Willcox MDP, Argüeso P, Georgiev GA, Holopainen JM, Laurie GW, Millar TJ, Papas EB, Rolland JP, Schmidt TA, Stahl U, Suarez T, Subbaraman LN, Uçakhan OÖ, Jones L. TFOS DEWS II Tear Film Report. Ocul Surf 2017;15(3):366-403.Abstract
The members of the Tear Film Subcommittee reviewed the role of the tear film in dry eye disease (DED). The Subcommittee reviewed biophysical and biochemical aspects of tears and how these change in DED. Clinically, DED is characterized by loss of tear volume, more rapid breakup of the tear film and increased evaporation of tears from the ocular surface. The tear film is composed of many substances including lipids, proteins, mucins and electrolytes. All of these contribute to the integrity of the tear film but exactly how they interact is still an area of active research. Tear film osmolarity increases in DED. Changes to other components such as proteins and mucins can be used as biomarkers for DED. The Subcommittee recommended areas for future research to advance our understanding of the tear film and how this changes with DED. The final report was written after review by all Subcommittee members and the entire TFOS DEWS II membership.
PURPOSE: To compare diagnostic performance and structure-function correlations of multifocal electroretinogram (mfERG), full-field flash ERG (ff-ERG) photopic negative response (PhNR) and transient pattern-reversal ERG (PERG) in a non-human primate (NHP) model of experimental glaucoma (EG). METHODS: At baseline and after induction of chronic unilateral IOP elevation, 43 NHP had alternating weekly recordings of retinal nerve fiber layer thickness (RNFLT) by spectral domain OCT (Spectralis) and retinal function by mfERG (7F slow-sequence stimulus, VERIS), ff-ERG (red 0.42 log cd-s/m(2) flashes on blue 30 scotopic cd/m(2) background, LKC UTAS-E3000), and PERG (0.8° checks, 99% contrast, 100 cd/m(2) mean, 5 reversals/s, VERIS). All NHP were followed at least until HRT-confirmed optic nerve head posterior deformation, most to later stages. mfERG responses were filtered into low- and high-frequency components (LFC, HFC, >75 Hz). Peak-to-trough amplitudes of LFC features (N1, P1, N2) and HFC RMS amplitudes were measured and ratios calculated for HFC:P1 and N2:P1. ff-ERG parameters included A-wave (at 10 ms), B-wave (trough-to-peak) and PhNR (baseline-to-trough) amplitudes as well as PhNR:B-wave ratio. PERG parameters included P50 and N95 amplitudes as well as N95:P50 ratio and N95 slope. Diagnostic performance of retinal function parameters was compared using the area under the receiver operating characteristic curve (A-ROC) to discriminate between EG and control eyes. Correlations to RNFLT were compared using Steiger's test. RESULTS: Study duration was 15 ± 8 months. At final follow-up, structural damage in EG eyes measured by RNFLT ranged from 9% above baseline (BL) to 58% below BL; 29/43 EG eyes (67%) and 0/43 of the fellow control eyes exhibited significant (>7%) loss of RNFLT from BL. Using raw parameter values, the largest A-ROC findings for mfERG were: HFC (0.82) and HFC:P1 (0.90); for ff-ERG: PhNR (0.90) and PhNR:B-wave (0.88) and for PERG: P50 (0.64) and N95 (0.61). A-ROC increased when data were expressed as % change from BL, but the pattern of results persisted. At 95% specificity, the diagnostic sensitivity of mfERG HFC:P1 ratio was best, followed by PhNR and PERG. The correlation to RNFLT was stronger for mfERG HFC (R = 0.65) than for PhNR (R = 0.59) or PERG N95 (R = 0.36), (p = 0.20, p = 0.0006, respectively). The PhNR flagged a few EG eyes at the final time point that had not been flagged by mfERG HFC or PERG. CONCLUSIONS: Diagnostic performance and structure-function correlation were strongest for mfERG HFC as compared with ff-ERG PhNR or PERG in NHP EG.
PURPOSE: To expand understanding of presentation, diagnosis, and outcomes of hemorrhagic occlusive retinal vasculitis (HORV). DESIGN: Retrospective case series. PARTICIPANTS: Thirty-six eyes of 23 patients. METHODS: The American Society of Cataract and Refractive Surgery (ASCRS) and the American Society of Retina Specialists (ASRS) formed a joint task force to define clinical characteristics of HORV and to study its prevalence, cause, treatment, and outcomes. An online registry was established on both societies' web sites. Surveys were e-mailed to members of both societies soliciting cases of suspected HORV. A literature search was performed to uncover additional cases. MAIN OUTCOME MEASURES: Historical data including intraoperative characteristics, images, treatment regimens, and visual and anatomic outcomes. RESULTS: Characteristic findings of HORV included unremarkable postoperative day 1 undilated examination, delayed-onset painless vision loss, mild anterior chamber and vitreous inflammation, sectoral retinal hemorrhages in areas of ischemia, and predilection for venules and peripheral involvement. Based on predetermined diagnostic criteria, 36 eyes of 23 patients were diagnosed with HORV. All eyes received intraocular vancomycin via intracameral bolus (33/36), via intravitreal injection (1/36), or through the irrigation bottle (2/36). Patients sought treatment with HORV 1 to 21 days after surgery or intravitreal injection. Visual results usually were poor: 22 of 36 eyes (61%) had 20/200 or worse visual acuity and 8 of 36 eyes (22%) had no light perception (NLP). Neovascular glaucoma developed in 20 of 36 eyes (56%). Seven eyes received additional intravitreal vancomycin after surgery; 5 of these 7 eyes had NLP visual acuity at the most recent examination. Three eyes received intravitreal corticosteroids and had final visual acuities of 20/40, 20/70, and hand movements. CONCLUSIONS: Hemorrhagic occlusive retinal vasculitis is a rare, potentially devastating condition that can develop after cataract surgery or intraocular injection. All cases in this series were associated with intraocular vancomycin. Disease course and findings suggest that HORV is caused by a delayed hypersensitivity reaction to vancomycin. Early treatment with corticosteroids likely is beneficial. Subsequently, anti-vascular endothelial growth factor injections and panretinal photocoagulation are important to prevent neovascular glaucoma, a common complication. Avoidance of additional intravitreal vancomycin is recommended if HORV is suspected.
When searching real-world scenes, human attention is guided by knowledge of the plausible size of target object (if an object is six feet tall, it isn't your cat). Computer algorithms typically do not do this, but perhaps they should.
Apophysomyces is a rare fungal organism causing rhino-orbito-cerebral mycotic infections with high morbidity and mortality, typically in immunocompetent individuals. Several cases of Apophysomyces elegans orbital disease have been reported. Herein, we report a case of Apophysomyces variabilis infection involving the orbit, sinuses, and calvarium in an immunocompetent 74-year-old woman, with a review of the literature. Unlike prior cases of A. elegans classic rhino-orbito-cerebral infection, our case included diffuse calvarial lytic lesions and overlying soft tissue nodules, but without parenchymal intracranial involvement. There was radiographic and clinical evidence of infarction of the orbital contents and cavernous sinus thrombosis. Anastomoses between the superior orbital (ophthalmic) vein and diploic veins of the calvarium are believed to be primarily responsible for the unusual mode of spread on the extradural surface of the brain. Although the patient stabilized without definitive surgical intervention, her disease slowly and intermittently progressed for over a year after presentation, requiring multiple courses of antifungal treatment.
A 38-year-old woman presented with multiple bilateral recurrent eyelid cysts. Her medical history was notable for Gorlin (nevoid basal cell carcinoma) syndrome. Histopathologic and immunohistochemical examinations revealed that the lesions were intratarsal keratinous cysts. They were similar in appearance to sporadic intratarsal keratinous cysts and closely resembled odontogenic keratocysts of the jaw. Eyelid cysts occur in up to 40 percent of patients with Gorlin syndrome; however, their description has been cursory and for the most part, outside of the ophthalmic literature. Although ophthalmologists are familiar with the periocular basal cell carcinomas that occur in patients with Gorlin syndrome, up to 10 percent of patients never develop a basal cell carcinoma, but may manifest other ophthalmic findings. Awareness of these other features may contribute to the earlier diagnosis of the syndrome. We discuss the clinical and histopathologic features of intratarsal keratinous cysts in Gorlin syndrome, comparing them to sporadic intratarsal keratinous cysts, other eyelid cysts, and jaw cysts that also characterize this syndrome. We briefly review the ocular and systemic manifestations of Gorlin syndrome and recent genetic and therapeutic developments so that the eyelid cysts may be appreciated within the appropriate context of Gorlin syndrome as a whole.
Nonhuman primates are commonly used for cognitive neuroscience research and often surgically implanted with cephalic recording chambers for electrophysiological recording. Aerobic bacterial cultures from 25 macaques identified 72 bacterial isolates, including 15 Enterococcus faecalis isolates. The E. faecalis isolates displayed multi-drug resistant phenotypes, with resistance to ciprofloxacin, enrofloxacin, trimethoprim-sulfamethoxazole, tetracycline, chloramphenicol, bacitracin, and erythromycin, as well as high-level aminoglycoside resistance. Multi-locus sequence typing showed that most belonged to two E. faecalis sequence types (ST): ST 4 and ST 55. The genomes of three representative isolates were sequenced to identify genes encoding antimicrobial resistances and other traits. Antimicrobial resistance genes identified included aac(6')-aph(2"), aph(3')-III, str, ant(6)-Ia, tetM, tetS, tetL, ermB, bcrABR, cat, and dfrG, and polymorphisms in parC (S80I) and gyrA (S83I) were observed. These isolates also harbored virulence factors including the cytolysin toxin genes in ST 4 isolates, as well as multiple biofilm-associated genes (esp, agg, ace, SrtA, gelE, ebpABC), hyaluronidases (hylA, hylB), and other survival genes (ElrA, tpx). Crystal violet biofilm assays confirmed that ST 4 isolates produced more biofilm than ST 55 isolates. The abundance of antimicrobial resistance and virulence factor genes in the ST 4 isolates likely relates to the loss of CRISPR-cas. This macaque colony represents a unique model for studying E. faecalis infection associated with indwelling devices, and provides an opportunity to understand the basis of persistence of this pathogen in a healthcare setting.
BACKGROUND: Conjunctival pyogenic granulomas are commonly seen after ocular surgeries or at an ocular wound site. The aim of this study is to describe a novel histological classification for medically uncontrolled conjunctival pyogenic granulomas (MUCPG), and to explore whether the diversity in clinical features correlates to different histological subtypes of MUCPG. METHODS: This is an observational cross-section case series. We reviewed 46 consecutive patients with conjunctival pyogenic granulomas who did not respond to topical corticosteroids and underwent surgical excision from January 1, 2006 through December 31, 2015. Clinical features and histological findings were presented and analyzed. RESULTS: Ocular surgery, accidental injury, and chalazion were the main predisposing causes of MUCPG. The lesions tended to occur unilaterally on the bulbar conjunctiva. Forty patients (87%) presented an enrichment of inflammatory cells and proliferated capillaries in their pathological sections (inflammatory pattern). Six patients (13%) showed relatively few inflammatory cells and capillaries within fibrous stroma (fibrous pattern). Patients with the inflammatory pattern were older (p = 0.025) and tended to be located in bulbar conjunctiva (p = 0.002). The predisposing causes were also different between two histological subtypes (p = 0.007). CONCLUSIONS: We found the correlation between clinical presentation and histological subtypes in patients with MUCPG, indicating this disease may need a new classification scheme.
PurposeTo determine the association of maternal factors and exposure during pregnancy with the incidence in newborns of epibulbar dermoid (ED), a congenital ocular surface benign tumor.Patients and methodsThis is a retrospective, paired case-control study in which 121 children with ED (case group) and 121 children without ED (control group) were recruited. Questionnaire-based interviews with mothers of participants were performed and maternal medical records during pregnancy were reviewed. The questionnaire investigated basic information, personal history, environmental exposure, exposure to maternal diseases, symptoms and corresponding medical treatments during pregnancy, and parental socioeconomic status. The case and control participants were matched for sex, birth weight, gestational age, and parental socioeconomic status level. Univariate and multivariate logistic regression analyses were conducted with ED as the main outcome variable.ResultsFactors significantly associated with ED were: history of maternal inevitable miscarriage (odds ratio (OR), 2.59; 95% confidence intervals (CI), 1.13-5.90), common cold in the first trimester (OR, 3.94; CI, 1.74-8.93), and paternal smoke exposure >half a pack per day during pregnancy (OR, 4.81; CI, 1.74-13.28).ConclusionHistory of maternal miscarriage, common cold exposure in the first trimester, and paternal smoking (>half a pack per day) during pregnancy could result in significant risk factors for ED of newborns. These data also imply that paternal smoking delivers nicotine to maternal respiratory system and uterine microenvironment that may both affect microvascular development and predispose the fetus to future ED.
Purpose: Pathologic angiogenesis is a component of many diseases, including neovascular age-related macular degeneration, proliferation diabetic retinopathy, as well as tumor growth and metastasis. The purpose of this project was to examine whether the system of adeno-associated viral (AAV)-mediated CRISPR (clustered regularly interspaced short palindromic repeats)-associated endonuclease (Cas)9 can be used to deplete expression of VEGF receptor 2 (VEGFR2) in human vascular endothelial cells in vitro and thus suppress its downstream signaling events. Methods: The dual AAV system of CRISPR/Cas9 from Streptococcus pyogenes (AAV-SpGuide and -SpCas9) was adapted to edit genomic VEGFR2 in primary human retinal microvascular endothelial cells (HRECs). In this system, the endothelial-specific promoter for intercellular adhesion molecule 2 (ICAM2) was cloned into the dual AAV vectors of SpGuide and SpCas9 for driving expression of green fluorescence protein (GFP) and SpCas9, respectively. These two AAV vectors were applied to production of recombinant AAV serotype 5 (rAAV5), which were used to infect HRECs for depletion of VEGFR2. Protein expression was determined by Western blot; and cell proliferation, migration, as well as tube formation were examined. Results: AAV5 effectively infected vascular endothelial cells (ECs) and retinal pigment epithelial (RPE) cells; the ICAM2 promoter drove expression of GFP and SpCas9 in HRECs, but not in RPE cells. The results showed that the rAAV5-CRISPR/Cas9 depleted VEGFR2 by 80% and completely blocked VEGF-induced activation of Akt, and proliferation, migration as well as tube formation of HRECs. Conclusions: AAV-CRISRP/Cas9-mediated depletion of VEGFR2 is a potential therapeutic strategy for pathologic angiogenesis.
The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated nuclease (Cas)9 is an effective instrument for revising the genome with great accuracy. This system has been widely employed to generate mutants in genomes from plants to human cells. Rapid improvements in Cas9 specificity in eukaryotic cells have opened great potential for the use of this technology as a therapeutic. Herein, we summarize the recent advancements of CRISPR-Cas9 use in research on human cells and animal models, and outline a basic and clinical pipeline for CRISPR-Cas9-based treatments of genetic eye diseases.
PURPOSE: To evaluate the clinical outcome of umbilical cord patch (UCP) transplantation for deep corneal ulcers with perforations and descemetoceles. METHODS: In this retrospective, noncomparative, interventional case series, 11 eyes of 11 patients with corneal perforation or descemetocele were included. The thickness and microstructure of UCP were measured. All eyes were treated with UCP and amniotic membrane transplantation for corneal reconstruction. Corneal ulcer healing, corneal thickness, anterior chamber formation, and best-corrected visual acuity (BCVA) were recorded and analyzed. RESULTS: The thickness of human UCP is 398.6 ± 102.8 μm (n = 5) with compact aligned fibers. The average age was 56.2 ± 15.8 (ranging from 22 to 75) years. The mean follow-up period was 7.1 ± 1.7 (ranging from 5 to 10) months. Four patients had descemetocele and 7 had perforation. The anterior chambers in all the 7 perforated corneas were formed at postoperative day 1. All patients regained a normal corneal thickness and smooth corneal surface within the first postoperative month. The vision improved in 10 eyes and remained unchanged in 1 eye. No recurrence nor side effects occurred during the follow-up. CONCLUSIONS: UCP can serve as an alternative material in the treatment of corneal perforations and descemetoceles. This treatment option is also beneficial in those countries with limited cornea donors and eye bank services.
Despite recent advances in the medical management of diabetic retinal disease, there remain established indications for vitreoretinal surgery in the treatment of severe proliferative diabetic retinopathy. These include non-clearing vitreous hemorrhage and tractional retinal detachment. Advances in surgical instrumentation, technique, and experience have led to improved visual outcomes, as well as a corresponding decrease in the incidence of postoperative complications. However, the presence of systemic and ocular factors in diabetic patients increases the risk of adverse events compared to non-diabetic individuals. This review will focus on the most important postoperative complications following pars plana vitrectomy, with specific considerations for the diabetic patient.
Corneal epithelial stem cells are adult somatic stem cells located at the limbus and represent the ultimate source of transparent corneal epithelium. When these limbal stem cells become dysfunctional or deficient, limbal stem cell deficiency (LSCD) develops. LSCD is a major cause of corneal scarring and is particularly prevalent in chemical and thermal burns of the ocular surface. LSCD leads to conjunctivalization of the corneal surface, neovascularization, recurrent or persistent epithelial defects, ocular surface inflammation, and scarring that, in turn, lead to decreased vision, pain, and impaired quality of life. Several techniques have been reported for limbal stem cell transplantation (LSCT). We introduce the surgical techniques, examine the success rate, and discuss the postoperative complications of conjunctival limbal autograft (CLAU), cultivated limbal stem cell transplantation (CLET), simple limbal epithelial transplantation (SLET), and limbal allograft, including keratolimbal allografts (KLAL) and living-related conjunctival allograft (LR-CLAL).
Anti-VEGF therapy has been proven to be effective in the treatment of pathological angiogenesis. However, therapy resistance often occurs, leading to development of alternative approaches. The present study examines if AMPK negatively regulates ALK1-mediated signaling events and associated angiogenesis. Thus, we treated human umbilical vein endothelial cells with metformin as well as other pharmacological AMPK activators and showed that activation of AMPK inhibited Smad1/5 phosphorylation and tube formation induced by BMP9. This event was mimicked by expression of the active mutant of AMPKα1 and prevented by the dominant negative AMPKα1. Metformin inhibition of BMP9 signaling is possibly mediated by upregulation of Smurf1, leading to degradation of ALK1. Furthermore, metformin suppressed BMP9-induced angiogenesis in mouse matrigel plug. In addition, laser photocoagulation was employed to evaluate the effect of metformin. The data revealed that metformin significantly reduced choroidal neovascularization to a level comparable to LDN212854, an ALK1 specific inhibitor. In conjunction, metformin diminished expression of ALK1 in endothelium of the lesion area. Collectively, our study for the first time demonstrates that AMPK inhibits ALK1 and associated angiogenesis/neovascularization. This may offer us a new avenue for the treatment of related diseases using clinically used pharmacological AMPK activators like metformin in combination with other strategies to enhance the treatment efficacy or in the case of anti-VEGF resistance.
PURPOSE: Fibrovascular contraction and tractional retinal detachment (TRD) are recognized complications associated with the use of anti-vascular endothelial growth factor agents in vasoproliferative vitreoretinopathies. The authors characterize TRDs that developed after intravitreal bevacizumab or ranibizumab therapy for vascularly active retinopathy of prematurity.
METHODS: This is an international, multicenter, interventional, retrospective, case series. Thirty-five eyes from 23 infants were included. Inclusion required anti-vascular endothelial growth factor treatment of Type 1 retinopathy of prematurity with progression to TRD.
RESULTS: Mean gestational age was 26 ± 2 weeks, and mean birth weight was 873 ± 341 g. Mean postmenstrual age on the day of injection was 35 ± 2 weeks. Retinal detachment was noted a mean of 70 days (median, 34; range, 4-335) after injection. Eleven percent detached within 1 week, 23% within 2 weeks, and 49% within 4 weeks. The highest stage of retinopathy of prematurity noted was 4A in 29%, 4B in 37%, and 5 in 34% of eyes. Time to RD negatively correlated with postmenstrual age at the time of injection (Rho = -0.54; P < 0.01). Three TRD configurations were observed: 1) conventional peripheral elevated ridge or volcano-shaped Stage 5 detachment, 2) midperipheral detachment with tight circumferential vectors, and 3) very posterior detachment with prepapillary contraction. Full or partial reattachment was achieved with surgical intervention in 86% of eyes.
CONCLUSION: Progressive atypical TRD may occur after anti-vascular endothelial growth factor injections for retinopathy of prematurity. The configuration of the detachment varies with the extent of primary retinal vascularization present at the time of treatment.
AIMS: To evaluate the efficacy and safety of rituximab (RTX) induction and maintenance treatment for patients with scleritis and granulomatosis with polyangiitis (GPA), Wegener's. METHODS: Nine patients (12 eyes) with scleritis with GPA who did not respond to corticosteroids and more than one immunosuppressive agent who received ongoing maintenance RTX treatment were identified. Demographics and outcome measures were recorded. RESULTS: Median follow-up time of 30 months (range, 15 to 87 months). All 12 eyes achieved remission during the RTX maintenance period with a median time in remission of 14 months (range, 5-76 months), and median interval between RTX initiation and inactive disease of 5 months (range, 2-8 months). Two eyes in two patients relapsed. One received steroid eye drops, and the other received a short-term increased dose of intravenous corticosteroids. CONCLUSIONS: RTX was effective as an induction and maintenance treatment in our small cohort of patients with GPA-associated scleritis.
PURPOSE: The purpose was to evaluate the effectiveness and safety of rituximab (RTX) for the treatment of patients with aggressive ocular cicatricial pemphigoid (OCP). METHODS: A review of patient records at a tertiary referral center with biopsy confirmed OCP who presented between 2006 and 2016. Sixty-one eyes of 32 patients with symptomatic OCP who received treatment with RTX monotherapy or RTX in combination with additional immunomodulatory treatment (IMT) were evaluated. Main outcomes included clinically evident remission of disease, the percentage of corticosteroid sparing patients, stage of OCP (Foster), best corrected visual acuity, and treatment complications. Remission was defined as absence of progressive scarring and active ocular inflammation for ≥ 2 months. Partial remission/responding was defined as disease control and clinical improvement for ≥ 2 months. RESULTS: Mean age at the initiation of RTX treatment was 59.1 years (range, 24-80 years) with a median follow-up time after RTX initiation of 32 months (range, 14 to 127 months). Twenty-six patients achieved clinical remission with an average sustained remission of 24.5 months (from 9 months to 84 months). RTX monotherapy was used in six patients, RTX in combination with intravenous immunoglobulin in 14 patients, and RTX with intravenous immunoglobulin and/or with other IMT agent in six patients. Seven eyes (11.5%) of six patients had favorable response to RTX and achieved response and partial remission, while inflammation remained active in the other seven eyes (11.5%) of four patients though there was no progressive scarring. At the last visit, three patients (9.4%) were on topical corticosteroid, three patients (9.4%) were treated with systemic corticosteroid treatments, and the other 26 patients (81.2%) achieved corticosteroid sparing therapy. Five eyes (8.2%) progressed one Foster stage. No other cicatrization progression or worsening of LogMAR visual acuity (p = 0.641) was observed during the follow-up period. Adverse events included leukopenia in three patients (9.4%), anemia in two patients (6.2%), liver enzyme elevation in three patients (9.4%) who were also on another concomitant IMT drug, and Epstein-Barr Virus infection and sinus infection in one patient each (3.1%). No other severe adverse events were noted during the follow-up period. CONCLUSIONS: These retrospective data suggest that RTX is efficacious and well tolerated when included for the treatment of OCP. Controlled studies are necessary to identify the role of this IMT agent in the therapeutic arsenal, especially its optimum dose and duration of administration.