Occult retinal neovascularization following intravitreal bevacizumab and laser treatment for retinopathy of prematurity.

BACKGROUND: We present a patient with retinopathy of prematurity (ROP) who developed worsening plus disease after complete regression of stage 3 ROP. The use of fundus fluorescein angiography (FFA) aided the visualization of occult neovascularization that caused the disease progression. CASE PRESENTATION: The patient was at high risk for ROP due to low birth weight of 690 g and gestational age of 25 weeks. After the diagnosis of stage 3 ROP in zone I without plus disease, she was treated initially with bilateral intravitreal bevacizumab (IVB) and followed by laser photocoagulation 5 weeks later. Despite the resolution of ROP stage, the plus disease worsened. Neither systemic risk factors nor skip laser areas were observed. Hence, FFA was performed and subsequently identified occult neovascularization with active leakage. Additional IVB and laser treatment in the capillary dropout area inside vascularized retina were added. The plus disease improved but mild arteriolar tortuosity persisted. CONCLUSIONS: Worsening of plus disease after completion of laser ablation and IVB with complete regression of stage 3 ROP is rare. Systemic risk factors such as continuous oxygen therapy and cardiovascular disease should be ruled out. FFA aided in identifying occult neovascularization and prompted further treatment.

Feature-Based Classification of Mild Cognitive Impairment and Alzheimer's Disease Based on Optical Coherence Tomographic Angiographic Image.

Alzheimer's disease is a type of neurodegenerative disorder that is characterized by the progressive degeneration of brain cells, leading to cognitive decline and memory loss. It is the most common cause of dementia and affects millions of people worldwide. While there is currently no cure for Alzheimer's disease, early detection and treatment can help to slow the progression of symptoms and improve quality of life. This research presents a diagnostic tool for classifying mild cognitive impairment and Alzheimer's diseases using feature-based machine learning applied to optical coherence tomographic angiography images (OCT-A). Several features are extracted from the OCT-A image, including vessel density in five sectors, the area of the foveal avascular zone, retinal thickness, and novel features based on the histogram of the range-filtered OCT-A image. To ensure effectiveness for a diverse population, a large local database for our study was collected. The promising results of our study, with the best accuracy of 92.17,% will provide an efficient diagnostic tool for early detection of Alzheimer's disease.

Dopachrome tautomerase is a retinoblastoma-specific gene, and its proximal promoter is preferentially active in human retinoblastoma cells.

Purpose: Retinoblastoma (RB) is a malignant childhood intraocular tumor. Current treatment options for RB have undesirable side effects. A comprehensive understanding of gene expression in human RB is essential for the development of safe and effective new therapies. Methods: We reviewed published microarray and RNA sequencing studies in which gene expression profiles were compared between human RB and normal retina tissues. We investigated the expression of genes of interest using quantitative reverse transcription PCR. We examined the activities of cloned promoter DNA fragments with luciferase assay. Results: Dopachrome tautomerase (DCT) was among the most overexpressed genes in RB in published studies. We found that DCT was highly expressed in six of 13 samples microdissected from Thai RB tissues. Expression of DCT was absent or barely detected in retina tissues, various human ocular cells, and major organs. We also demonstrated that the -657 to +411 DCT promoter fragment efficiently directs RB cell-specific transcription of the luciferase reporter gene in cell lines. Conclusions: The present work highlights that DCT is one of the most RB-specific genes. The regulatory elements required for this cell-specific gene expression are likely located within its proximal promoter.

Clinical outcomes and prognosis of Thai retinoblastoma patients.

BACKGROUND: Retinoblastoma (RB) outcomes in Thailand are unfavorable compared to those of developed countries. This study aims to determine whether the clinical outcomes of patients with RB significantly improved after the implementation of new therapeutic approaches and which clinical factors affect survival and globe-saving outcomes. METHODS: The medical records of patients newly diagnosed with RB and treated at Siriraj Hospital between January 2005 and December 2018 were reviewed retrospectively. Clinical data, treatments, and outcomes were collected and analyzed. RESULTS: In 194 eyes (144 patients), leukocoria was the most common presenting feature (76.8%); 129 (66.5%) eyes were staged in group E of the International Classification of Intraocular Retinoblastoma. Of the 149 enucleated eyes, 35 had high-risk histopathological features, mostly choroidal invasion; 45 eyes (23.2%) could be salvaged. The 5-year overall survival rate was 90.3%, an improvement compared to the previous study. The 5-year enucleation-free survival rates of Groups A and B, C, D and E were 100%, 83.1%, 36.7% and 16.6% respectively. Factors associated with a lower survival rate were interval from symptom onset to diagnosis >3 months (hazard ratio (HR): 5.8: 95% confidence interval (CI): 1.637, 20.579) and buphthalmos (HR: 12.57: 95% CI: 3.936, 40.153). Factors associated with high-risk features were secondary glaucoma (HR: 11.016: 95% CI: 1.24, 98.10) and pseudohypopyon (HR: 14.110: 95% CI: 2.16, 92.05). CONCLUSIONS: Survival rates and globe-saving rates appear to have improved; however, advanced-stage presentation remains the major hindrance. Further studies with a larger cohort and longer follow-up are warranted.

Molecular and clinical characterization of Thai patients with achromatopsia: identification of three novel disease-associated variants in the CNGA3 and CNGB3 genes.

PURPOSE: Achromatopsia (ACHM) is an autosomal recessive cone disorder characterized by pendular nystagmus, photophobia, reduced visual acuity, and partial or total absence of color vision. Mutations in six genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6) have been reported in ACHM. There is no information on these disease-associated genes in Thai population. This study aimed to investigate the molecular and clinical characteristics in Thai patients with ACHM. METHODS: Seven unrelated Thai patients with ACHM were recruited. Detailed ophthalmologic examination was performed. Polymerase chain reaction (PCR)-coupled single-strand conformation polymorphism (SSCP) screening followed by Sanger sequencing was used to identify sequence variants in all exons and splice junctions of three genes (CNGA3, CNGB3, and GNAT2). The pathogenicity of the detected variants was interpreted. Segregation analysis was performed to determine variant sharing in available family members. RESULTS: Four patients displayed different SSCP migration patterns. Sequence analysis revealed a reported pathogenic and a novel disease-associated variant in the CNGA3 gene. For the CNGB3 gene, we found two novel disease-associated variants and a reported variant of uncertain significance (VUS). Segregation analysis confirmed that the variants identified in each patient were present in the heterozygous state in their corresponding family members, which was consistent with an autosomal recessive mode of inheritance. CONCLUSIONS: This study demonstrated the first molecular and clinical characterization of ACHM in Thai patients. The identification of disease-associated genes in a specific population leads to a personalized gene therapy benefiting those affected patients.

Outcomes of pediatric retinoblastoma treated with ICEV regimen: A single-center study.

Retinoblastoma is the most common intraocular malignancy in children. The aim of this study was to investigate the efficacy and toxicity of combination ifosfamide, carboplatin, etoposide, and vincristine (ICEV) in advanced-stage pediatric retinoblastoma [International Classification of Retinoblastoma (ICRB) group D or E], and in ICRB group C in the second eye in simultaneously treated bilateral retinoblastoma. The medical records of retinoblastoma patients treated with concurrent ICEV regimen and focal therapy were retrospectively reviewed. The ICEV treatment protocol was, as follows: ifosfamide 1800 mg/m2 on Days 1-3; MESNA 600 mg/m2 on Days 1-3; carboplatin 560 mg/m2 on Day 1; etoposide 150 mg/m2 on Days 1-3; and vincristine 1.5 mg/m2 on Day 1. Of 16 retinoblastoma patients, 13 had bilateral disease. Seven first eyes in bilateral disease that were enucleated prior to ICEV therapy were excluded. Twenty-two eyes were finally included (six group C, six group D, and ten group E). Median follow-up was 3.4 years, and the median number of ICEV courses was 7. Fifteen globes could be salvaged, 12 responded to ICEV (six group C, five group D, and one group E), and three unresponsive eyes could be salvaged with external beam radiation therapy (EBRT). Enucleation-free and relapse-free survival was 68.2 and 54.5%, respectively. The results of this study suggest ICEV as an alternative therapeutic approach for globe salvage in pediatric retinoblastoma, especially in ICRB groups C and D with manageable acute toxicity. Further study in larger cohort is needed to confirm the effectiveness of treatment.

A novel start codon mutation of the MERTK gene in a patient with retinitis pigmentosa.

PURPOSE: Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of inherited retinal degenerations characterized by progressive loss of photoreceptor cells and RPE functions. More than 70 causative genes are known to be responsible for RP. This study aimed to identify the causative gene in a patient from a consanguineous family with childhood-onset severe retinal dystrophy. METHODS: To identify the defective gene, whole exome sequencing was performed. Candidate causative variants were selected and validated using Sanger sequencing. Segregation analysis of the causative gene was performed in additional family members. To verify that the mutation has an effect on protein synthesis, an expression vector containing the first ten amino acids of the mutant protein fused with the DsRed2 fluorescent protein was constructed and transfected into HEK293T cells. Expression of the fusion protein in the transfected cells was measured using fluorescence microscopy. RESULTS: By filtering against public variant databases, a novel homozygous missense mutation (c.3G>A) localized in the start codon of the MERTK gene was detected as a potentially pathogenic mutation for autosomal recessive RP. The c.3G>A mutation cosegregated with the disease phenotype in the family. No expression of the first ten amino acids of the MerTK mutant fused with the DsRed2 fluorescent protein was detected in HEK293T cells, indicating that the mutation affects the translation initiation site of the gene that may lead to loss of function of the MerTK signaling pathway. CONCLUSIONS: We report a novel missense mutation (c.3G>A, p.0?) in the MERTK gene that causes severe vision impairment in a patient. Taken together with previous reports, our results expand the spectrum of MERTK mutations and extend our understanding of the role of the MerTK protein in the pathogenesis of retinitis pigmentosa.

Risk factor-based models to predict severe retinopathy of prematurity in preterm Thai infants.

PURPOSE: To develop prediction models for severe retinopathy of prematurity (ROP) based on risk factors in preterm Thai infants to reduce unnecessary eye examinations in low-risk infants. METHODS: This retrospective cohort study included preterm infants screened for ROP in a tertiary hospital in Bangkok, Thailand, between September 2009 and December 2020. A predictive score model and a risk factor-based algorithm were developed based on the risk factors identified by a multivariate logistic regression analysis. Validity scores, and corresponding 95% confidence intervals (CIs), were reported. RESULTS: The mean gestational age and birth weight (standard deviation) of 845 enrolled infants were 30.3 (2.6) weeks and 1264.9 (398.1) g, respectively. The prevalence of ROP was 26.2%. Independent risk factors across models included gestational age, birth weight, no antenatal steroid use, postnatal steroid use, duration of oxygen supplementation, and weight gain during the first 4 weeks of life. The predictive score had a sensitivity (95% CI) of 92.2% (83.0, 96.6), negative predictive value (NPV) of 99.2% (98.1, 99.6), and negative likelihood ratio (NLR) of 0.1. The risk factor-based algorithm revealed a sensitivity of 100% (94, 100), NPV of 100% (99, 100), and NLR of 0. Similar validity was observed when "any oxygen supplementation" replaced "duration of oxygen supplementation." Predictive score, unmodified, and modified algorithms reduced eye examinations by 71%, 43%, and 16%, respectively. CONCLUSIONS: Our risk factor-based algorithm offered an efficient approach to reducing unnecessary eye examinations while maintaining the safety of infants at risk of severe ROP. Prospective validation of the model is required.

Generation of an EYS-associated retinitis pigmentosa patient-derived human pluripotent stem cell line (MUi038-A).

Mutations in the eyes shut homolog (EYS) gene are one of the common causes of autosomal recessive retinitis pigmentosa (RP). The lack of suitable animal models hampers progress understanding of the disease mechanism and drug development. This study reported the reprogramming of CD34+ hematopoietic stem/progenitor cells from a patient with compound heterozygous EYS mutations (c.6416 G > A and c.7228 + 1 G > A) into the induced pluripotent stem cell line, MUi038-A, using non-integrating vectors. The MUi038-A demonstrates pluripotency, tri-lineage differentiation potential, and a normal karyotype, offering a valuable model for studying the mechanism of EYS-related RP and new therapeutic development.

Validation of the postnatal growth and retinopathy of prematurity (G-ROP) screening criteria in a Thai cohort.

PURPOSE: To validate Postnatal Growth and Retinopathy of Prematurity (G-ROP) criteria for Thai infants. STUDY DESIGN: A retrospective review of infants receiving ROP screening during 2009-2020. METHODS: Baseline characteristics, clinical progression and final ROP outcomes were collected. G-ROP was applied to infants who met at least one of the following 6 criteria: birth weight (BW) below 1051 g, gestational age (GA) under 28 weeks, weight gain (WG) less than 120 g during postnatal day 10-19, WG less than 180 g during day 20-29, WG less than 170 g during day 30-39 and hydrocephalus. RESULTS: A total of 684 infants (boys, 53.4%) were included. Median (IQR) BW was 1200 (960-1470) grams and median GA was 30 (28-32) weeks. Prevalence of ROP was 26.6%, with 28 (4.1%) having type 1, 19 (2.8%) type 2 and, 135 (19.7%) having other ROP. Treatment was performed in 26 infants (3.8%). Sensitivity of G-ROP to include type 1, 2 or treatment-requiring ROP cases was 100% with 36.9% specificity, excluding 235 (34.4%) cases of unnecessary screening. To adjust for our setting of initial eye examination at 4 weeks' postnatal date, the last 2 criteria of G-ROP were replaced by the occurrence of grade 3 or 4 intraventricular hemorrhage (IVH). This modified G-ROP criteria yielded 100% sensitivity, 42.5% specificity and excluded 271 (39.6%) cases of unnecessary screening. CONCLUSION: G-ROP criteria can be applied to our hospital setting. Occurrence of IVH grade 3 or 4 was proposed as an alternative in modified G-ROP criteria.