2016

Purpose: To describe spectral-domain optical coherence tomography (OCT) methods for quantifying neuroretinal rim tissue in glaucoma and to compare these methods to the traditional retinal nerve fiber layer thickness diagnostic parameter. Methods: Neuroretinal rim parameters derived from three-dimensional (3D) volume scans were compared with the two-dimensional (2D) Spectralis retinal nerve fiber layer (RNFL) thickness scans for diagnostic capability. This study analyzed one eye per patient of 104 glaucoma patients and 58 healthy subjects. The shortest distances between the cup surface and the OCT-based disc margin were automatically calculated to determine the thickness and area of the minimum distance band (MDB) neuroretinal rim parameter. Traditional 150-μm reference surface-based rim parameters (volume, area, and thickness) were also calculated. The diagnostic capabilities of these five parameters were compared with RNFL thickness using the area under the receiver operating characteristic (AUROC) curves. Results: The MDB thickness had significantly higher diagnostic capability than the RNFL thickness in the nasal (0.913 vs. 0.818, P = 0.004) and temporal (0.922 vs. 0.858, P = 0.026) quadrants and the inferonasal (0.950 vs. 0.897, P = 0.011) and superonasal (0.933 vs. 0.868, P = 0.012) sectors. The MDB area and the three neuroretinal rim parameters based on the 150-μm reference surface had diagnostic capabilities similar to RNFL thickness. Conclusions: The 3D MDB thickness had a high diagnostic capability for glaucoma and may be of significant clinical utility. It had higher diagnostic capability than the RNFL thickness in the nasal and temporal quadrants and the inferonasal and superonasal sectors.

Mucins are a group of highly glycosylated glycoproteins responsible for the protection of wet-surfaced epithelia. Recent data indicate that transmembrane mucins differ in their contribution to the protective function of the ocular surface, with MUC16 being the most effective barrier on the apical surface glycocalyx. Here, we investigated the role of the mucoprotective drug rebamipide in the regulation of transmembrane mucin biosynthesis using stratified cultures of human corneal and conjunctival epithelial cells. We find that the addition of rebamipide to corneal, but not conjunctival, epithelial cells increased MUC16 protein biosynthesis. Rebamipide did not affect the levels of MUC1, 4 and 20 compared to control. In these experiments, rebamipide had no effect on the expression levels of Notch intracellular domains, suggesting that the rebamipide-induced increase in MUC16 biosynthesis in differentiated corneal cultures is not regulated by Notch signaling. Overall these findings indicate that rebamipide induces the differential upregulation of MUC16 in stratified cultures of human corneal epithelial cells, which may have implications to the proper restoration of barrier function in ocular surface disease.

The first aim of this study was to clarify whether cigarette smoking affects tear secretion, goblet cell density, and tear MUC5AC concentration. The second purpose was to evaluate the correlations of conjunctival goblet cell density with tear MUC5AC concentration and other ocular surface evaluation factors. This cross-sectional study included 88 office workers. All subjects were required to fill in dry eye and smoking questionnaires, in addition to ocular surface evaluation. Tear wash fluid was collected from inferior fornix, and conjunctival epithelium was obtained by impression cytology. Tear MUC5AC concentration was quantified using enzyme-linked immunoassay, and conjunctival goblet cell density was counted after Periodic-acid Schiff staining. Tear MUC5AC concentration had significant positive correlation with conjunctival goblet cell density (r = 0.181, P = 0.03). In current smokers, Schirmer I test value, goblet cell density and tear MUC5AC concentration were significantly lower than non-smokers. Pack-years of smoking have significant negative correlation with goblet cell density (r = -0.174, P = 0.036) and tear MUC5AC concentration (r = -0.183, P = 0.028). We concluded that smoking might decrease tear secretion, goblet cell density and tear MUC5AC concentration. In addition, MUC5AC concentration in tears depends on goblet cell density in the conjunctiva among office workers.

Importance: Extended-spectrum β-lactamase (ESBL)-producing Escherichia coli are highly antibiotic resistant, and primary ocular infection by ESBL E coli has rarely been reported. A novel mutation conferring phagocytosis resistance would position a strain well to infect the cornea. Observations: A woman with recurrent keratitis presented with a corneal ulcer, which was culture positive for ESBL E coli. Resistant to nearly all other antimicrobials, the infection was treated with amikacin and polymyxin B-trimethoprim, and the ulcer resolved over 3 weeks. Analysis of the E coli genome showed it to belong to multilocus sequence type 131 (ST131). This isolate was found to possess a novel deletion in yrfF, an essential regulator of bacterial capsule synthesis. Disruption of yrfF, which confers mucoidy and increased virulence, has not been previously observed in ESBL E coli from any infection site. This novel variant was experimentally proven to cause the mucoid phenotype, and corresponding resistance to phagocytic killing. Conclusions and Relevance: Increased resistance to immune clearance in an ESBL E coli lineage already known for its virulence is an unsettling development. This phenotype, which likely positioned it as an unusual cause of corneal ulcer, can be easily recognized in the laboratory, which should help limit its spread.

Children born very preterm are at greater risk of ophthalmic morbidities, including strabismus, than children born at term. We evaluated perinatal factors associated with strabismus at age 2 years in a large population of infants delivered before 28 weeks' gestation. A total of 996 infants in the multicenter ELGAN (Extremely Low Gestational Age Newborn) study who had a retinal exam in infancy and a developmental assessment at 2 years corrected age are included. Their mothers were interviewed about the pregnancy, and both mother and newborn charts were reviewed. Certified examiners administered the Bayley Scales of Infant Development-II and performed an examination of ocular alignment. Time-oriented logistic regression risk models were created to evaluate the associations of characteristics and exposures with the development of strabismus. Overall, 14% (n = 141) of the children had strabismus at 2 years, and 80% of strabismic children had esotropia. Characteristics associated with strabismus were birth before 26 weeks' gestation, severe fetal growth restriction, and maternal history of aspirin ingestion. Associated postnatal factors included a SNAP-II (Score for Neonatal Acute Physiology) illness severity value ≥30, brain ventriculomegaly, type I retinopathy of prematurity, and ventilator-dependent severe bronchopulmonary dysplasia. Strabismus in very preterm populations is associated with a number of antenatal and postnatal antecedents as well as clinical and imaging correlates indicative of brain damage in these children. Routine ophthalmologic assessments in the early years can allow appropriate and timely interventions.

IMPORTANCE: Age-related macular degeneration (AMD) remains the leading cause of blindness in developed countries, and affects more than 150 million worldwide. Despite effective anti-angiogenic therapies for the less prevalent neovascular form of AMD, treatments are lacking for the more prevalent dry form. Similarities in risk factors and pathogenesis between AMD and atherosclerosis have led investigators to study the effects of statins on AMD incidence and progression with mixed results. A limitation of these studies has been the heterogeneity of AMD disease and the lack of standardization in statin dosage. OBJECTIVE: We were interested in studying the effects of high-dose statins, similar to those showing regression of atherosclerotic plaques, in AMD. DESIGN: Pilot multicenter open-label prospective clinical study of 26 patients with diagnosis of AMD and the presence of many large, soft drusenoid deposits. Patients received 80 mg of atorvastatin daily and were monitored at baseline and every 3 months with complete ophthalmologic exam, best corrected visual acuity (VA), fundus photographs, optical coherence tomography (OCT), and blood work (AST, ALT, CPK, total cholesterol, TSH, creatinine, as well as a pregnancy test for premenopausal women). RESULTS: Twenty-three subjects completed a minimum follow-up of 12 months. High-dose atorvastatin resulted in regression of drusen deposits associated with vision gain (+ 3.3 letters, p = 0.06) in 10 patients. No subjects progressed to advanced neovascular AMD. CONCLUSIONS: High-dose statins may result in resolution of drusenoid pigment epithelial detachments (PEDs) and improvement in VA, without atrophy or neovascularization in a high-risk subgroup of AMD patients. Confirmation from larger studies is warranted.

PURPOSE: To report outcomes of autologous simple limbal epithelial transplantation (SLET) performed for unilateral limbal stem cell deficiency (LSCD) at multiple centres worldwide. METHODS: In this retrospective, multicentre, interventional case series, records of patients who had undergone autologous SLET for unilateral LSCD, with a minimum of 6 months of follow-up, were reviewed. The primary outcome measure was clinical success, defined as a completely epithelised, avascular corneal surface. Kaplan-Meier survival curves were constructed and survival probability was calculated. A Cox proportional hazards analysis was done to assess association of preoperative characteristics with risk of failure. Secondary outcome measures included the percentage of eyes achieving visual acuity of 20/200 or better, percentage of eyes gaining two or more Snellen lines and complications encountered. RESULTS: 68 eyes of 68 patients underwent autologous SLET, performed across eight centres in three countries. Clinical success was achieved in 57 cases (83.8%). With a median follow-up of 12 months, survival probability exceeded 80%. Presence of symblepharon (HR 5.8) and simultaneous keratoplasty (HR 10.8) were found to be significantly associated with a risk of failure. 44 eyes (64.7%) achieved a visual acuity of 20/200 or better, and 44 eyes (64.7%) gained two or more Snellen lines. Focal recurrences of pannus were noted in 21 eyes (36.8%) with clinical success. CONCLUSION: Autologous SLET is an effective and safe modality for treatment of unilateral LSCD. Clinical success rates and visual acuity improvement are equal to or better than those reported with earlier techniques.

Primary open angle glaucoma (POAG) is a complex disease and is one of the major leading causes of blindness worldwide. Genome-wide association studies have successfully identified several common variants associated with glaucoma; however, most of these variants only explain a small proportion of the genetic risk. Apart from the standard approach to identify main effects of variants across the genome, it is believed that gene-gene interactions can help elucidate part of the missing heritability by allowing for the test of interactions between genetic variants to mimic the complex nature of biology. To explain the etiology of glaucoma, we first performed a genome-wide association study (GWAS) on glaucoma case-control samples obtained from electronic medical records (EMR) to establish the utility of EMR data in detecting non-spurious and relevant associations; this analysis was aimed at confirming already known associations with glaucoma and validating the EMR derived glaucoma phenotype. Our findings from GWAS suggest consistent evidence of several known associations in POAG. We then performed an interaction analysis for variants found to be marginally associated with glaucoma (SNPs with main effect p-value <0.01) and observed interesting findings in the electronic MEdical Records and GEnomics Network (eMERGE) network dataset. Genes from the top epistatic interactions from eMERGE data (Likelihood Ratio Test i.e. LRT p-value <1e-05) were then tested for replication in the NEIGHBOR consortium dataset. To replicate our findings, we performed a gene-based SNP-SNP interaction analysis in NEIGHBOR and observed significant gene-gene interactions (p-value <0.001) among the top 17 gene-gene models identified in the discovery phase. Variants from gene-gene interaction analysis that we found to be associated with POAG explain 3.5% of additional genetic variance in eMERGE dataset above what is explained by the SNPs in genes that are replicated from previous GWAS studies (which was only 2.1% variance explained in eMERGE dataset); in the NEIGHBOR dataset, adding replicated SNPs from gene-gene interaction analysis explain 3.4% of total variance whereas GWAS SNPs alone explain only 2.8% of variance. Exploring gene-gene interactions may provide additional insights into many complex traits when explored in properly designed and powered association studies.

INTRODUCTION: Establishing a diagnosis of mitochondrial disease in adults remains a clinician's challenge. We report a case of syndrome reminiscent of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) in an adult patient who carries m.10158T>C mutation in complex I respiratory chain gene MT-ND3 (mitochondrially encoded NADH dehydrogenase 3). CASE REPORT: This 26-year-old man from Thailand presented with new-onset headaches, seizures, stroke-like episodes, and poor vision due to optic neuropathy and cortical blindness. Instead of expected mutations in the mitochondrial tRNA gene that are frequently associated with MELAS, the mutation in MT-ND3 with variable tissue heteroplasmy (blood 5.3%, muscle 89.5%) was demonstrated. The patient's clinical features, blood biomarkers, neuroimaging findings, muscle biopsy with histochemical and functional in vitro analysis, and genetic studies were analyzed and compared with all previously reported ND3 disease cases. CONCLUSIONS: ND3 disease due to m.10158T>C mutation was previously described only in patients with Leigh or Leigh-like syndrome. Our findings thus indicate that ND3 disease can manifest with atypical phenotype in adults. The diagnosis of mitochondrial disease caused by other than typical MELAS-associated mutations in adults with stroke-like episodes, headaches, and seizures should be considered. An analysis of tissue other than blood, which is more likely to harbor a tissue-specific mitochondrial DNA mutation at a measurable level, may be necessary for diagnosis.

OPINION STATEMENT: Susac syndrome is a microangiopathy of the brain, retina, and cochlea. Several lines of evidence support the concept that this disease is an acquired autoimmune disorder. Prospective, randomized, controlled studies of treatments are not available because the disease is rare. Furthermore, the average period of follow-up in reported cases is short, limiting a complete understanding of the natural history of the disease. Empirical treatment strategies are therefore based upon expert recommendations and anecdotal reports of response to various immunomodulators, and the appropriate duration of therapy is not known. In our opinion, the encephalopathic form of Susac syndrome should be treated early and aggressively to avoid cognitive dysfunction and disability. Induction therapy with pulse methylprednisolone frequently proves to be inadequate. Additional agents, including intravenous immunoglobulins, intravenous cyclophosphamide, or rituximab are often necessary to induce a sustained remission. Maintenance therapy with oral glucocorticoids combined with intravenous immunoglobulins, mycophenolate mofetil, methotrexate, azathioprine, cyclophosphamide, or rituximab is typically necessary to achieve a sustained remission. Aspirin may be used as an adjunctive agent, although evidence showing efficacy is scant. The response to treatment should be closely monitored by frequent clinical examinations, brain MRI, and fluorescein angiography. Once disease remission has been established, it appears prudent to continue maintenance treatment for at least two additional years, although the real long-term risk of future relapses remains unknown. Establishing a multicenter patient registry and biorepository is essential to study the pathogenesis of the disease, further define the duration of disease, identify reliable biomarkers that aid early diagnosis and assess risk of relapse, and develop effective disease-specific therapies.

Sporadic optic pathway gliomas (OPGs) have been reported to cause more vision loss than OPGs associated with neurofibromatosis type-1, but long-term visual outcome data are limited. The purpose of this study was to report the visual outcomes of a cohort of pediatric patients with sporadic OPGs. This was a retrospective, cohort study at a tertiary care pediatric hospital and cancer institute. The study included all patients with sporadic OPGs evaluated from 1990 to 2014. The primary outcome was visual acuity at final follow-up. Secondary outcomes were risk factors for a poor visual outcome and the rate of progression. There were 59 pediatric patients included in the study. Median age at presentation was 2.5 years old and median follow-up was 5.2 years. In the worse eye at final follow-up, 16 patients (27 %) were 20/30 or better, 9 patients (15 %) were between 20/40 and 20/80, and 34 patients (58 %) were 20/100 or worse. In the better eye at final follow-up, 33 patients (56 %) were 20/30 or better, 11 patients (19 %) were between 20/40 and 20/80, and 15 patients (25 %) were 20/100 or worse. Risk factors for a poor visual outcome included younger age at presentation, optic nerve pallor, and tumor extent. Of the 54 patients (92 %) who received treatment, 40 (74 %) experienced disease progression during or after treatment. A majority of pediatric patients with sporadic OPGs had significant long-term visual impairment. In spite of treatment, tumor progression is common. Serial ophthalmic examinations with quantitative vision measurements are essential in the management of sporadic OPGs.

Management of neoangiogenesis remains a high-value therapeutic goal. A recently uncovered association between the DNA damage repair pathway and pathological angiogenesis could open previously unexplored possibilities for intervention. An attractive and novel target is the Eyes absent (EYA) tyrosine phosphatase, which plays a critical role in the repair versus apoptosis decision after DNA damage. This study examines the role of EYA in the postnatal development of the retinal vasculature and under conditions of ischemia-reperfusion encountered in proliferative retinopathies. We find that the ability of the EYA proteins to promote endothelial cell (EC) migration contributes to a delay in postnatal development of the retinal vasculature when Eya3 is deleted specifically in ECs. By using genetic and chemical biology tools, we show that EYA contributes to pathological angiogenesis in a model of oxygen-induced retinopathy. Both in vivo and in vitro, loss of EYA tyrosine phosphatase activity leads to defective assembly of γ-H2AX foci and thus to DNA damage repair in ECs under oxidative stress. These data reveal the potential utility of EYA tyrosine phosphatase inhibitors as therapeutic agents in inhibiting pathological neovascularization with a range of clinical applications.

PURPOSE: To investigate the association between oral contraceptive (OC) use and glaucoma prevalence in the United States. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 3406 female participants, aged 40 years or older, from the 2005 to 2008 National Health and Nutrition Examination Survey, who reported a presence or absence of glaucoma or ocular hypertension completed both the vision and the reproductive health questionnaires and underwent eye examinations. METHODS: Multivariate regression analysis was used to assess the correlation between OC use and self-reported glaucoma or ocular hypertension (n = 231 cases), controlling for potential confounders, including age, ethnicity, systemic comorbidities such as hypertension and stroke, ocular diseases such as cataract and diabetic retinopathy, and reproductive health factors, including age at menopause, age at menarche, history of hormone replacement therapy, and gynecological surgical history. MAIN OUTCOME MEASURES: The outcome variable was self-reported glaucoma or ocular hypertension. RESULTS: After adjusting for confounders, those with ≥3 years of OC use had greater odds (odds ratio, 1.94; 95% confidence interval, 1.22-3.07) of self-reported glaucoma or ocular hypertension. Other factors associated with higher glaucoma or ocular hypertension prevalence included older age, African American race, and later age at menarche. CONCLUSIONS: Oral contraceptive use may be associated with increased risk of self-reported glaucoma or ocular hypertension.

Familial exudative vitreoretinopathy (FEVR) is characterized by delayed retinal vascular development, which promotes hypoxia-induced pathologic vessels. In severe cases FEVR may lead to retinal detachment and visual impairment. Genetic studies linked FEVR with mutations in Wnt signaling ligand or receptors, including low-density lipoprotein receptor-related protein 5 (LRP5) gene. Here, we investigated ocular pathologies in a Lrp5 knockout (Lrp5(-/-)) mouse model of FEVR and explored whether treatment with a pharmacologic Wnt activator lithium could bypass the genetic defects, thereby protecting against eye pathologies. Lrp5(-/-) mice displayed significantly delayed retinal vascular development, absence of deep layer retinal vessels, leading to increased levels of vascular endothelial growth factor and subsequent pathologic glomeruloid vessels, as well as decreased inner retinal visual function. Lithium treatment in Lrp5(-/-) mice significantly restored the delayed development of retinal vasculature and the intralaminar capillary networks, suppressed formation of pathologic glomeruloid structures, and promoted hyaloid vessel regression. Moreover, lithium treatment partially rescued inner-retinal visual function and increased retinal thickness. These protective effects of lithium were largely mediated through restoration of canonical Wnt signaling in Lrp5(-/-) retina. Lithium treatment also substantially increased vascular tubular formation in LRP5-deficient endothelial cells. These findings suggest that pharmacologic activation of Wnt signaling may help treat ocular pathologies in FEVR and potentially other defective Wnt signaling-related diseases.

PURPOSE: To present the case of a patient who developed spontaneous closure of an idiopathic macular hole after four failed attempts at surgical closure. METHODS: This is a retrospective case review of the medical record of a single patient. No statistical analysis was performed. The patient is a 71-year-old white woman with neurofibromatosis Type 1 who presented to the retina clinic of one of the authors. RESULTS: The patient underwent four vitrectomies with long acting gas by two surgeons over the course of 2 years. After each surgery, the hole either did not close or it closed and then reopened within 1 year. Five months after the last surgery (1 year after the hole last reopened), the patient presented with improved vision and spontaneous closure of the macular hole. The hole has remained closed since then. CONCLUSION: This case demonstrates that spontaneous closure of a macular hole, associated with excellent visual recovery, can occur after multiple surgical failures. We propose that enhanced scar formation due to neurofibromatosis Type 1 was responsible for both the numerous failures following initially successful surgery (centrifugal traction) and for the spontaneous closure (centripetal traction).

Glaucoma is an optic neuropathy that is characterized by the progressive degeneration of the optic nerve, leading to visual impairment. Glaucoma is the main cause of irreversible blindness worldwide, but typically remains asymptomatic until very severe. Open-angle glaucoma comprises the majority of cases in the United States and western Europe, of which, primary open-angle glaucoma (POAG) is the most common type. By contrast, in China and other Asian countries, angle-closure glaucoma is highly prevalent. These two types of glaucoma are characterized based on the anatomic configuration of the aqueous humour outflow pathway. The pathophysiology of POAG is not well understood, but it is an optic neuropathy that is thought to be associated with intraocular pressure (IOP)-related damage to the optic nerve head and resultant loss of retinal ganglion cells (RGCs). POAG is generally diagnosed during routine eye examination, which includes fundoscopic evaluation and visual field assessment (using perimetry). An increase in IOP, measured by tonometry, is not essential for diagnosis. Management of POAG includes topical drug therapies and surgery to reduce IOP, although new therapies targeting neuroprotection of RGCs and axonal regeneration are under development.

When searching through volumetric images [e.g., computed tomography (CT)], radiologists appear to use two different search strategies: "drilling" (restrict eye movements to a small region of the image while quickly scrolling through slices), or "scanning" (search over large areas at a given depth before moving on to the next slice). To computationally identify the type of image information that is used in these two strategies, 23 naïve observers were instructed with either "drilling" or "scanning" when searching for target T's in 20 volumes of faux lung CTs. We computed saliency maps using both classical two-dimensional (2-D) saliency, and a three-dimensional (3-D) dynamic saliency that captures the characteristics of scrolling through slices. Comparing observers' gaze distributions with the saliency maps showed that search strategy alters the type of saliency that attracts fixations. Drillers' fixations aligned better with dynamic saliency and scanners with 2-D saliency. The computed saliency was greater for detected targets than for missed targets. Similar results were observed in data from 19 radiologists who searched five stacks of clinical chest CTs for lung nodules. Dynamic saliency may be superior to the 2-D saliency for detecting targets embedded in volumetric images, and thus "drilling" may be more efficient than "scanning."

One set of missense mutations in the neuron specific beta tubulin isotype 3 (TUBB3) has been reported to cause malformations of cortical development (MCD), while a second set has been reported to cause isolated or syndromic Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3). Because TUBB3 mutations reported to cause CFEOM had not been associated with cortical malformations, while mutations reported to cause MCD had not been associated with CFEOM or other forms of paralytic strabismus, it was hypothesized that each set of mutations might alter microtubule function differently. Here, however, we report two novel de novo heterozygous TUBB3 amino acid substitutions, G71R and G98S, in four patients with both MCD and syndromic CFEOM3. These patients present with moderately severe CFEOM3, nystagmus, torticollis, and developmental delay, and have intellectual and social disabilities. Neuroimaging reveals defective cortical gyration, as well as hypoplasia or agenesis of the corpus callosum and anterior commissure, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia. These new TUBB3 substitutions meld the two previously distinct TUBB3-associated phenotypes, and implicate similar microtubule dysfunction underlying both. © 2015 Wiley Periodicals, Inc.