Nan-Kai Wang

Aims Sodium–glucose cotransporter‐2 inhibitors (SGLT2is) are proposed to alleviate the development of inflammatory eye diseases. However, the association between SGLT2i and retinal vascular occlusion remains unclear. Therefore, this study aims to explore the effects of SGLT2i on the incidence of retinal vascular occlusion. Materials and Methods This retrospective cohort study analysed electronic medical records data from the largest multi‐institutional database in Taiwan. Individuals who initiated SGLT2is and dipeptidyl peptidase 4 inhibitors (DPP4is) between 2016 and 2019 were included in our analysis. To conduct a homogenous comparison, inverse probability of treatment weighting with propensity scoring was employed. The primary outcome was retinal vascular occlusion, and the secondary outcomes were retinal vascular occlusion‐related complications (macular oedema, vitreous haemorrhage …

Copy number variations (CNVs) have emerged as significant contributors to the elusive genetic causality of inherited eye diseases. In this study, we describe a case with optic atrophy and a brain aneurysm, in which a de novo CNV 3q29 deletion was identified. A 40-year-old female patient was referred to our department after undergoing aneurysm transcatheter arterial embolization for a brain aneurysm. She had no history of systemic diseases, except for unsatisfactory best-corrected visual acuity (BCVA) since elementary school. Electrophysiological tests confirmed the findings in retinal images, indicating optic nerve atrophy. Chromosomal microarray analysis revealed a de novo deletion spanning 960 kb on chromosome 3q29, encompassing OPA1 and six neighboring genes. Unlike previously reported deletions in this region associated with optic atrophy, neuropsychiatric disorders, and obesity, this patient displayed a unique combination of optic atrophy and a brain aneurysm. However, there is no causal relationship between the brain aneurysm and the CNV. In conclusion, the optic atrophy is conclusively attributed to the OPA1 deletion, and the aneurysm could be a coincidental association. The report emphasizes the likelihood of underestimating OPA1 deletions due to sequencing technology limitations. Recognizing these constraints, healthcare professionals must acknowledge these limitations and consistently search for OPA1 variants/deletions in Autosomal Dominant Optic Atrophy (ADOA) patients with negative sequencing results. This strategic approach ensures a more comprehensive exploration of copy-number variations, ultimately …

Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO‐related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO‐related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2α and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2α and preserving mitochondrial dysfunction by α‐ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our …

Purpose: This study investigated the associations between vascular endothelial growth factor (VEGF) polymorphisms and retinopathy of prematurity (ROP) risk.Methods: Infants born prematurely at any time from 2009 to 2018 were included. Five single-nucleotide polymorphisms (SNPs) of VEGF were analyzed using real-time PCR in all infants. Multivariate logistic regression was applied to model the associations between VEGF polymorphisms and ROP susceptibility, severity, and premature clinicopathologic characteristics.Results: A total of 334 patients were included and categorized into three groups: those without ROP, those with mild ROP (ie, ROP not requiring treatment), and those with severe ROP (ie, ROP for whom treatment was indicated). Among the female patients with ROP, those with VEGF rs3025035 CT (3.231-fold; 95% confidence interval [CI], 1.238–8.431) and a combination of CT and TT genotypes (2.643-fold; 95% CI, 1.056–6.619) exhibited significantly higher risks of severe ROP compared with those with wild-type genotypes. Female ROP infants with VEGF rs3025010 C (TC+ CC) alleles had a lower risk of ROP stage≥ 3 (odds ratio [OR]= 0.406; 95% CI, 0.165–0.999) than those with TT homozygotes. ROP patients with the VEGF rs10434 A allele (GA+ AA) exhibited higher risks of necrotizing enterocolitis (OR= 2.750; 95% CI, 1.119–6.759) and lower risk of bronchopulmonary dysplasia (OR= 0.390; 95% CI, 0.173–0.877) than those with GG homozygotes did.Conclusions: VEGF polymorphisms affect ROP risks differently in male and female infants. In female infants, VEGF rs3025035 with T alleles may predict ROP severity, and …

A 25-year-old female with diabetes and hypertension presented with progressive painless blurred vision in her left eye ten days after she received her third dose of the SARS-CoV-2 mRNA vaccine BNT162b2 (Pfizer-BioNTech). The clinical examination confirmed the diagnosis of Central Retinal Vein Occlusion (CRVO) complicated with macular edema. Three doses of anti-vascular endothelial growth factor (VEGF) were injected intravitreally. Visual acuity was improved from 20/100 to 20/30, but recurrence was noted at 6 months. Several cases of retinal vein occlusion (RVO) after COVID-19 vaccination have been reported. However, the present case is the youngest female individual documented to have CRVO after SARS-CoV-2 vaccination. This case demonstrates that the macular edema might be recurrent in patients with risk factors for CRVO who receive SARS-CoV-2 vaccination, suggesting the need for careful consideration of the treatment strategy and close follow-up. Although the definite pathogenesis still needs to be carefully determined, this report highlights the possible association between RVO and mRNA-based COVID-19 vaccination, even in young individuals.

BackgroundOptic atrophy-13 with retinal and foveal abnormalities (OPA13) (MIM #165510) is a mitochondrial disease in which apparent bilateral optic atrophy is present and sometimes followed by retinal pigmentary changes or photoreceptors degeneration. OPA13 is caused by heterozygous mutation in the SSBP1 gene, associated with variable mitochondrial dysfunctions.ResultsWe have previously reported a 16-year-old Taiwanese male diagnosed with OPA13 and SSBP1 variant c.320G>A (p.Arg107Gln) was identified by whole exon sequence (WES). This variant was assumed to be de novo since his parents were clinically unaffected. However, WES and Sanger sequencing further revealed the proband’s unaffected mother carrying the same SSBP1 variant with a 13% variant allele frequency (VAF) in her peripheral blood. That finding strongly indicates the maternal gonosomal mosaicism contributing to …

Purpose: This study investigated the clinical characteristics of patients with PROM1-related inherited retinal diseases (IRDs).Methods: Patients diagnosed with IRDs who had mutations in PROM1 were identified at Linkou Chang Gung Memorial Hospital and Kaohsiung Medical University Hospital in Taiwan. Information on clinical characteristics and best-corrected visual acuity was recorded. Color fundus (CF) images, fundus autofluorescence photography (FAF), spectral-domain optical coherence tomography (SD-OCT), and electroretinograms (ERGs) were analyzed to examine patient phenotypes. PROM1 variants were detected using whole exome sequencing and verified by Sanger sequencing.Results: Fourteen patients from nine families with PROM1-related IRDs were analyzed. Most patients exhibited chorioretinal atrophy in the macular area, with or without extramacular involvement on CF. Similarly, hypo-autofluorescence confined to the macular area, with or without extramacular involvement, was present for most patients on FAF. Furthermore, SD-OCT revealed outer retinal tubulations and focal or diffuse retinal thinning. ERGs showed variable findings, including maculopathy with normal ERG, subnormal cone response, and extinguished rod and cone responses. We detected five variants of the PROM1 gene, including c. 139del, c. 794del, c. 1238T> A, c. 2110C> T, and c. 1117C> T.Conclusions: In this study, we evaluated 14 Taiwanese patients with five PROM1 variants. Additionally, incomplete penetrance of heterozygous PROM1 variants was observed. Furthermore, patients with autosomal dominant PROM1 variants had lesions in …

Retinopathy of prematurity (ROP), a vasoproliferative vitreoretinal disorder, is the leading cause of childhood blindness worldwide. Although angiogenic pathways have been the main focus, cytokine-mediated inflammation is also involved in ROP etiology. Herein, we illustrate the characteristics and actions of all cytokines involved in ROP pathogenesis. The two-phase (vaso-obliteration followed by vasoproliferation) theory outlines the evaluation of cytokines in a time-dependent manner. Levels of cytokines may even differ between the blood and the vitreous. Data from animal models of oxygen-induced retinopathy are also valuable. Although conventional cryotherapy and laser photocoagulation are well established and anti-vascular endothelial growth factor agents are available, less destructive novel therapeutics that can precisely target the signaling pathways are required. Linking the cytokines involved in ROP to other maternal and neonatal diseases and conditions provides insights into the management of ROP. Suppressing disordered retinal angiogenesis via the modulation of hypoxia-inducible factor, supplementation of insulin-like growth factor (IGF)-1/IGF-binding protein 3 complex, erythropoietin, and its derivatives, polyunsaturated fatty acids, and inhibition of secretogranin III have attracted the attention of researchers. Recently, gut microbiota modulation, non-coding RNAs, and gene therapies have shown promise in regulating ROP. These emerging therapeutics can be used to treat preterm infants with ROP.

Inherited retinal dystrophies (IRDs) are a group of heterogeneous diseases caused by genetic mutations that specifically affect the function of the rod, cone, or bipolar cells in the retina. Electroretinography (ERG) is a diagnostic tool that measures the electrical activity of the retina in response to light stimuli, and it can help to determine the function of these cells. A normal ERG response consists of two waves, the a-wave and the b-wave, which reflect the activity of the photoreceptor cells and the bipolar and Muller cells, respectively. Despite the growing availability of next-generation sequencing (NGS) technology, identifying the precise genetic mutation causing an IRD can be challenging and costly. However, certain types of IRDs present with unique ERG features that can help guide genetic testing. By combining these ERG findings with other clinical information, such as on family history and retinal imaging, physicians can effectively narrow down the list of candidate genes to be sequenced, thereby reducing the cost of genetic testing. This review article focuses on certain types of IRDs with unique ERG features. We will discuss the pathophysiology and clinical presentation of, and ERG findings on, these disorders, emphasizing the unique role ERG plays in their diagnosis and genetic testing.

This study aims to investigate the outcomes and risk factors associated with poor vision (vision less than counting fingers, 2.0 logMAR, Snellen vision 20/2000) in patients with posterior or combined persistent fetal vasculature (PFV), with or without surgery. We retrospectively reviewed the medical records of patients who were diagnosed with PFV from January 2008 to April 2021. We included 51 eyes of 44 patients who presented with PFV, of which 38 eyes underwent surgical correction (pars plicata/plana vitrectomy, with or without lensectomy, and intraocular lens implantation) at the median age of 6.0 months (range: 0.7 to 82.0). The mean follow-up was 68.8 months ± 38.0 months. The axial length change in the eyes undergoing surgery was significantly higher than the eyes without surgery (p = 0.025). Initial anterior chamber collapse and retinal detachment were associated with poor vision (p = 0.006 and p = 0.002, respectively). In addition, 37% of eyes with posterior or combined PFV had vision better than counting fingers. Surgery for eyes with PFV could result in better eye growth. Visual outcomes remained poor and were associated with the level of macular abnormality. Initial anterior chamber collapse and retinal detachment at presentation were the risk factors for poor visual outcomes. Vitrectomy for selected PFV eyes is valuable and associated with a better cosmetic outcome (better eye growth).

Iron accumulation causes cell death and disrupts tissue functions, which necessitates chelation therapy to reduce iron overload. However, clinical utilization of deferoxamine (DFO), an iron chelator, has been documented to give rise to systemic adverse effects, including ocular toxicity. This study provided the pathogenic and molecular basis for DFO-related retinopathy and identified retinal pigment epithelium (RPE) as the target tissue in DFO-related retinopathy. Our modeling demonstrated the susceptibility of RPE to DFO compared with the neuroretina. Intriguingly, we established upregulation of hypoxia inducible factor (HIF) 2a and mitochondrial deficit as the most prominent pathogenesis underlying the RPE atrophy. Moreover, suppressing hyperactivity of HIF2a and preserving mitochondrial dysfunction by a-ketoglutarate (AKG) protects the RPE against lesions both in vitro and in vivo. This supported our observation that AKG supplementation alleviates visual impairment in a patient undergoing DFO-chelation therapy. Overall, our study established a significant role of iron deficiency in initiating DFO-related RPE atrophy. Inhibiting HIF2a and rescuing mitochondrial function by AKG protect RPE cells and can potentially ameliorate patients’ visual function.

This retrospective cohort study aimed to assess the systemic effects of three commonly available anti-vascular endothelial growth factor intravitreal injections in patients with diabetes, using data taken from a multi-institutional database in Taiwan. Patient data were sourced from the multi-institutional Chang Gung Research Database. Participants were divided into groups based on treatment with bevacizumab, ranibizumab, or aflibercept. Baseline characteristics were matched among the groups by the inverse probability of treatment weighting. The incidence rate of outcome events was calculated as the number of events divided by 100 person-years of follow-up. The cumulative incidence function was used to estimate the incidence rate of the outcome events among groups. The incidence of ischemic stroke was higher in the ranibizumab group than the bevacizumab and aflibercept groups (1.65, 0.92, and 0.61 per 100 person-years, respectively). The incidence of major adverse lower-limb events was higher in the bevacizumab group (2.95), followed by ranibizumab (2.00) and aflibercept (0.74). Major bleeding was relatively higher in bevacizumab (12.1) compared to ranibizumab (4.3) and aflibercept (3.8). All-cause death was higher for both bevacizumab (3.26) and aflibercept (2.61) when compared to ranibizumab (0.55), and all-cause admission was found to be highest with bevacizumab (58.6), followed by aflibercept (30.2), and ranibizumab (27.6). The bevacizumab group demonstrated a greater decrease in glycated hemoglobin compared to the baseline level (−0.33%). However, a few differences in the clinical condition between the groups …

ObjectivesTo evaluate corneal topography in full-term and preterm children with or without retinopathy of prematurity (ROP).MethodsWe enrolled children aged from 2 years to 12 years between January 2019 and May 2021 in the following four groups: full-term (group 1), premature without ROP (group 2), untreated premature with ROP (group 3), and laser-treated and/or intravitreal injection (IVI) of anti-vascular endothelial growth factor (VEGF)-treated premature with ROP (group 4). Corneal topography was measured with the Galilei Placido-dual Scheimpflug analyzer G4 every half year, and was compared among the groups using generalized estimating equation models at approximately 7 years of age.ResultsWe included 77, 178, 45, and 131 participants in groups 1, 2, 3, and 4, respectively. The mean (standard deviation) number of visits per patient was 2.9 (1.4). Compared with full-term eyes, premature eyes …

PURPOSETo evaluate the neurodevelopmental outcomes in premature infants who received intravitreal anti−vascular endothelial growth factor (anti-VEGF) injections to treat retinopathy of prematurity (ROP).DESIGNRetrospective cohort study.METHODSThis study was conducted using the database from the Taiwan Premature Infant Follow-up Network. Demographic data, systemic risk factors, ROP status, and neurodevelopmental assessment using the Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) were collected. Patients were divided into 4 groups: prematurity without ROP, ROP without treatment, ROP with laser treatment, and ROP with intravitreal anti-VEGF treatment. A generalized estimating equation was used for analyzing repeated measurements of Bayley-III at the corrected ages of 6, 12, and 24 months.RESULTSA total of 2090 patients with a mean gestational age of 31.2 …

BackgroundCones are essential for color recognition, high resolution, and central vision; therefore cone death causes blindness. Understanding the pathophysiology of each cell type in the retina is key to developing therapies for retinal diseases. However, studying the biology of cone cells in the rod-dominant mammalian retina is particularly challenging. In this study, we used a bacterial artificial chromosome (BAC) recombineering method to knock in the “CreERT2” sequence into the Gnat2 and Arr3 genes, respectively and generated three novel inducible CreERT2 mice with different cone cell specificities.ResultsThese models (Gnat2CreERT2, Arr3T2ACreERT2, and Arr3P2ACreERT2) express temporally controllable Cre recombinase that achieves conditional alleles in cone photoreceptors. Cre-LoxP recombination can be induced as early as postnatal day (PD) two upon tamoxifen injection at varying efficiencies …

2. DiscussionCHARGE syndrome is a rare congenital disease with multiple anomalies in several organs. 4 An early diagnosis is challenging an d crucial. The diagnosis is based on clinical characteristics and examinations in different organ systems. Therefore, multidisciplinary team care is essential for the evaluation and management of patients with CHARGE syndrome. In our case, the patient was diagnosed with mosaic Turner syndrome at birth by chromosome tests, and the pre-existed diagnosis might affect some of the clinical judgments in her early disease management. Although co-existed genetic or chromosomal abnormality with CHARGE syndrome is rare, other developmental anomalies may mimic CHARGE syndrome and share similar clinical features. 5

Purpose:To compare between oral and intravenous (IV) ultrawide-field fluorescein angiography in pediatric patients with a history of prematurity of retinopathy or prematurity.Methods:Pediatric patients (< 18 year old; n= 107 patients) who underwent ultrawide-field fluorescein angiography for retinopathy of prematurity were categorized into oral and IV fluorescein angiography (FA) groups. Quality of FA images was graded on the order of retinal vessels visible. Reported outcomes were proportions of graded FA images, peak fluorescein intensity, and the time to first dye appearance and to reach peak fluorescence.Results:Image quality analysis revealed that 91.5% of IV FA images had excellent image quality compared with only 55.6% of oral FA images (P< 0.01). There were still 83.3% of oral-contrast images with good or excellent image quality. The average time required for first dye appearance and peak …

Electroretinogram (ERG) is a sensitive and useful tool for the measurement of the retinaRetinas’s electrical response to flash stimuli. It provides a functional evaluation of the photoreceptorsPhotoreceptors and downstream associated retinal cells. Similar to those conducted on humans, mouse ERGs include the amplitudes of a- and b-waves as well as the implicit time from those ERGs. Applications of ERGs include identification of retinal phenotypes, measurement of retinal function (at one and various time points), and evaluation of treatment efficacy. However, there are some differences between the manifestation of disease in patientsPatients as compared to mouse models that should be taken into consideration when implementing mouse ERGs. Herein, this chapter will introduce how to perform and obtain mouse ERGs.

There has been limited research regarding the status of foveal hypoplasia and the characteristics of the optical components of the eye in patients with familial exudative vitreoretinopathy (FEVR) and retinopathy of prematurity (ROP). In this retrospective cohort study, patients were classified into five groups: patients with stage 1 and 2 FEVR (FEVR group), patients with ROP who received treatment (treated ROP group), patients with ROP who did not receive treatment (untreated ROP group), patients without ROP who had been born preterm (preterm group), and healthy patients who had been born at term (full-term group). Visual acuity, refractive error, characteristics of the optical components, and features of the fovea were compared. In total, 179 eyes from 100 patients were included. Patients in the FEVR group had the highest degrees of myopia (p < 0.001). The axial length of patients in the FEVR group was …

Study Objectives The association between sleep apnea (SA) and cataract was confirmed in a comprehensive large-scale study. This study aimed to investigate whether SA was associated with increased risk of cataract. Methods The 18-year nationwide retrospective population-based cohort study used data retrieved from the Taiwan National Health Insurance Database. We selected adult patients with a diagnosis of SA, based on diagnostic codes (suspected SA cohort) or on presence of diagnosis after polysomnography (SA cohort), and matched each of them to 5 randomly selected, and age- and sex-matched control participants. The incidence rate of cataract was compared between patients with SA and the controls. The effect of SA on incident cataract was assessed using multivariable Poisson regression and Cox regression analyses. Results A total of 6,438 patients in the suspected SA cohort were matched …