Genetics in neovascular age-related macular degeneration susceptibility and treatment response to anti-VEGF intravitreal injection: A case series study.

BACKGROUND: To identify genotypes associated with neovascular age-related macular degeneration (nAMD) and investigate the associations between genotype variations and anti-vascular endothelial growth factor (VEGF) treatment response. METHODS: This observational, retrospective, case series study enrolled patients diagnosed with nAMD who received anti-VEGF treatment in National Taiwan University Hospital with at least one-year follow-up between 2012 and 2020. A genome-wide association study (GWAS) was conducted on enrolled patients and controls. Correlations between the genotypes identified from GWAS and the treatment response of functional/anatomical biomarkers, including visual acuity (VA), presence of intraretinal or subretinal fluid (SRF), serous or fibrovascular pigmented epithelium detachment (PED), and disruption of the ellipsoid zone (EZ), were analysed. RESULTS: In total, 182 patients with nAMD and 1748 controls were enrolled. GWAS revealed 16 single nucleotide polymorphisms (SNPs) as risk loci for nAMD, including seven loci in CFH and ARMS2/HTRA1 and nine novel loci, including rs117517872 and rs79835234(COPB2-DT), rs7525578(RAP1A), rs2123738(LOC105376755), rs1374879(CNTN3), rs3812692(SAR1A), rs117501587(PRKCA), rs9965945(CNDP1), and rs189769231(MATK). Our study revealed rs800292(CFH), rs11200638(HTRA1), and rs2123738(LOC105376755) correlated with poor treatment response in VA (P = 0.005), SRF (P = 0.044), and fibrovascular PED (P = 0.007), respectively. Rs9965945(CNDP1) was correlated with poor response in disruption of EZ (P = 0.046) and serous PED (P = 0.049). CONCLUSIONS: Among the 16 SNPs found in the GWAS, four loci-CFH, ARMS2/HTRA1, and two novel loci-were correlated with the susceptibility of nAMD and anatomical/functional responses after anti-VEGF treatment.

Metabolomics facilitates differential diagnosis in common inherited retinal degenerations by exploring their profiles of serum metabolites.

The diagnosis of inherited retinal degeneration (IRD) is challenging owing to its phenotypic and genotypic complexity. Clinical information is important before a genetic diagnosis is made. Metabolomics studies the entire picture of bioproducts, which are determined using genetic codes and biological reactions. We demonstrated that the common diagnoses of IRD, including retinitis pigmentosa (RP), cone-rod dystrophy (CRD), Stargardt disease (STGD), and Bietti's crystalline dystrophy (BCD), could be differentiated based on their metabolite heatmaps. Hundreds of metabolites were identified in the volcano plot compared with that of the control group in every IRD except BCD, considered as potential diagnosing markers. The phenotypes of CRD and STGD overlapped but could be differentiated by their metabolomic features with the assistance of a machine learning model with 100% accuracy. Moreover, EYS-, USH2A-associated, and other RP, sharing considerable similar characteristics in clinical findings, could also be diagnosed using the machine learning model with 85.7% accuracy. Further study would be needed to validate the results in an external dataset. By incorporating mass spectrometry and machine learning, a metabolomics-based diagnostic workflow for the clinical and molecular diagnoses of IRD was proposed in our study.

Two-Year Real-World Results for Aflibercept Using the Treat-and-Extend Regimen in Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy.

INTRODUCTION: To evaluate the real-world efficacy of aflibercept using the treat-and-extend (TnE) regimen in treating neovascular age-related macular degeneration (nAMD) and polypoidal choroidal vasculopathy (PCV), and to analyze biomarkers using optical coherence tomography (OCT) to predict treatment outcomes. METHODS: Patients diagnosed with nAMD or PCV who received an intravitreal injection of aflibercept following the TnE regimen for ≥ 2 years were retrospectively reviewed. Data on best-corrected visual acuity (BCVA), number of injections, treatment interval, and OCT biomarkers, including central macular thickness, presence of subretinal fluid (SRF), and serous pigmented epithelial detachment, were collected at baseline and at 3, 6, 12, 18, and 24 months after the first injection. RESULTS: A total of 43 patients were enrolled in this study, 24 of whom were diagnosed with nAMD and 19 with PCV. The BCVA in logMAR (mean ± standard deviation) improved from 0.75 ± 0.41 (baseline) to 0.60 ± 0.41 (P = 0.002) at 3 months after treatment initiation, and further improved to 0.66 ± 0.46 at 24 months (P = 0.137). The number of injections (mean ± standard deviation) within the 2-year treatment course was 10.95 ± 3.65. At month 24 of the TnE regimen, the treatment interval was extended to ≥ 16 weeks in 60.5% of all cases and to 78.9% of the PCV cases. After three loading injections, persistent subretinal fluid and intraretinal fluid were predictive of more frequent injections (P = 0.026) and poorer visual outcomes (P = 0.050), respectively. CONCLUSION: Aflibercept combined with a TnE regimen was effective in treating nAMD and PCV in a real-world setting. The treatment interval could be extended to ≥ 16 weeks in 60.5% of the cases after a 2-year treatment regimen. OCT can be used to predict the treatment course and visual outcomes.

Optical coherence tomography as a useful adjunct in the early detection of meningioma with optic nerve compression.

A 48-year-old woman presented with persistent clouding vision in her lower field in the right eye for 5 months. A small retinal hemorrhage was initially reported. Her visual acuity was 20/30 in the right eye and 20/20 in the left, with normal color vision and pupil response. Fundus examination did not reveal any retinal hemorrhage. Although optical coherence tomography (OCT) showed normal macula and retinal nerve fiber layers in both eyes, asymmetric thinning of the ganglion cell inner plexiform layer was found in the superior macula of the right eye in ganglion cell analysis (GCA). Visual field examination revealed a subtle inferonasal scotoma. Compressive optic neuropathy (CON) was suspected. The visual evoked potential test revealed delayed P100 latency. A tuberculum sellae meningioma was found with right medial optic canal extension. The visual acuity of the right eye returned to 20/25 after decompression surgery. OCT can be used to differentiate between retinopathy and optic neuropathy. GCA can help in the early detection of CON and achieve a good visual outcome after surgery.

HYPERREFLECTIVE FOCI AS IMPORTANT PROGNOSTIC INDICATORS OF PROGRESSION OF RETINITIS PIGMENTOSA.

PURPOSE: To investigate the presence and clinical relevance of hyperreflective foci (HRFs) in retinitis pigmentosa. METHODS: Seventy seven retinitis pigmentosa cases were retrospectively reviewed. The 10-mm wide cross-line macular scans in optical coherence tomography were acquired. Hyperreflective foci were classified according to the location in optical coherence tomography: outer layers within the macula (HRF-outer-central), macular border beyond the central 3 mm (HRF-outer-perifoveal), and choroid (HRF-choroidal). The visual acuity at baseline, at 12 months, and other fundus characteristics were collected. RESULTS: The mean logMAR best-corrected visual acuity decreased from 0.59 ± 0.66 (20/78 in Snellen) to 0.74 ± 0.81 (20/106 in Snellen) in 1 year. Sixty-six (42.9%), 105 (68.2%), and 98 (63.6%) eyes were classified to HRF-outer-central, HRF-outer-perifoveal, and HRF-choroidal group, respectively. Hyperreflective foci were positively correlated with poorer vision, central macular thinning, and ellipsoid zone disruption (all P < 0.001). Worse vision was associated with older age, macular involvement, and the coexistence of two or three HRF groups (P = 0.014, 0.047, 0.019, <0.001, respectively). Hyperreflective foci developed more frequently in patients with thick choroid than in those with thin choroid. The coexistence of three HRF groups was correlated with quicker visual deterioration (P = 0.034). CONCLUSION: Hyperreflective foci are common in retinitis pigmentosa and can be a negative prognostic indicator of macular thickness and visual preservation. Thick choroid was associated with all groups of HRFs, especially HRF-choroidal.

The Clinical Contribution of Full-Field Electroretinography and 8-Year Experiences of Application in a Tertiary Medical Center.

Electroretinography (ERG) is an important and well-established examination for retinal and visual pathway diseases. This study reviewed the medical records of patients who received full-field ERG (ffERG) at a single medical center between 2012 and 2019, which was an 8-year experience in the clinical contribution of ERG. Based on the indication for scheduling ffERG and the final diagnosis, patients could be classified into six groups: 'retinal dystrophies', 'other retinal or macular diseases', 'optic neuropathies', 'visual complaints', 'systemic diseases', and 'others'. A total of 1921 full-field electroretinograms (ffERGs) (1655 patients) were included. The average number of ffERGs performed per year was 262 and the number of annual ffERGs was constant. The 'retinal dystrophies' group accounted for 36.5% of the studied population, followed by the 'other retinal or macular diseases' group (20.2%). The most common systemic disease was central nervous system disease. The rates of abnormal ffERGs in the 'systemic diseases', 'optic neuropathies', and 'visual complaints' groups were 27.3%, 22.6%, and 10.1%, respectively (p < 0.001). Higher rates were found in patients <20 years old in the 'systemic diseases' and 'optic neuropathies' groups; epilepsy and optic nerve atrophy were the most common diagnoses, respectively. In brief, by quantifying the functional response in the retina, ffERG is indispensable for diagnosis and prognosis in ophthalmologic and multidisciplinary practice.

Clinical features and prognosis of polypoidal choroidal vasculopathy with different morphologies of branching vascular network on optical coherence tomography angiography.

This study highlights the clinical features and treatment response of polypoidal choroidal vasculopathy (PCV) among three different branching vascular network (BVN) morphologies in optical coherence tomography angiography (OCTA), and further correlates the BVN features with those under fluorescent angiography (FA) and indocyanine green angiography (ICGA). In total, we reviewed 70 eyes with PCV followed up for > 12 months. OCTA, ICGA and FA images were obtained at baseline and post-treatments. BVN was assessed using OCTA and divided into three types by a previously described BVN classification: type 1 (trunk), type 2 (glomeruli), and type 3 (stick). At baseline, type 1 BVN had the poorest vision and thinnest subfoveal choroidal thickness (SFCT), whereas type 3 had the best vision and thickest SFCT. The aforementioned trend sustained after treatments. Each BVN morphology in OCTA showed typical features in FA + ICGA and encompassed significant correlation (p = 0.004). In conclusion, OCTA is an innovative imaging tool for the detection and classification of BVN in PCV. Furthermore, OCTA has advantages of being noninvasive and free of systemic toxicities. The BVN can be divided into three types based on morphological characteristics in OCTA, which play crucial roles in clinical presentations and treatment outcomes.

Leber's Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations.

Leber's congenital amaurosis (LCA), one of the most severe inherited retinal dystrophies, is typically associated with extremely early onset of visual loss, nystagmus, and amaurotic pupils, and is responsible for 20% of childhood blindness. With advances in molecular diagnostic technology, the knowledge about the genetic background of LCA has expanded widely, while disease-causing variants have been identified in 38 genes. Different pathogenetic mechanisms have been found among these varieties of genetic mutations, all of which result in the dysfunction or absence of their encoded proteins participating in the visual cycle. Hence, the clinical phenotypes also exhibit extensive heterogenicity, including the course of visual impairment, involvement of the macular area, alteration in retinal structure, and residual function of the diseased photoreceptor. By reviewing the clinical course, fundoscopic images, optical coherent tomography examination, and electroretinogram, genotype-phenotype correlations could be established for common genetic mutations in LCA, which would benefit the timing of the diagnosis and thus promote early intervention. Gene therapy is promising in the management of LCA, while several clinical trials are ongoing and preliminary success has been announced, focusing on RPE65 and other common disease-causing genes. This review provides an update on the genetics, clinical examination findings, and genotype-phenotype correlations in the most well-established causative genetic mutations of LCA.

Hyperreflective foci in predicting the treatment outcomes of diabetic macular oedema after anti-vascular endothelial growth factor therapy.

This retrospective study evaluated the association of hyperreflective foci (HRF) with treatment response in diabetic macular oedema (DME) after anti-vascular endothelial growth factor (VEGF) therapy. The medical records, including of ophthalmologic examinations and optical coherence tomography (OCT) images, of 106 patients with DME treated with either intravitreal ranibizumab or aflibercept were reviewed. The correlations between best-corrected visual acuity (BCVA) changes and HRF along with other OCT biomarkers were analysed. The mean logMAR BCVA improved from 0.696 to 0.461 after an average of 6.2 injections in 1 year under real-world conditions. Greater visual-acuity gain was noted in patients with a greater number of HRF in the outer retina at baseline (p = 0.037), along with other factors such as poor baseline vision (p < 0.001), absence of epiretinal membrane (p = 0.048), and presence of subretinal fluid at baseline (p = 0.001). The number of HRF after treatment was correlated with the presence of hard exudate (p < 0.001) and baseline haemoglobin A1C (p = 0.001). Patients with proliferative diabetic retinopathy had greater HRF reduction after treatment (p = 0.018). The number of HRF in the outer retina, in addition to other baseline OCT biomarkers, could be used to predict the treatment response in DME after anti-VEGF treatment.

Recurrent retinal detachment after diabetic vitrectomy.

PURPOSE: To investigate the characteristics of recurrent retinal detachment (RD) after diabetic vitrectomy (DV). METHODS: Consecutive cases underwent vitrectomy for recurrent RD after DV was collected and separated into the following four groups for analysis: rhegmatogenous RD (RRD), pure tractional RD (Proliferative Subgroup 1), combined RD with proliferative tissue within the equator (Proliferative Subgroup 2), and combined RD with both posterior and peripheral proliferations (Proliferative Subgroup 3). RESULTS: Of the 41 cases enrolled, retinal reattachment was achieved in 73.2%. Over all, visual acuity was statistically better after operation (p = 0.001). All cases in the RRD group (four cases) had reattachment and a better final vision (p = 0.008). In the proliferative subgroups, those with pure tractional RD (Subgroup 1, seven cases) had the best visual acuity at the time of recurrent RD (p = 0.002). Subgroups 2 and 3 showed statistically significant better final visual acuity (p = 0.045 and 0.019, respectively). Poor preoperative vision (p = 0.001), non-attachment (p = 0.004), and neovascular glaucoma (p = 0.001) were associated with poor prognosis. CONCLUSIONS: Visual acuity may improve after operation for recurrent RD after diabetic vitrectomy. Visual prognosis was better in cases with pure RRD. In the proliferative subgroups, vision was impaired by the development of neovascular glaucoma and retinal non-attachment.

Survival outcomes of eye-sparing surgery for adenoid cystic carcinoma of lacrimal gland.

PURPOSE: To survey adenoid cystic carcinoma of lacrimal glands in Asian population and investigate the predictability in prognosis following the 8th edition American Joint Committee on Cancer (AJCC) staging guideline. STUDY DESIGN: Retrospective study. METHODS: The clinical entities and surgical outcomes of the patients who were histologically confirmed with a diagnosis of lacrimal adenoid cystic carcinoma in National Taiwan University Hospital between January 1995 and December 2015 were retrospectively reviewed. RESULTS: Enrolled were 11 patients. The median follow-up was 7.2 years. Eight patients (72.7%) were diagnosed as T1 or T2 disease, and three patients (27.3%) were diagnosed as T3 or T4 disease according to the AJCC 8th edition guideline. Eye-sparing surgery with radiotherapy was performed in nine patients. Local recurrence was noted in six patients (54.5%) with median disease-free interval of 23.5 months. Six patients (54.5%) developed distant metastases, including lung, bone, and cranial invasions. Overall survival rate during the study period was 54.6%. Five-year overall survival was 81.8% and ten-year overall survival was 68.2%. The Log-rank test for overall survival and disease-free survival between patients with less than T3 disease (p=0.001) and patients with T3 or T4 disease (p=0.006) revealed significant differences. CONCLUSION: This study highlighted the aggressive nature of adenoid cystic carcinoma of lacrimal glands. Eye-sparing surgery with adjunctive radiotherapy may achieve relatively optimal disease control in diseases staged T1 or T2, but in advanced disease metastasis and mortality are usually inevitable.

Characterizing Branching Vascular Network Morphology in Polypoidal Choroidal Vasculopathy by Optical Coherence Tomography Angiography.

This study analyze the morphological characteristics of branching vascular networks (BVN) in polypoidal choroidal vasculopathy (PCV) using optical coherence tomography angiography (OCTA), and correlate imaging characteristics with clinical presentations. We presented a retrospective observational case series for fifty cases of PCV confirmed by indocyanine green angiography. Macular OCTA were done by the AngioVue. The PCV cases were classified by distinct morphologic patterns of BVN by two retina specialists and clinical features were analyzed. The sensitivity of polyp detection by OCTA was 86% after manual segmentation and that of BVN was 90%. Three distinct morphologic patterns of BVN were identified. (1) The "Trunk" pattern (47%) exhibited major vessel trunk with features including presence of drusens, thin choroid, and larger BVN area. (2) The "Glomeruli" pattern (33%) showed anastomotic vascular network without major trunk. (3) The "Stick" pattern (20%) had localized BVN and the thickest choroid. Subtypes 2 and 3 held higher recurrence rate. In conclusions, the precise visualization of BVN on OCTA supported that OCTA might be a noninvasive tool to study the morphology of BVN in PCV, which exhibits three different morphological types. Identifying the morphology of BVN has the potential to prognosticate outcomes in PCV patients.

Vitrectomy for complications of proliferative diabetic retinopathy in young adults: clinical features and surgical outcomes.

PURPOSE: To investigate the clinical manifestations and surgical results after vitrectomy for proliferative diabetic retinopathy (PDR) in young patients. METHODS: Clinical features of patients between 18 to 40 years old who received vitrectomy for PDR between January 2009 and January 2015 were retrospectively reviewed. Those older than 40 years who received vitrectomy for PDR during the same period were retrospectively enrolled and compared as the control group. RESULTS: There were 68 eyes (52 patients) in the study group and 77 eyes (61 patients) in the control group. The average age at operation was 33.15 ± 4.92 years and 56.67 ± 7.52 years, respectively (p < 0.001). At presentation, those in the study group had significantly higher proportions of active fibrovascular proliferation and traction retinal detachment, and with significantly higher-severity gradings than those in the control group. After operation, the recurrent detachment rates were 13.2% in the study group and 1.3% in the control group (p = 0.006), and the final anatomical success rates were 91.2% in the study group and 100% in the control group (p = 0.009). The most significant risk factor for poor visual outcome in the study group was neovascular glaucoma (NVG) (p = 0.001). Patients with Type 1 and Type 2 diabetes mellitus subgroups shared similar clinical features and visual outcome. CONCLUSIONS: Younger patients who received vitrectomy for PDR presented with more severe anatomical features at the time of vitrectomy and had a higher rate of post-operative recurrent detachment. More than 90% achieved final anatomical success. NVG was associated with worse visual outcome.

Exploring the Divergence Range for Stereopsis Maintenance With a Computer-Simulated Troposcope in Patients With Intermittent Exotropia.

PURPOSE: To investigate whether sensory input or motor signal of the extraocular muscle is the main activator of suppression in human intermittent exotropia (X(T)). METHODS: A case-control study was performed. Ten subjects with X(T) and 10 control participants were enrolled. The divergence range between both eyes when binocular vision was maintained was measured by using stereotests with a self-written computer program mimicking a troposcope. The break point, defined as the deviation angle at which stereopsis broke during eye deviation, was compared between the experimental and control groups by using a t test. RESULTS: The median near deviation angle in the experimental group was 42.5 prism diopters (PD) (mean, 44.5 ± 10.82 PD). The mean break point was 40.45 ± 10.79 PD in the X(T) group and 26.86 ± 2.62 PD in the control group (P = 0.003). The mean ratio of the break point to the near deviation angle was 0.92 ± 0.23 in the X(T) group, with the ratio close to 1 in 7 of 10 subjects. CONCLUSIONS: Binocular vision can be maintained if similar images are projected onto corresponding retinas during the tropic phase of X(T). The antidiplopic mechanism in X(T) patients (i.e., suppression) is evoked by sensory input from binocular rivalry rather than by motor signal of the extraocular muscle.