 reported a dramatic reduction in the amplitude and a delay in the implicit time of rabbit eyes 1 day after PRP with a partial recovery of amplitude 4 weeks after treatment. The present study demonstrated partial recovery of the amplitudes and the latencies 6 weeks after the ﬁ nal treatment. Capoferri et al 5 performed ERGs in 16 patients with PDR prior to PRP, in the interval between laser sessions, within 36 hrs of the ﬁ nal session and 4 months later. The analysis of the results showed a signi ﬁ cant decrease in the peak amplitudes of both a- and b-waves in photopic and dark-adapted conditions that occurred as early as between treatment sessions and remained depressed at 4-month follow-up. The lack of recovery in Capoferri et al ’ s study 5 contrasts with the present ﬁ ndings which demonstrated partial recovery of retinal function 6 weeks after completion of PRP. Considering pathophysiology of the PRP, not only func- tional tissue loss would be occurring, but also the burning RPE and retina is associated with cytokine release and subsequent in ﬂ ammation cascades. Hence, in ﬂ ammation and retinal tissue loss are two main components of treat- ment-related ERG drops. Retinal tissue loss is an irrever- sible process; however, the in ﬂ ammation would be resolved over the time which results in improved ERG parameters 6 weeks (in this study) after completion of PRP. It must be noted that glycemic control may affect the ERG parameters; in this study, glycemic status variable was controlled indirectly, by consideration of the stage of diabeticretinopathy through DRSS. One possible explana- tion for lack of recovery in Capoferri et al ’ s study 5 may be uncontrolled glycemic status and/or post-laser in ﬂ amma- tion which might affect ERG changes after the completion of PRP.
visual acuity in 6 m with a Snellen E chart (LED visual chart projector, LC-13, MEDIZ Inc., City, Korea), slit- lamp biomicroscopy (BM 900, Haag-Streit, Bern, Switzerland) using a Volk 90D lens (Volk Optical, Mentor, Ohio, USA), fundus photography with high-reso- lution spectral-domain optical coherence tomography (SD- OCT, Spectralis, Heidelberg Engineering, Heidelberg, Germany) and ﬂ uorescein angiography (HRA II Heidelberg, Heidelberg, Germany) for evaluating the DR. Subjects with any history of previous treatments for diabeticretinopathy including surgery and laser therapy, BCVA of 20/200 and worse, any type of signi ﬁ cant opa- city, any ocular disease other than diabeticretinopathy that may change the visual evoked potential responses, pre- and post-PRP signi ﬁ cant macular edema (all sessions of treatment) and any history of systemic diseases other than diabetes were excluded. It is necessary to note that in this study, the screening process for evaluation of diabetic macular edema in 1 week after each laser therapy session with high-resolution SD-OCT (Spectralis, Heidelberg Engineering, Heidelberg, Germany) and ﬂ uorescein angio- graphy (HRA II Heidelberg, Heidelberg, Germany) was performed and patients with macular edema were excluded to avoid a possible change in visual evoked potential components.
After pupillary dilation, the presence of DR was graded from 2- ﬁ eld (one centered on the optic disc; and the other centered on the fovea) fundus photographs (Canon CR6- 45NM; Canon, Inc., Tokyo, Japan) according to the Early Treatment for DiabeticRetinopathy Study (ETDRS) standards. 11 Fundus photographs were read in a blind manner. DR was diagnosed if any characteristic lesion was present: microaneurysms, hemorrhages, cotton wool spots, intraretinal microvascular abnormalities, hard exu- dates, venous bleeding and new vessels. Data from the worst eye were used in current analyses. This study was in compliance with the Helsinki Declaration and approved by the ethics Committee of the First Af ﬁ liated Hospital of China Medical University. All the participants signed an informed consent form.
This study provides a topographic point of view of OCTA of the macula, since the new software of our device gives us the global densities and densities divided into nine areas (in a grid of 3×3 cells and in the nine areas of the Early TreatmentDiabeticRetinopathy Study diagram). In this way, it provides knowledge about the most affected region of the macula in DR. In our study, we collected data from the grid of 3×3 cells on the protocol of 4.5 mm×4.5 mm. Our data indicate that the loss of capil- laries in DR is more pronounced in the nasal and central sectors than in the temporal sectors.
Methods: A hospital-based cross-sectional study was conducted from February 2012 to November 2018. DR was assessed using Early TreatmentDiabeticRetinopathy Study criteria. Vision-threatening DR (VTDR) was diagnosed if subjects had severe non- proliferative DR (NPDR), proliferative DR (PDR), or clinically signi ﬁ cant macular edema (CSME). Multivariate logistic regression models were applied to explore the associations. Results: Among the 2696 participants, the overall prevalence of DR was 25.1%, of which the prevalence of mild NPDR, moderate NPDR, and VTDR was 10.8%, 4.5%, and 9.9%, respectively. Serum CA125 level was signi ﬁ cantly higher in participants with DR and increased with the severity of DR (P = 0.013). After accounting for age, gender, smoking, drinking, duration of diabetes, anti-diabetic agents use, systolic blood pressure, pulse pres- sure, weight, hemoglobin A1c and fasting plasma glucose levels, CA125 level was signi ﬁ - cantly associated with subjects in any-severity DR (odds ratio [OR] 1.006 [95% con ﬁ dence interval CI: 1.002 – 1.010], P = 0.006) and VTDR (1.008 [1.003 – 1.013], P = 0.001). When CA125 was treated as categorized variables, the prevalence of VTDR might increase as improving CA125 quartiles (P value for trend = 0.017).
Ophthalmology clinic notes were reviewed to determine, for each eye, the most severe stage of DR, characterized as no retinopathy, nonproliferative diabeticretinopathy (NPDR), or proliferative diabeticretinopathy (PDR). The determina- tion of the presence of DR and, if applicable, its severity, was determined by the attending ophthalmologist caring for the patient, based on review of diagnostic tests (eg, color fundus photography, optical coherence tomography) and ﬁ ndings from the DFE (eg, presence of microaneurysms, dot/blot hemorrhages, neovascularization, etc.). Several additional measures of DR severity were recorded: prior treatment for diabetic macular edema (DME), including laser, intravitreal anti-vascular endothelial growth factor (anti-VEGF), or intravitreal steroids; prior surgery for PDR (eg, for vitreous hemorrhage or retinal detachment); and best-corrected visual acuity (BCVA) at ﬁ nal study visit. BCVA was assessed using a Snellen visual acuity chart, with manifest refraction as
The results of this study are supported by an explora- tory analysis of data from the RIDE/RISE trials, which demonstrated that ranibizumab reduced the risk of worsen- ing of DR severity, with improvement in DR severity seen in many patients. 24,25 Among patients who received rani- bizumab 0.3 or 0.5 mg every 4 weeks (n=468), 13.2% and 14.5% of patients, respectively, had an ≥ 3 Early TreatmentDiabeticRetinopathy Study severity level improvement from baseline at 2 years, compared with 1.3% of sham patients (n=239; P<0.001). Furthermore, 37.2% and 35.9% of patients, respectively, had an ≥ 2 Early TreatmentDiabeticRetinopathy Study severity level improvement over the same period, compared with 5.4% of sham patients (P<0.001). 24 Similar proportions of ranibizumab- treated patients maintained this level of improvement through to 3 years post baseline. 25 Recently, the clinical relevance of these changes has been explored in a post hoc analysis of patients enrolled in the RIDE/RISE trials, showing that improvements in DR severity were asso- ciated with greater VA gains, improved contrast sensitivity, and increased likelihood of resolution of macular edema. 26 In addition, an exploratory analysis by Bressler et al from the DRCR Network Protocol I study of 792 eyes from patients with center-involved DME causing VA impairment suggested that ranibizumab (0.5 mg every 4 weeks for 12 weeks, then as needed with either prompt or deferred [ ≥ 24 weeks] laser) was also associated with a reduced risk of DR worsening in eyes with and without PDR versus sham with prompt laser. 27 Similar ﬁ ndings were noted in uncontrolled case series with ranibizumab 28,29 as well as other anti-VEGF agents used for treatment of DME. 30 Additionally, the 2-year results of the DRCR Network Protocol S study comparing PRP with ranibizumab treatment for PDR demonstrated non- inferiority of ranibizumab (0.5 mg up to every 4 weeks based on a structured re-treatment program) to PRP (com- pleted in 1 – 3 visits, plus ranibizumab for DME); notably, 53% of patients in the PRP group received ranibizumab injections for DME. 8 The ﬁ ndings of this study suggest that anti-VEGF therapy with ranibizumab may have addi- tional utility as a treatment option for PDR when it has developed, including preservation of peripheral visual ﬁ eld that occurs following PRP and a marked reduction in the occurrence of macular edema in patients with PDR with- out concurrent macular edema at the time of diagnosis.
This was not congruent with Memon MS et al 9 who observed that total mean score of attitudes toward diabetes was 5.43±2.57. It was higher (6.62±2.03) in diabetic respondents as compared with non-diabetic respondents (4.70±2.59) with p<0.000. In light of results of the current study; the mean practice score was 13.83±0.7. This was in agreement with Panigrahi S et al 31 who observed that the mean practice score was 12.47±0.32 and explained this by the fact that most of the diabetic patients had the wrong concept, that they should undergo ocular examination only when their vision got affected. The bivariate logistic regression in current study showed that age, education level, family history of diabetes, family history of diabeticretinopathy, hypertension and weight/kg were signi ﬁ cantly associated with DR. Unadjusted analysis showed no sig- ni ﬁ cant association between DR and gender.
Objective: The aim of this study was to develop automated software for screening and diagnosing diabeticretinopathy (DR) from fundus photograph of patients with diabetes mellitus. Methods: The extraction of clinically significant features to detect pathologies of DR and the severity classification were performed by using MATLAB R2015a with MATLAB Image Processing Toolbox. In addition, the graphic user interface was developed using the MATLAB GUI Toolbox. The accuracy of software was measured by comparing the obtained results to those of the diagnosis by the ophthalmologist.
Anonymized data were remotely extracted from 19 centers using the same EMR system (Medisoft Ophthalmology, Medisoft Limited, Leeds, UK) in November 2014. Each site is the only NHS provider of diabeticretinopathy care to their local population and very few patients switch between providers or access care privately. All patients were first time presenters to eye providers after being referred from UK national diabeticretinopathy screening program, a nationwide program implemented through the National Health Service (NHS) and maintained by rigorous quality assurance measures. 15 Patients who received anti-vascular endothelial growth factor (anti-VEGF) injections during the study period were excluded. Data was extracted through the EMR compulsory DR structured assessment module as described previously. 16 Demographic data was extracted from the hospital’s patient administration system to the EMR. All patients had data extracted from the time of their first DR structured assessment entry onto the EMR to the date of their last clinical entry before the data extraction on November 26 th , 2014.
Diabeticretinopathy (DR) is a vision-threatening complication of diabetes. It can range in severity from mild, moderate, or severe nonproliferative DR (NPDR) to proliferative DR (PDR; the most severe form of the disease). The most common cause of vision loss in DR is the development of ﬂ uid around the light-sensitive cells in the center of the retina (called diabetic macular edema [DME]). Effective treatments are available, but not all patients achieve the same level or speed of improvement following treatment with the same drug. The purpose of this study was to take a look back at the clinical trials that ﬁ rst demonstrated the ef ﬁ cacy of ranibizumab in eyes with DR and DME in order to determine which factors made it more likely that a patient would achieve a rapid, robust improvement in DR severity during treatment with ranibizumab. This study found that patients with the most robust early improvements in DR severity (by month 6) were more likely to have had moderately severe or severe NPDR or PDR at the start of treatment (rather than less severe DR) and had their DME disappear after just 3 months of treatment.
Abstract: Diabeticretinopathy (DR) is the most common complication of diabetes mellitus in the eye. Although the clinical treatment for DR has already developed to a relative high level, there are still many urgent problems that need to be investigated in clinical and basic science. Currently, many in vivo animal models and in vitro culture systems have been applied to solve these problems. Many approaches have also been used to establish different DR models. How- ever, till now, there has not been a single study model that can clearly and exactly mimic the developmental process of the human DR. Choosing the suitable model is important, not only for achieving our research goals smoothly, but also, to better match with different experimental proposals in the study. In this review, key problems for consideration in choosing study mod- els of DR are discussed. These problems relate to clinical relevance, different approaches for establishing models, and choice of different species of animals as well as of the specific in vitro culture systems. Attending to these considerations will deepen the understanding on current study models and optimize the experimental design for the final goal of preventing DR. Keywords: animal model, in vitro culture, ex vivo culture, neurovascular dysfunction
Abstract: Diabeticretinopathy (DR) is a retinal vascular disorder associated with both type 1 and type 2 diabetes mellitus (DM). It is characterized by speci ﬁ c loss of pericytes, which leads to an augmented blood vessel permeability, and development of new blood vessels (retinal neovascularization). Moreover, stiffening of eye membrane, in ﬂ ammation, and apoptosis of endothelial cells also lead to damage of the blood – retinal barrier and blindness in most cases unless it ’ s detected and managed early. Hence, this review was intended to assess the potential roles of Netrin-1 and -4 as new/alternative biomarkers and therapeutic options for DR. Netrin-1 and -4 have been the most known ligands and are well known for their role in neural guidance. DR has both neural and vascular components; therefore, biomarkers used for both neural and vascular retinal tissues are potentially important. According to different experimental and clinical studies, as compared to the normal groups, there was a signi ﬁ cant increment in both retinal Netrin-1 and -4 mRNA and protein levels in the retinopathy groups. In addition, exogenous supplementation of these proteins is also used as a therapeutic agent for DR.
The ﬁ ndings of this study showed that patients with early diabeticretinopathy performed worse in TNO (global) vs Titmus (local) tests of stereopsis. This difference supports the parallel and the serial types of processing. Considering that larger ganglion cells in the retina might have been further damaged than the small ganglion cell, the presence of two parallel magnocellular and parvocellular pathways of proces- sing for depth perception is supported. The extensive evi- dence regarding the thickness reduction in the ganglion cell layer and the retinal nerve ﬁ ber layer in the early stages of DR 2–6,8–10,29,31–33 further supports the parallel pathways of depth perception. Our ﬁ ndings also do not rule out the serial model of processing. The global process is believed to involve two serial stages: 1) the processing of local disparity in early visual areas of V1V2 by disparity selective cells, binocular cells with localized receptive ﬁ eld; and 2) proces- sing corrugations of disparity by cells with much larger receptive ﬁ elds in higher visual brain areas that involve the integration of local stereoscopic information over large spa- tial distances. Our ﬁ ndings might indicate that the damage to the global pathway has happened in higher cortical areas. Further investigations with advanced imaging techniques such as fMRI, and PET scanning are required to provide support for this model. Our ﬁ ndings in early diabetic patients revealed that there might be different underlying mechanisms for local and global stereopsis.
The advent of anti-vascular endothelial growth factor (VEGF) therapy has greatly improved outcomes in the treatment of diabeticretinopathy. 4,5 From 2001 to 2012, while the general overall rate of vitrectomy among a large managed-care cohort rose by 31%, the rate of pars plana vitrectomy (PPV) among diabetics decreased by 43%. 6 However, despite these improvements, many patients still undergo surgical intervention for complications of disease – primarily non- clearing vitreous hemorrhage (NCVH) and tractional retinal detachment (TRD). 7,8 Since the advent of vitrectomy in the 1970s, surgical techniques and instrumen- tation have improved substantially, perhaps in part due to the use of smaller gauge
Patients and Methods: Sixty eyes of 60 participants were included in this prospective study: 40 diabetic patients [20 with non-proliferative diabeticretinopathy (NPDR group), 20 with proliferative diabeticretinopathy (PDR group)] and 20 age- and gender-matched normal healthy subjects (control group). After full ophthalmological examination and fundus ﬂ uor- escein angiography, OCTA was performed for all participants. Quantitative OCTA para- meters, such as the foveal avascular zone (FAZ) area, the super ﬁ cial capillary plexus vessel density (%) (SCP-VD) and the deep capillary plexus vessel density (%) (DCP-VD) in, whole and parafoveal areas were measured. Correlations between BCVA and OCTA parameters were analyzed.
This study is a nonrandomized retrospective study and was conducted in 2017. The study adhered to the tenets of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) at the University of Padjajaran. Patient informed consent was not required by the IRB because the data were collected retrospectively, and patient data were deidenti ﬁ ed to protect patient priv- acy. Data were collected retrospectively from the electro- nic medical records at the Netra Eye Hospital in Bandung, Indonesia of patients that underwent IVB injection before laser treatment and patients treated with PRP before IVB injection. Inclusion criteria included patients >18 years of age with PDR or severe non-proliferative diabetic retino- pathy (NPDR) who were treated with the above therapies and complied with testing and follow-up. The diagnostic criteria of NPDR are diabeticretinopathy with one or more of the following: hemorrhage in four quadrants, venous beading in two quadrants, and/or intraretinal microvascu- lar abnormalities in one quadrant. 5 PDR is de ﬁ ned as diabeticretinopathy with neovascularization. 5 Exclusion criteria included patients with signi ﬁ cant media opacities, neovascular glaucoma, and history of intraocular laser treatment or surgery within 3 months of treatment.
signi ﬁ cant associations were observed for the ﬁ rst major car- diovascular event (a priori composite of cardiovascular death, non-fatal myocardial infarction, or nonfatal ischaemic stroke) individually for retinopathy (HR: 1.39, 95% CI: 1.09 – 1.76), peripheral neuropathy (1.40, 1.19 – 1.66) and nephropathy (1.35, 1.15 – 1.58). The ﬁ ndings showed that the cumulative burden of microvascular disease is a determinant of future cardiovascular risk. 48 This present study adds to the evidence that atherosclerosis is associated with diabetic microvascular complications. The exact mechanisms underlying the associa- tion between the two remains unclear. A possible explanation is that atherosclerosis and microvascular complication share same physiopathologic mechanism (for example, endothelial injury, chronic in ﬂ ammation and enhanced oxidative stress) and other independent accelerating risk factors (for example, smoking, hypertension and hyperlipidemia). 49