Characterization and validation of a chronic retinal neovascularization rabbit model by evaluating the efficacy of anti-angiogenic and anti-inflammatory drugs

AIM: To establish a rabbit model with chronic condition of retinal neovascularization (RNV) induced by intravitreal (IVT) injection of DL-2-aminoadipic acid (DL-AAA), a retinal glial (Müller) cell toxin, extensive characterization of DL-AAA induced angiographic features and the suitability of the model to evaluate anti-angiogenic and anti-inflammatory therapies for ocular vascular diseases. METHODS: DL-AAA (80 mmol/L) was administered IVT into both eyes of Dutch Belted rabbit. Post DL-AAA delivery, clinical ophthalmic examinations were performed weekly following modified McDonald-Shadduck Scoring System. Color fundus photography, fluorescein angiography (FA), and optical coherence tomography (OCT) procedures were performed every 2 or 4wk until stable retinal vascular leakage was observed. Once stable retinal leakage (12wk post DL-AAA administration) was established, anti-vascular endothelial growth factor (VEGF) (bevacizumab, ranibizumab and aflibercept) and anti-inflammatory (triamcinolone, TAA) drugs were tested for their efficacy after IVT administration. Fluorescein angiograms were scored before and after treatment following a novel grading system, developed for the DL-AAA rabbit model. RESULTS: Post DL-AAA administration, eyes were presented with moderate to severe retinal/choroidal inflammation which was accompanied by intense vitreous flare and presence of inflammatory cells in the vitreous humor. Retinal hemorrhage was restricted to the tips of neo-retinal vessels. FA revealed maximum retinal vascular leakage at 2wk after DL-AAA injection and then persisted as evidenced by stable mean FA scores in weeks 8 and 12. Retinal vascular angiographic and tomographic features were stable and consistent up to 36mo among two different staggers induced for RNV at two different occasions. Day 7, mean FA scores showed that 1 µg/eye of bevacizumab, ranibizumab, aflibercept and 2 µg/eye of TAA suppress 65%, 90%, 100% and 50% retinal vascular leakage, respectively. Day 30, bevacizumab and TAA continued to show 66% and 44% suppression while ranibizumab effect was becoming less effective (68%). In contrast, aflibercept was still able to fully (100%) suppress vascular leakage on day 30. On day 60, bevacizumab, ranibizumab and TAA showed suppression of 7%, 12%, and 9% retinal vascular leakage, respectively, however, aflibercept continued to be more effective showing 50% suppression of vascular leakage. CONCLUSION: The DL-AAA rabbit model mimics RNV angiographic features like RNV and chronic retinal leakage. Based on these features the DL-AAA rabbit model provides an invaluable tool that could be used to test the therapeutic efficacy and duration of action of novel anti-angiogenic formulations, alone or in combination with anti-inflammatory compounds.

Baseline predictors for subretinal fibrosis in neovascular age-related macular degeneration

To find baseline predictors for subretinal fibrosis (SF) in neovascular age-related macular degeneration (nAMD). Forty-five eyes of 45 participants with treatment-naïve nAMD were consecutively enrolled and treated according to a standardized treat-and-extend protocol. Spectral-domain optical coherence tomography (OCT), color fundus photography and fluorescein angiography as well as novel imaging modalities polarization-sensitive OCT and OCT angiography (OCTA) were performed to detect SF after 1 year and find baseline predictors for SF development. Baseline OCTA scans were evaluated for quantitative features such as lesion area, vessel area, vessel junctions, vessel length, vessel endpoints and mean lacunarity. Additionally, the type of macular neovascularization, the presence of subretinal fluid, intraretinal fluid (IRF), subretinal hyperreflective material (SHRM), retinal hemorrhage as well as best-corrected visual acuity (BCVA) were evaluated. After 12 months 8 eyes (18%) developed SF. Eyes with SF had worse baseline BCVA (p = .001) and a higher prevalence of IRF (p = .014) and SHRM at baseline (p = .017). There was no significant difference in any of the evaluated quantitative OCTA parameters (p > .05) between eyes with and without SF. There were no quantitative baseline microvascular predictors for SF in our study. Low baseline BCVA, the presence of IRF and SHRM, however, are easily identifiable baseline parameters indicating increased risk.

Data Homogeneity Effect in Deep Learning-Based Prediction of Type 1 Diabetic Retinopathy

This study is aimed at evaluating a deep transfer learning-based model for identifying diabetic retinopathy (DR) that was trained using a dataset with high variability and predominant type 2 diabetes (T2D) and comparing model performance with that in patients with type 1 diabetes (T1D). The Kaggle dataset, which is a publicly available dataset, was divided into training and testing Kaggle datasets. In the comparison dataset, we collected retinal fundus images of T1D patients at Chang Gung Memorial Hospital in Taiwan from 2013 to 2020, and the images were divided into training and testing T1D datasets. The model was developed using 4 different convolutional neural networks (Inception-V3, DenseNet-121, VGG1, and Xception). The model performance in predicting DR was evaluated using testing images from each dataset, and area under the curve (AUC), sensitivity, and specificity were calculated. The model trained using the Kaggle dataset had an average (range) AUC of 0.74 (0.03) and 0.87 (0.01) in the testing Kaggle and T1D datasets, respectively. The model trained using the T1D dataset had an AUC of 0.88 (0.03), which decreased to 0.57 (0.02) in the testing Kaggle dataset. Heatmaps showed that the model focused on retinal hemorrhage, vessels, and exudation to predict DR. In wrong prediction images, artifacts and low-image quality affected model performance. The model developed with the high variability and T2D predominant dataset could be applied to T1D patients. Dataset homogeneity could affect the performance, trainability, and generalization of the model.

Ocular ultrasonography for detection of posterior segment pathology in adult patients presenting with blurred vision

Background and objective: Ocular posterior segment lesions can affect individuals of both sexes at all ages. Such lesions can lead to serious manifestations such as retinal detachment and retinal hemorrhage, leading to permanent loss of eyesight. This study aimed to determine the association between age and gender and changes in ocular posterior segment based on ultrasonography findings. Methods: This prospective cross-sectional study included 50 patients with blurry vision who had been referred from ophthalmology outpatient clinics to the radiology department of Rizgary Teaching Hospital in Erbil, Kurdistan region in Iraq. Required data were collected using a researcher-designed questionnaire, and the patients were examined using a high resolution 7.5-10 MHz linear array ultrasound transducer. Results: The most frequent complications associated with ocular posterior segment pathologies were old vitreous hemorrhage (72%), posterior vitreous detachment (36%), and retinal detachment (34%). Diabetes and hypertension were the most frequent diseases associated with ocular posterior segment pathology. A significant association was seen between the patients' age with old vitreous hemorrhage (P = 0.003). A significant association was seen between the patients’ medical conditions with old vitreous hemorrhage and retinal detachment. There was no significant correlation between the patients’ gender and the studied ocular posterior segment pathologies. Conclusion: Age has a strong correlation with old vitreous hemorrhage, chronic medical conditions such as diabetes, and hypertension correlated with old vitreous hemorrhage and retinal detachment. Keywords: Ocular ultrasonography; Posterior segment pathology; Blurred vision; Age; Gender.

Improving the Diagnosis of Abusive Abdominal Trauma

Background/Objective: Abusive abdominal trauma (AAT) in children when missed can be fatal. In addition, differentiating from accidental trauma is essential in evaluating for other injuries and protecting from continued inflicted injuries. Abdominal CT remains the gold standard study to evaluate for abdominal injuries. Our purpose is to identify findings in presentation, clinical evaluation, the abdominal CT, and other imaging that can improve the diagnosis of abusive abdominal trauma. Methods: A retrospective (2011-2020) study compared children younger than 3 years that had abdominal CT scans for abusive trauma to those with accidental blunt abdominal trauma. Demographic information, clinical presentation, physical exam findings, final diagnoses, lab values, and imaging studies were collected. Descriptive analysis and Fisher’s exact test were used to determine significance of findings. Results: 226 (125 male, average age 11 months) patients had AAT and 90 (48 male, average age 18 months) patients had accidental trauma. 30 patients in the abusive group and 19 patients in the accidental group had positive CT. Most (70%) children with AAT and positive CT had no explanation for the trauma. Fall injury was reported in 27% of abusive (88.9% younger than 1 years) and 32% (83.3% older than 1 year) of accidental trauma. Retinal hemorrhage, abdominal bruising, subdural hematoma, and rib fractures were significantly (p<0.05) more common in the abusive group. In addition, 13 (43%) of patients with AAT and positive CT had rib fractures while none were detected on CT in the accidental group. Conclusions: In children younger than 3 years with abdominal trauma that present with a history of a fall or unknown injury, abusive abdominal trauma should be suspected. These children should subsequently be evaluated for other injuries. Children should be evaluated for nonaccidental trauma if rib fractures are visualized on abdominal CT, as these were only seen in AAT.

Frequency of retinal hemorrhage after thrombolysis with streptokinase in patients presenting with ST-elevation myocardial infarction: A single-center experience at a large tertiary care center in Lahore, Pakistan

Background: Thrombolytic therapy with streptokinase is the mainstay of pharmacological treatment in acute myocardial infarction in Pakistan. Retinal hemorrhage is a common complication of streptokinase-induced thrombolysis and is often overlooked which can lead to permanent vision loss. Therefore, this study was carried out to determine the frequency of retinal hemorrhage after thrombolysis with streptokinase in patients presenting with ST-elevation myocardial infarction (STEMI). Patients and methods: It was an observational, cross-sectional study conducted at the Emergency Department of Mayo Hospital Lahore from 11-08-2015 to 10-02-2016. The patients underwent injection of streptokinase (1.5 million U) intravenously over 60 min and intravenous heparin 5,000 U bolus followed by 1,000 U/hour. Then patients were followed up for 24 hours followed by the ophthalmoscopy to confirm the presence of retinal hemorrhage. The data were entered and analyzed using SPSS version 20. Results: A total of 130 patients were included in this study. The mean age of patients was 62±9.86 years. The male to female ratio was 1.6:1. The retinal hemorrhage was present in 17 (13.08%) patients. About 80 (61.5%) were diabetics and 96 (73.8%) were hypertensive. Stratified variables like age, gender, hypertension, and diabetes were not found associated with retinal hemorrhage (p-value ≥0.05). Conclusion: Retinal hemorrhage was found in 13.08% after streptokinase injection in patients presenting with STEMI. Although the association was statistically insignificant but still the proportion of retinal hemorrhage was substantially high in these patients. This higher percentage demands vigilant monitoring with the drug for timely diagnosis of this ignored complication which latter can be proved hazardous to the vision.

Retinal Hemorrhage after SARS-CoV-2 Vaccination

To report retinal vein occlusion (RVO) and age-related macular degeneration (AMD)-related submacular hemorrhage developing after administration of SARS-CoV-2 vaccines, a single-center, retrospective observational case series was conducted. Clinical data including fundus photographs and optical coherence tomography (OCT) scans were reviewed. Twenty-three eyes of 21 patients were included with the median age at symptom presentation being 77 years (range: 51–85 years). Twelve eyes (52.2%) had submacular hemorrhage and 11 (47.8%) had RVO. Twelve patients (60.9%) had been vaccinated with the Pfizer vaccine (BNT162b2) and 8 with the AstraZeneca (ChAdOx1) vaccine. Sixteen patients (76.2%) experienced ocular disease exacerbation after the first vaccination and 4 (19.0%) after the second vaccination. The median visual acuity (logarithm of the minimal angle of resolution; logMAR) before symptom development was 0.76 (interquartile range: 0.27–1.23); the median logMAR at symptom presentation was 1.40 (interquartile range 0.52–1.70). The median time between vaccination and symptom exacerbation was 2.0 days (interquartile range: 1.0–3.0 days). Five patients (23.8%) underwent tests for hematological abnormalities, including the presence of anti-PF4 antibodies; all were negative. Further studies with larger patient group for evaluation of effect of SARS-CoV-2 vaccination on retinal hemorrhage are necessary.

Vitreous hemorrhage: A rare ophthalmic adverse effect due to imatinib treatment

Introduction Imatinib is generally well tolerated by patients. The most common ophthalmic side effects are eyelid edema and periorbital edema. Other side effects which occur at rates of <1% include blepharitis, blurred vision, conjunctival hemorrhage, conjunctivitis, retinal hemorrhage, etc. An uncommon case is here reported of a 51-year-old male with chronic myeloid leukemia who developed vitreous hemorrhage due to imatinib after 9 months of treatment. Case report A 51-year-old male with leukocytosis detected in the blood test examination was referred to the Hematology Department. The bone marrow biopsy result was compatible with chronic myeloid leukemia. Imatinib treatment (400 mg/day) was started. In the ninth month of imatinib treatment, the patient complained of a sudden decrease in vision. Vitreous hemorrhage was detected in the left eye and the patient underwent surgery. Vitreous hemorrhage recurred 1 month after the operation. On the fourth day after the discontinuation of imatinib treatment, the patient's ophthalmic complaints improved significantly. The Naranjo algorithm was applied and a score of 9 was detected. The vitreous hemorrhage of the patient was attributed to imatinib, and so the treatment of the patient was switched to bosutinib. Discussion Imatinib is an oral signal inhibitor that targets tyrosine kinase for BCR/ABL, platelet-derived growth factor, stem cell factor, and c-kit (CD117). The conjunctiva and sclera have a large amount of c-kit positive mast cells which are inhibited by imatinib. The inhibition of c-kit positive mast cells by imatinib may be responsible for further exposure of the conjunctival mucosa to injuries.

Retinal abnormalities in universal eye screening of healthy, full-term newborn infants in Jakarta. The incidence and its risk factors: a pilot study

Aim To screen for ocular abnormalities in healthy full-term newborn infants using wide-field digital imaging and to analyze factors associated with the findings. Methods A total of 1208 full-term newborn infants at a tertiary eye hospital (Cipto Mangunkusumo National Referral Hospital) and a district hospital in Jakarta (Koja Hospital) were enrolled to the study. All eligible newborns underwent fundus examination within 48 h after birth using the RetCam shuttle (Natus Medical Incorporated, USA). Retinal findings were documented and analyzed according to obstetric and neonatal risk factors. Results Of the 1208 newborn infants enrolled, ocular abnormalities were found in 150 infants (12.4%). Retinal hemorrhage (RH) was the most common finding (88%) in which 2.67% involved the macula, followed by chorioretinitis (4.67%). Univariate analysis showed caesarean section (C-section) (OR 0.27, 95% CI 0.18–0.41, p < 0.001) was a protective factor against RH, while prolonged labor increased the risk of developing RH (OR 1.84, 95% CI 1.24–2.72, p = 0.002). Further multivariate analysis showed similar protective association between C-section and risk of RH (OR 0.29, 95% CI 0.19–0.44, p < 0.001), while other risk factors were not. Conclusions Our study showed that universal eye screening in healthy neonates is beneficial in the early diagnosis, monitoring and treatment of ocular abnormalities such as retinal hemorrhage, chorioretinitis and retinoblastoma. Retinal hemorrhage is the most common ocular abnormality and is associated with the delivery method and the duration of labor. Universal eye screening is visual-saving and life-saving for neonates with chorioretinitis, retinoblastoma as well as other abnormalities and should be mandatory in newborn screening.

Elevated retinal artery vascular resistance determined by novel visualized technique of laser speckle flowgraphy in branch retinal vein occlusion

We aimed to investigate the increase in resistivity of the retinal artery in the branch retinal vein occlusion (BRVO)-affected area, and to visualize it. Thirty-two eyes of 32 patients with BRVO were measured by laser speckle flowgraphy (LSFG). The retinal artery and vein running to the BRVO-affected area and vertically symmetrical vessels in the unaffected area were examined. We applied the LSFG parameter beat strength over mean blur rate (BOM), calculated using a similar method to the pulsatility index used in Doppler flowmetry to evaluate resistivity of the vessels. Our results showed that the BOM map could clearly visualize the increase of resistivity in the retinal artery as a two-dimensional map. The BOM of the arteries in the affected area was significantly higher than that of the unaffected area (P = 0.001). Multiple regression analysis showed that the ratio of BOM in retinal arteries of the affected area to the unaffected was significantly associated with the extent of retinal hemorrhage (β = 0.447, P = 0.009). In conclusion, the index of resistivity of the retinal artery in the BRVO-affected area was higher and could be visualized in a two-dimensional map. These findings and techniques would contribute to elucidate the pathophysiology of BRVO.