The local or global stereopsis tests are generally used in clinics and screenings to evaluate binocular status in the pediatric population, with amblyopia, and are rarely used for diagnosis and monitoring of systemic diseases. Some limited research on neurodegenerative diseases such as Parkinson ’ s disease, schizophrenia, and multiple sclerosis have reported deterioration of stereopsis in these patients. 20–23 Stereopsis in patients with DM has not been previously investigated at any stages of DR. Since strong evidence exists for neurodegeneration in early stages of diabeticretinopathy, 12 we speculate that some functional changes in depth perception may also be present at this stage. Early detection of subclinical DR with an easy and low cost functional test such as stereopsis can provide earlier detection of visual changes and subsequent appropriate decision in diagnosis and management of DM. Further analysis of stereopsis with local and global tests can shed light into the mechanisms underlying these two types of processing. The purpose of this study was to compare global (TNO) vs local (Titmus) stereopsis in patients with DM (with no background retinopathy or very mild non-proliferative retinopathy) with healthy indi- viduals (control).
Our ﬁ ndings regarding the effect of baseline DR sever- ity on the response to ranibizumab treatment are consistent with the results of other analyses of the RIDE/RISE trials that focused on later timepoints. Dhoot et al evaluated characteristics predictive of clinically meaningful DR improvements after 12 and 24 months of treatment with ranibizumab in RIDE/RISE and found that baseline DR severity was predictive of 2-step or greater DR improve- ment at both months 12 and 24. 25 Wykoff et al 20 also evaluated the long-term outcomes from RIDE/RISE and found that the highest rate of 2-step or greater DR improvement at month 24 occurred in eyes with moder- ately severe to severe NPDR at baseline (78.4% in the ranibizumab 0.3 mg group and 81.1% in the ranibizumab 0.5 mg group). These improvements were seen as early as month 3 in approximately one-third of eyes with moder- ately severe to severe NPDR at baseline. 20 Our new pre- dictive analyses of early improvements, taken together with the past long-term results, suggest that it may be most bene ﬁ cial to initiate anti-VEGF therapy in eyes with DR as soon as the condition has progressed to
This was a non-randomized, retrospective study. The medical charts of 40 eyes of 40 Japanese patients with a unilateral, idiopathic, full-thickness MH (18 men, 22 women) who had been treated at the Matsumoto Dental University Hospital between September 2008 and October 2016 were reviewed. Only eyes successfully closed after the initial surgery were studied. In addition, patients with a BCVA ≥ 20/30 at 6 months after surgery were used to investigate the stereoa- cuity. The fellow eyes also had good BCVA of ≥ 20/20 with- out retinal diseases. Patients with secondary MH associated with rhegmatogenous retinal detachment, an epiretinal mem- brane (ERM), high pathological myopia, and diabetic retino- pathy were excluded. 16 Eyes with glaucoma and uveitis were also excluded. In this retrospective study, the patients with a BCVA < 20/30 were excluded because of these criteria and short follow-up periods.
sectional design of our study limited the causal interferon between tumor biomarkers levels and the presence of DR. Whether elevated CA125 levels lead to the development of DR or act as the consequence of DR were still unknown. Further prospective researches with a similar conception were required to validate the associations and elucidate the mechanisms. Second, differences in study methodologies, ascertainment and classi ﬁ cation of DR and population characteristics, could lead to comparisons between studies. The assessment and monitoring of DR in this study was based on two- ﬁ eld fundus photographs and it may contri- bute to underestimation of the presence of low-grade DR, especially mild and moderate NPDR, if the pathological lesions were in the peripheral regions of retina. The highly sensitive seven- ﬁ eld fundus photographs, which have been used in several investigations including the Early Treatment DiabeticRetinopathy Study (ETDRS), can play a critical role in detecting a more accurate perception of development of DR. And it should be noted that serum CA125 was a non-speci ﬁ c marker, benign conditions would in ﬂ uence the expression level of serum CA125, we have included related condition in exclusion criteria,
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.
Arterial stiffness is considered to be an accurate re ﬂ ec- tion of atherosclerosis and vascular function. 18 The rela- tionship between arterial stiffness and DR has been established. 13,19 In these studies, pulse wave velocity (PWV) is used as a parameter for arterial stiffness. Although PWV is a common marker of arterial stiffness and re ﬂ ects vascular damage, 20 it is reported to be affected by several factors, including blood pressure at the time of measurement and autonomic nerve function. 21 Recently, the cardio-ankle vascular index (CAVI) has emerged as a new indicator to estimate the degree of stiffness of the systemic arteries and a convenient measure of functional changes in early atherosclerosis. 22 Evidence shows that CAVI is superior to PWV mainly because it is not affected by blood pressure. 23 – 25 In addition, CAVI has been applied in the clinical practice to measure arterial stiffness in subjects with cardiovascular diseases, hypertension, and obesity. 26–28
The retinal microvascular changes in DR may lead to visually fatal complications, including macular ischemia, neovascularization and macular edema. 9 Recent research has highlighted the potential role of this new imaging modality in assessing the retinal microvascular abnormal- ities in various retinal diseases, including DR. 7–10 The quantitative OCTA parameters, such as foveal avascular zone (FAZ) area, vessel density, and perfusion density in the super ﬁ cial and deep capillary plexus, may have a useful role in the early detection of subclinical disease and may also provide valuable biomarkers in monitoring the progres- sion of DR and preventing its severe complications. 11 – 13
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 Treatment DiabeticRetinopathy 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.
which is usually confirmed with fluorescence fundus angiography imaging. PDR is the more advanced stage of DR. In PDR, proliferating neovasculature contributes to severe complications, eg, vitreous hemorrhage, retinal scars, and tractional retinal detachment, all of which often need vitreoretinal surgery. However, the endpoint of PDR is variable, and irreversible vision loss is attributed to retinal structure damage and layer thinning. Thus, the Early Treat- ment of Diabetes Retinopathy Study (ETDRS) has staged NPDR with mild, moderate, and severe grades, aimed to screen risk factors and to detect the earlier stages of DR for nonsurgical treatment, eg, retinal photocoagulation or antiangiogenic therapy. 10,11
Recently, a novel OCT-based technique called OCT angiography (OCTA) has been developed . This OCTA technique is based in a newly developed software that employs an image processing algorithm, which ana- lyses the decorrelation of the signal received by the OCT in a specific geographic location at two different time- points. Similar to Doppler ultrasonography, the detection of two consecutive signals in a retinal vessel allows the de- tection of blood flow, and permits a two-dimensional re- construction of the retinal vascular network. The main advantage of this technique is that it does not need the use of an intravenous dye, and therefore can be performed in a day-by-day basis in all patients. In the field of diabeticretinopathy, OCTA represents an interesting opportunity to evaluate the status of the perifoveal vascular network at different times of the disease, to identify early changes such as capillary dilation, enlargement of foveal avascular zone (FAZ), paramacular areas of capillary nonperfusion and presence of microaneurisms in a non-invasive way [13–18].
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 Treatment DiabeticRetinopathy 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 Treatment DiabeticRetinopathy 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.
Studies were regarded eligible if they accord with the fol- lowing criterias: (1) the study population included patients with DME; (2) the DEX implant (Ozurdex) was included as an intervention; (3) there was a comparison between the DEX implant (Ozurdex®) and anti-VEGF. Through our ana- lysis of the studies, we determined the following primary outcomes. First, the mean BCVA and mean improvement from baseline in BCVA [time points: baseline, 6 months, and 12 months]. BCVA was obtained using the Early Treatment DiabeticRetinopathy Study (ETDRS). Second, the mean CST and mean change from baseline in CST or foveal thickness, and central macular thickness (CMT) was demonstrated on optical coherence tomography (OCT) [time points: baseline, 6 months, and 12 months]. Add- itional outcomes collected included the following: 1) total number of serious adverse events (SAEs) at the end of each study; 2) elevation of intraocular pressure (IOP>21 mmHg, required glaucoma agents for IOP control, or IOP elevation by at least 5 mmHg from baseline at any follow-up visit; 3) the number of cataracts; 4) the mean number of intravitreal injections; and 5) the study design should be randomized controlled trials (RCTs).
stages as non-proliferative diabeticretinopathy (NPDR) and proliferative diabeticretinopathy (PDR). NPDR can be subdivided into mild, moderate and severe. Mild NPDR is an early stage with microaneurysm (MA) and dot/blot hemorrhage (HA) occurring. Flame-shaped hemorrhages (FSHs), hard exudates (HEs) and cotton-wool spots (CWSs) occur in moderate NPDR stage as the disease progresses. In the severe NPDR stage, many more MAs, HAs or venous beading (VB) occurs. The PDR stage is the advanced stage of DR. The significant pathologies are new abnormal blood vessels that called neovascularization (NV), pre-retinal hemorrhages (PHs), vitreous hemorrhage (VH), and fibrous proliferation (FP), which is the cause of tractional retinal detachment. Screening and diagnosing DR early can prevent visual loss and blindness in these diabetic patients. In distant rural area, however, there is no ophthalmologist available. Therefore, we developed automation software that can screen and diagnose
In order to prevent DR comprehensively, it is essential to explore the in ﬂ uence of risk factors and develop an early arti ﬁ cial intelligence (AI) warning system for lesion related to retinopathy. Currently, there are some studies based on AI to detect DR, while the speci ﬁ city or sensi- tivity is still limited, and the algorithms remain controversial. 6,7 Further, there is no prediction model established based on factors affecting DR. Back propaga- tion arti ﬁ cial neural network (BP-ANN) algorithm is a multi-layer feed forward network trained according to error back propagation algorithm and is one of the most widely applied neural network models. 8 However, there is still no report on the prediction model for DR using BP- ANN. This study aimed to establish a prediction model of DR based on physiological and biochemical indicators by using BP-ANN, and to provide a basis for predicting presence of DR.
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.
as 100%. However, we consider the accuracy of BCDRT diagnoses of diabetic macular edema to be acceptable, and one can expect that very few cases of macular edema will be missed using BCDRT. This system is in agreement with the Guidelines for Ocular Telehealth for DR from ATA, and belongs to the “category 2” system, which is defined as the ability to distinguish patients in two categories: (1) those who have non-sight-threatening DR or (2) sight-threatening DR . In addition, the BCDRT system also guarantees the low rate of unread- able photographs for DR screening (≤ 5%) recom- mended by the British Diabetic Association . There is good evidence that pupillary dilation reduces the pro- portion of patients with ungradable retinal images. For example, in the Vine Hill study, ungradable retinal images only occurred in 0.5% of the 201 screened dia- betic patients under mydriasis . However, pupillary dilation requires a higher level of medical supervision in many settings, and places some constraints on patients in performing certain visual tasks until the pupillary dilation dissipates . The proportions of ungradable retinal images differ between DR telehealth screening systems. In the study by Ahmed and associates , 35% of the total images were judged inadequate to be graded fully, and the patients with ungradable eyes were significantly older than those with gradable eyes. Scan- lon and associates 19 have previously shown that for patients 70 years and older, approximately 25% of non- mydriatic images are unreadable. A total of 74.5% (126/ 169) of ungradable eyes had early to obvious central cat- aract, and 10 eyes (6%) had a corneal scar . In the present study, the proportion of media opacity in ungradable images is lower: 73.3% (11/15) of the 15 patients with ungradable images, and who were later referred to in-person examination, were diagnosed with moderate to severe cataract or corneal scar. Further- more, we seldom encountered small pupil size and poor focus or poor patient fixation cases. Therefore, the ungradable rate in the present study (4.88%) seems to be much less than Scanlon’s report. In the study by Gomez-Ulla and associates, the ungradable rate (5.2%) was similar to our result . Cavallerano and associates
The progression to vision-threatening proliferative diabeticretinopathy (PDR) primarily depends on the stage of DR severity. The Early Treatment DiabeticRetinopathy Study (ETDRS) has revealed that the risk of progression from severe non-proliferative diabeticretinopathy (NPDR) to proliferative diabeticretinopathy (PDR) is approximately 52% in one year. 4 Since the time of ETDRS, the management of diabetes has changed significantly. 5 Thus, more recent clinical trials or epidemiologic studies have revealed varying rates of PDR progression from baseline DR in 4 years ranging from 5.3 to 11.0%. 6-10 The key classification of DR was originally defined in the Airlie House Symposium in 1968 and modified in several landmark trials to date. 11,12 In
and VA impairment despite previous anti-VEGF treatment, had modest improvement in visual gain despite signi ﬁ cant reductions in retinal thickness on OCT. 137 In phakic eyes receiving continuous anti-VEGF therapy for DME, the addition of intravitreous corticosteroids did not result in signi ﬁ cant visual improvements. 138,139 Recent reports sum- marizing observational studies investigating dexametha- sone implants in DME have reported similar ﬁ nal VA outcomes when compared to anti-VEGF monotherapy, but superior visual gains in real-life practice. 140–142 There appears to be a predictive correlation between the early response to anti-VEGF therapy with the visual and anato- mical outcomes following a switch to intravitreal corticos- teroids. Those with poor responses to anti-VEGF demonstrated a more robust increase in BCVA. 143 Side effects of cataract in phakic eyes and intraocular pressure elevation without regard to lens status have accompanied all steroids studied, although to varying degrees. 144–149 However, there may be a role for long-acting intraocular corticosteroids in reducing overall treatment burden in DME as early data from both the TYBEE and PALADIN studies have recently demonstrated. 150–152 Likewise, intra- vitreal triamcinolone 4 mg injections for DME reduced 2 step progression in severity of diabeticretinopathy com- pared to focal/grid laser at 3 years. 110 Similar data obtained from the DR-Pro-DEX Study and others demonstrated that the dexamethasone and ﬂ uocinolone implants signi ﬁ cantly delayed the progression and reduced the severity of DR over a 24-month study period. 153,154
Spectral domain Optical coherence tomography (SD- OCT) provides high resolution structural images with precise retinal thickness measurements . It is the tech- nique of choice for early detection of macular edema and for follow-up of diabetic maculopathy. The integrity of ellipsoid zone (EZ) has been found to directly correlate with severity of DR and decrease in best corrected vis- ual acuity (BCVA) [5, 6]. The OCT based macular thick- ness parameters, namely central subfield thickness (CST) and cube average thickness (CAT) have recently been
Diabetes mellitus (DM) is a progressive disease accompanied by metabolic disorders and microvascular complications such as retinopathy, neuropathy, and nephropathy. 1–4 Diabeticretinopathy (DR) is considered one of the most common and severe complica- tions of DM and a major cause of blindness worldwide. Also, it is associated with loss of productivity and quality of life, and may lead to additional socioeconomic burden. 5–7 About 4.8% (1.8 million) of global blindness was due to DR. 8–10 DR is a priority blinding disease and is now included in the disease control strategy of ‘ vision 2020 ’ initiative. 11 Symptoms of diabeticretinopathy include; seeing spots or ﬂ oaters, blurred vision, having a dark or empty spot in the center of vision and dif ﬁ culty seeing well at night. 12 Often, the early stages of DR have no visual symptoms. That is why the American Optometric Association (AOA) 13 recommended that everyone with diabetes have a comprehensive dilated eye examination once a year.