Development and validation of a semi-supervised deep learning model for automatic retinopathy of prematurity staging.

Retinopathy of prematurity (ROP) is currently one of the leading causes of infant blindness worldwide. Recently significant progress has been made in deep learning-based computer-aided diagnostic methods. However, deep learning often requires a large amount of annotated data for model optimization, but this requires long hours of effort by experienced doctors in clinical scenarios. In contrast, a large number of unlabeled images are relatively easy to obtain. In this paper, we propose a new semi-supervised learning framework to reduce annotation costs for automatic ROP staging. We design two consistency regularization strategies, prediction consistency loss and semantic structure consistency loss, which can help the model mine useful discriminative information from unlabeled data, thus improving the generalization performance of the classification model. Extensive experiments on a real clinical dataset show that the proposed method promises to greatly reduce the labeling requirements in clinical scenarios while achieving good classification performance.

Incomplete retinal vascularization with retinopathy of prematurity-like ridges in healthy full-term newborns.

PURPOSE: To describe the characteristics and clinical course of retinopathy of prematurity (ROP)-like ridges in healthy full-term newborns. METHODS: A retrospective medical record review was performed on newborns who underwent fundus photography within 72 h of birth between January 1st and December 31st, 2019 at Women & Children's Health Care Hospital of Huantai, China. The RetCam 3 wide-field digital imaging system was used for fundus photography. ROP-like ridges were discovered and described. RESULTS: Total of 5507 full-term infants underwent fundus photography. ROP-like ridges were discovered in 90 eyes from 57 infants (1.0%). Stage 1 ROP-like was seen in 63 of the eyes (70%), Stage 2 ROP-like in 26 of the eyes (28.9%), and Stage 3 ROP-like in 1 eye (1.1%). These ROP-like ridges were found in Zone II (41.1%) and Zone III (58.9%), but not in Zone I. Eight (8.9%) of the eyes had pre-plus-like diseases. No eyes had plus disease. All ROP-like ridges and pre-plus-like diseases were spontaneously regressed with a mean duration of 39.0 ± 8.2 days. Male sex (P = 0.003) was positively associated with ROP-like changes. CONCLUSION: Healthy full-term newborns may have incomplete retinal vascularization and ROP-like ridges at birth. These ROP-like ridges showed signs of spontaneous regression.

Dry-Lensectomy Assisted Lensectomy in the Management for End-Stage Familial Exudative Vitreoretinopathy Complicated With Anterior Segment Abnormalities.

Purpose: To report a modified technique of dry-lensectomy assisted lensectomy in the management of end-stage familial exudative vitreoretinopathy (FEVR) complicated with capsule-endothelial, iris-endothelial adhesion and secondary glaucoma. Methods: 24 eyes of 16 patients with severe complications of advanced pediatric total retinal detachment caused by FEVR who received limbus-based dry-lensectomy were studied retrospectively. Preoperative and postoperative clinical information was collected and reviewed. Results: Among the 24 eyes, three eyes (12.50%) underwent lensectomy combined with vitrectomy and membrane peeling simultaneously. 21 (87.50%) eyes underwent lensectomy without membrane peeling due to severe corneal opacity or retinal vascular activity, of which eight underwent another vitrectomy combined with membrane peeling. At the last visit (mean:13.86 ± 5.24 months of follow-up), all eyes had a reconstructed anterior chamber with normal depth. Among 21 eyes having preoperative corneal opacity, 15 (71.43%) had a clearer cornea with reduced opacity, 5 (23.81%) showed similar corneal opacification without deterioration. Among 11 eyes undergone retrolental fibroplasia peeling, seven (63.64%) eyes showed partial retinal reattachment in open-funnel type. Conclusion: Dry-lensectomy offered a simple way to lower the intraocular pressure and simplified the surgery, which helped to solve the severe anterior segment complications and offer a chance for following retrolental fibroplasia peeling and potential visual gain for selected end-stage FEVR patients.

Early detection of ocular abnormalities in a Chinese multicentre neonatal eye screening programme-1-year result.

PURPOSE: Early detection of ocular abnormalities in newborns is essential for timely diagnosis and treatment. This study aimed to assess the 1-year result of a multicentre prospective neonatal eye examination programme with wide-field digital imaging system in China. METHODS: A multicentre collaborative prospective study group for neonatal eye screening was established in nine hospitals, including eight Maternal and Children's Hospitals, and one general hospital across China from July 2016 to June 2017. Ocular examinations were performed on newborns within 28 days after birth using a wide-field digital imaging system. Data were reviewed and analysed. The primary outcome was the prevalence of ocular abnormalities in neonates. RESULTS: We detected 13 514 (20.91%) abnormal cases in 64 632 newborns. The most frequent abnormality was retinal haemorrhage (RH; 11.83%). Most of mild RH resolved spontaneously. Among those who were beyond retinopathy of prematurity (ROP) screening criteria of China (gestational age ≥32 w and birthweight ≥2000 g), the total number of neonates with ocular abnormality was 12 218/62 799(19.45%). 59.44% of neonatal ocular abnormalities detected (accounting for 11.56% of all the screened population) needed further interference or observation. Among them, 258 patients (0.41% of all the screened population) needed immediate or timely intervention, including congenital cataract, retinal detachment, retinoblastoma and other ocular abnormalities. One thousand and ninety-eight patients (1.75% of all the screened neonates) should be followed up closely and needed further diagnosis or intervention if necessary, such as ROP or ROP-like retinopathy, familial exudative vitreoretinopathy and persistent hyperplasia of primary vitreous. Five thousand nine hundred and six patients (9.4%) with minor clinical significance needed short-term follow-up. CONCLUSIONS: This prospective multicentre study of newborn ocular examination showed a relatively high prevalence of ocular abnormalities. There are a relatively high percentage of congenital eye pathology that required further referral and treatment in those neonates who were not screened routinely. According to the benefits and risks associated with neonatal eye examinations, neonatal ocular screening programme can detect ocular abnormalities at the very early stage and may play a positive role in promoting paediatric eye health.

Peripheral Vascular Abnormalities Detected by Fluorescein Angiography in Contralateral Eyes of Patients With Persistent Fetal Vasculature.

BACKGROUND AND OBJECTIVE: To describe peripheral retinal vascular abnormalities in the contralateral eyes of patients with unilateral persistent fetal vasculature (PFV). PATIENTS AND METHODS: Retrospective medical record review of fluorescein angiography (FA) findings of patients with unilateral PFV. Width of the temporal peripheral avascular retina in contralateral eyes was measured in disc diameters (DD). Vascular abnormalities were described. RESULTS: In 45 included patients, mean width of temporal peripheral avascular areas in contralateral eyes was 1.87 ± 0.71 DD. Forty-three patients (95.6%) had temporal peripheral avascular areas of 1 DD or greater in contralateral eyes, with 16 having temporal peripheral avascular areas of 2 DD or greater. Vessel shunts, vascular tortuosity and dilatation, circumferential vessels, and abnormal capillary beds in the peripheral retina were observed in 23 (51.1%) contralateral eyes of patients with unilateral PFV. CONCLUSION: PFV patients should undergo careful evaluations of both eyes, preferably with FA, to identify vascular changes that are not visible clinically. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:506-511.].

Incontinentia pigmenti-associated ocular anomalies of paediatric incontinentia pigmenti patients in China.

PURPOSE: To characterize ocular manifestations in a cohort of paediatric patients with incontinentia pigmenti (IP) and to define the guidelines for grading of IP-associated retinopathy (IPR). METHODS: This retrospective review was performed on patients under the age of 18 years with a diagnosis of IP. Data included demographics, medical history, ocular examination, and accessory examination. Ocular and systemic physical examinations of the parents were carried out to determine the familial history. RESULTS: Sixty-one children (58 females and three males) with median age of 3.7 months were observed consecutively. The median follow-up duration was 13.4 months (range: 6.5-75.0 months). A total of 47 patients had various ocular anomalies. Among them, 28 patients had bilateral ocular anomalies and 19 had unilateral anomalies. Vitreoretinal changes were noted in 73 of 122 eyes, including eight eyes with retinal pigment epithelium changes only (Stage 1), 22 eyes with retinal vascular abnormalities (Stage 2), five eyes with epiretinal membranes or fibrotic hyperplasia combined with avascularized zones (Stage 3), six eyes with retinal neovascularization (Stage 3), one eye with vitreous haemorrhage (Stage 3), 10 eyes with partial retinal detachment (RD) (Stage 4a), 15 eyes with total RD (Stage 4b) and eight eyes with phthisis bulbi and secondary glaucoma (Stage 5). CONCLUSION: Various vitreoretinal manifestations can be found in paediatric patients with IP and classified into five stages, which are characterized by retinal vasculopathy.

Peripheral Retinal Nonperfusion in Pediatric Patients With Morning Glory Syndrome.

BACKGROUND AND OBJECTIVE: To report the association of morning glory syndrome (MGS) with peripheral retinal nonperfusion in pediatric patients with MGS. PATIENTS AND METHODS: The authors retrospectively analyzed the records of pediatric patients with MGS using fundus fluorescein angiography. The peripheral retinal vascular architecture was recorded and graded according to the severity of peripheral retinal nonperfusion. RESULTS: Eighty-six eyes of 74 patients were enrolled. Seventy-three of 86 eyes (84.88%) had peripheral retinal nonperfusion, in which mild severity was found in 31 of 86 eyes (36.05%), moderate in 17 of 86 eyes (19.77%), severe in 18 of 86 eyes (20.93%), and extreme in seven of 86 eyes (8.14%). Secondary complications of nonperfusion included leakage in six of 73 eyes (8.22%), fibrovascular proliferation in two of 73 eyes (2.74%), and tractional retinal detachment in one of 73 eyes (1.34%). CONCLUSION: There is a high prevalence of peripheral retinal nonperfusion in pediatric MGS eyes, with secondary complications in some, suggesting that more attention should be paid to the peripheral retina in MGS. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:674-679.].

miR-330-5p/Tim-3 axis regulates macrophage M2 polarization and insulin resistance in diabetes mice.

Obesity is associated with a state of low-grade inflammatory response in adipose tissue, and contributes to the development of type 2 diabetes. Immune cells such as macrophages can infiltrate adipose tissue and are responsible for the majority of inflammatory cytokine production. Therefore, adipose tissue promotes macrophage infiltration, resulting in local inflammation and insulin resistance. Tim-3 negatively regulates IFN-γ secretion and influences the ability to induce T cell tolerance in diabetes. MicroRNA contributes to the development of immunological tolerance and involves in macrophage polarization. However, the potential of Tim-3 to regulate macrophage polarization and the related microRNA has not been reported. In this experiment, 8-week-old C57BL/6 mice were fed a high-fat diet for 8 weeks. The adipose tissue macrophages were isolated, miR-330-5p and Tim-3 levels, and M1/M2 polarization were analyzed. In addition, insulin tolerance tests was detected. The results demonstrated that miR-330-5p levels increased but Tim-3 levels decreased, leading to M1 polarization and insulin tolerance in diabetes mice. In addition, inhibition of miR-330-5p enhanced Tim-3 levels, leading to M2 polarization and insulin tolerance attenuation in diabetes mice. Furthermore, we detected the inverse relationship between miR-330-5p and Tim-3. We found that Tim-3 mRNA contained conserved miR-330-5p binding sites in its 3'UTR, and miR-330-5p could directly regulate Tim-3 expression through these 3'UTR sites. Our study demonstrated that miR-330-5p served as a regulator of the M2 polarization and miR-330-5p/Tim-3 axis potentially down-regulated insulin resistance in diabetes, probably through enhancing the M2 polarization of macrophage.

A novel mimovirus encoding ChgA10-19 peptide with PD-L1 induces T cell tolerance and ameliorates the severity of diabetes.

Related studies demonstrate that type 1 diabetes (T1D) is caused by ß-cell antigen specific autoreactive CD8+ T cells. ChgA has recently been identified as the autoantigen in NOD mice and T1D patients. Therefore, attenuating the activation of ChgA specific CD8+ T cells might be a promising target for T1D therapy. The negative co-stimulatory PD-L1 inhibits T cell mediated alloimmunity and induces tolerance. In this experiment, a novel mimovirus encoding ChgA10-19 peptide with PD-L1 was constructed. The NOD.ß2m null HHD mice were administrated with mimovirus transduced DCs. After immunization, the activation and proliferation of CD8+ T cells were detected, diabetes incidence and pancreatic tissue destruction were also analyzed. The results demonstrated that transduced DCs attenuated CD8+ T cell activation and proliferation. In addition, transduced DCs inhibited CD8+ T response to ChgA stimulation, and ameliorated the severity of diabetes. These data suggested that mimovirus transduced DCs might provide novel clues for T1D therapy.

Early onset coats' disease initially treated as unilateral ROP at 39 weeks postmenstrual age: a case report.

BACKGROUND: This is the youngest case of Coats' disease, in terms of postmenstrual age (PMA), to be reported in the literature. This case highlights the remarkable variations in the clinical manifestations and the very early onset of Coats' disease. This case is unusual in both the age of onset and atypical clinical features, which resemble retinopathy of prematurity (ROP). CASE PRESENTATION: We report a case of a preterm boy born at 31 5/7 weeks gestational age who presented with atypical Coats' disease and was initially diagnosed as having ROP of only one eye at 39 weeks PMA. After initial laser treatment, severe exudative retinal detachment (ERD) occurred after initial laser treatment for ROP. Fundus fluorescein angiography (FFA) showed telangiectasia and anastomosis of peripheral retinal vessels and nonperfusion areas, and the diagnosis of Coats' disease was thus established. A series of intravitreal injections of ranibizumab (IVR) and laser ablations were performed to resolve the exudation and to ablate the abnormal vessels. At the last visit, the retinopathy was under control, and useful vision was preserved. CONCLUSIONS: Coats' disease resembling stage 3 ROP can be detected before the expected date of childbirth. Therefore, asymmetric ROP should be differentiated from Coats' disease.

Asymmetric Outcomes of Type 1 Retinopathy of Prematurity after Bilateral Intravitreal Ranibizumab Treatment.

Purpose. To present cases with retinopathy of prematurity (ROP), who were treated with intravitreal injection of ranibizumab (IVR) and had unpredictable asymmetric outcomes. Methods. A retrospective review was performed in infants with type 1 ROP and had bilateral IVR (0.25 mg/0.025 mL) as initial treatment. Patients were classified into the asymmetric outcome group and the symmetric outcome group. Results. Eighty-four patients (168 eyes) were included. There were 18 eyes of 9 patients (10.7%) in the asymmetric outcome group and 150 eyes of 75 patients (89.3%) in the symmetric outcome group. In the symmetric outcome group, 86 eyes (57.3%) had ROP regression, 60 eyes (40%) had reactivation requiring laser treatment, and 4 eyes (2.7%) progressed to retinal detachment requiring vitrectomy. In the asymmetric outcome group, one of the eyes of the 9 patients had ROP regression with/without reactivation after IVR, while the contralateral eyes had negative response, including remarkable posterior fibrosis, partial or total retinal detachment, and vitreous hemorrhage. There was statistically significant difference between the birth weight of the two groups. Conclusion. Contralateral eyes with ROP can take a different clinical course after ranibizumab treatment. High rate of reactivation after IVR is another concern that ophthalmologists should pay attention to.

Ranibizumab Injection as Primary Treatment in Patients with Retinopathy of Prematurity: Anatomic Outcomes and Influencing Factors.

PURPOSE: To investigate the anatomic outcomes and influencing factors of ranibizumab in the treatment of retinopathy of prematurity (ROP). DESIGN: Retrospective case series. PARTICIPANTS: A total of 283 eyes of 145 patients with type 1 ROP treated with intravitreal injection of ranibizumab (IVR) as primary treatment. METHODS: Retrospective review of infants who were diagnosed with type 1 ROP and accepted IVR (0.25 mg/0.025 ml) as primary treatment from January 2012 to August 2015. The anatomic outcomes and the influencing factors were analyzed. MAIN OUTCOME MEASURES: Anatomic outcomes of ROP eyes after IVR and the influencing factors. RESULTS: A total of 283 eyes of 145 patients were included in this study. There were a total of 266 eyes (94.0%) in the positive response group and 17 eyes (6.0%) in the negative/no response group after IVR. Within the positive response group, 139 eyes (48.6%) were in the regression without reactivation subgroup, and 127 eyes (44.9%) were in the regression with reactivation subgroup. A total of 152 eyes received additional laser or surgical treatment. At the last visit, 278 eyes (98.2%) had attached retinas, and 5 eyes (1.8%) had retinal detachment. A classification tree model showed that for patients with gestational age (GA) ≤29.5 weeks, the possibility of experiencing reactivation after IVR is higher than that of those with GA >29.5 weeks (61.6% vs. 29.6%). Moreover, for patients with GA ≤29.5 weeks, those diagnosed with zone II stage 2+ ROP have a lower possibility of experiencing reactivation than other patients (37.9% vs. 80%). CONCLUSIONS: Intravitreal injection of ranibizumab seemed to be effective in treating patients with ROP. After treatment, there were primarily 3 different outcomes. Our predictive tree model is helpful for ophthalmologists to evaluate the risk of reactivation.

Recurrence of Retinopathy of Prematurity After Intravitreal Ranibizumab Monotherapy: Timing and Risk Factors.

Purpose: To investigate timing and risk factors of recurrent retinopathy of prematurity (ROP) after intravitreal ranibizumab (IVR) monotherapy. Methods: Fifty eyes (the more severe eye) of 50 infants treated with IVR monotherapy for type 1 ROP were studied retrospectively. The mean follow-up time was 31 weeks after IVR. Recurrent ROP (recurrence of extraretinal fibrovascular proliferation [EFP]) was determined by RetCam wide-angle fundus imaging and binocular indirect ophthalmoscopy. Risk time of recurrence was estimated by Kaplan-Meier survival analysis with recurrence as the endpoint. Time-varying recurrence hazard rate was determined using the hazard function of life-table analysis. The risk factors of recurrence were explored by logistic regression analysis. Results: Recurrence of ROP occurred in 32 (64%) of 50 eyes at 7.9 ± 2.7 weeks after IVR. Most of recurrence (94%) occurred in 2.5 to 12.0 weeks following IVR treatment. The recurrence hazard rate reached its maximum at 8 weeks. Recurrence affecting the initial site of EFP occurred significantly earlier than recurrence only at the new vascular advancing edge (4.5 ± 1.4 weeks versus 9.1 ± 2.0 weeks after IVR, P < 0.001). The independent risk factors of recurrence included extensive retinal neovascularization (P = 0.005) and oxygen requirement after IVR (P = 0.016). Conclusions: Recurrence of type 1 ROP should be carefully watched in a long-term follow-up after IVR monotherapy, particularly in the first 12 weeks after IVR and for those with extensive retinal neovascularization or prolonged oxygen therapy.

Identification of novel KIF11 mutations in patients with familial exudative vitreoretinopathy and a phenotypic analysis.

KIF11 gene mutations cause a rare autosomal dominant inheritable disease called microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (MCLMR). Recently, such mutations were also found to be associated with familial exudative vitreoretinopathy (FEVR). Here, we report 7 novel KIF11 mutations identified by targeted gene capture in a cohort of 142 probands with FEVR who were diagnosed in our clinic between March 2015 and November 2015. These mutations were: p.L171V, c.790-2A>C, p.Q525*, p.Q842*, p.S936*, p.L983fs and p.R1025G. Phenotypic analysis revealed that all of the affected probands had advanced FEVR (stage 4 or above). Three had microcephaly, and one had chorioretinopathy, which indicated a phenotypic overlap with MCLMR. Two mutations were also found in the families of the affected probands. One parent with a p.R1025G mutation had an avascular peripheral retina and abnormal looping vessels. However, one parent with p.L983fs had normal retina, which indicated incomplete penetration of the genotype. Our results further confirmed that KIF11 is causative of FEVR in an autosomal dominant manner. We also suggest the examination of MCLMR-like features, such as microcephaly, chorioretinopathy, for patients with FEVR and wide-field fundus photography for patients with MCLMR in future practice.

Combination of Intravitreal Injection of Ranibizumab and Photocoagulation for the Treatment of Aggressive Posterior Retinopathy of Prematurity with Vitreous Hemorrhage.

To investigate the efficacy of intravitreal ranibizumab (IVR) combined with laser photocoagulation for aggressive posterior retinopathy of prematurity (AP-ROP) patients with vitreous hemorrhage, we conducted a retrospective observational case series study. A total of 37 eyes of 20 patients' medical records were reviewed. Patients first received IVR (0.25 mg/0.025 mL) and later photocoagulation. The mean postconceptual age of injection was 34.6 ± 1.4 weeks, and the mean follow-up period was 39.3 ± 8.3 weeks. During the follow-up, 96.6% eyes had various degree of rapid absorption of vitreous hemorrhage after IVR. The mean time of received first photocoagulation after IVR was 4.8 ± 2.9 weeks. Ten (27.0%) eyes received second laser therapy and the mean time of second laser therapy after IVR was 3.2 ± 0.8 weeks. All eyes exhibited adequate regression of ROP and were stable with attached retina. Fibrosis membrane was observed in seven eyes (18.9%) and three of them demonstrated mild ectopic macula. No significant side effects related to IVR were observed. So IVR could be conducted as primary treatment of AP-ROP associated with vitreous hemorrhage, which can improve the fundus visibility, followed by conventional photocoagulation. Further randomized controlled trials are necessary to compare the clinical efficacy and safety with conventional interventions.