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Chen C, Clay T, McLeod S, Peggy Chang HY, Gelb A, Dudley A. A Revised Estimate of Costs Associated With Routine Preoperative Testing in Medicare Cataract Patients With a Procedure-Specific Indicator. JAMA Ophthalmol. 2018;136(3):231–238.
Importance: Routine preoperative medical testing is not recommended for patients undergoing low-risk surgery, but testing is common before surgery. A 30-day preoperative testing window is conventionally used for study purposes; however, the extent of routine testing that occurs prior to that point is unknown. Objective: To improve on existing cost estimates by identifying all routine preoperative testing that takes place after the decision is made to perform cataract surgery. Design, Setting, and Participants: This cross-sectional study assessed preoperative care in a 50% sample of Medicare beneficiaries older than 66 years who underwent ambulatory cataract surgery in 2011. Data analysis was completed from March 2016 to October 2017. Main Outcomes and Measures: Using ocular biometry as a procedure-specific indicator to mark the start of the routine preoperative testing window, we measured testing rates in the interval between ocular biometry and cataract surgery and compared this with testing rates in the 6 months preceding biometry. We estimated the total cost of testing that occurred between biometry and cataract surgery. Results: A total of 440 857 patients underwent cataract surgery. A total of 423 710 (96.1%) had an ocular biometry claim before index surgery, of whom 264 514 (60.0%) were female; the mean (SD) age of the cohort was 76.1 (6.2) years. A total of 111 998 (25.4%) underwent surgery more than 30 days after biometry. Among patients with a biometry claim, the mean number of tests/patient/month increased from 1.1 in the baseline period to 1.7 in the interval between biometry and cataract surgery. Although preoperative testing peaked in all patients in the 30 days preceding surgery (1.8 tests/patient/month), the subset of patients with no overlap between postbiometry and presurgery periods experienced increased testing rates to 1.8 tests per patient per month in the 30 days after biometry, regardless of the elapsed time between biometry and surgery. The total estimated cost of routine preoperative testing in the full cohort was $22.7 million; we estimate that routine preoperative testing costs Medicare up to $45.4 million annually. Conclusions and Relevance: In this study of Medicare beneficiaries, routine preoperative medical testing occurs more often and is costlier than has been reported previously. Extra costs are attributable to testing that occurs prior to the 30-day window preceding surgery. As a cost-cutting measure, routine preoperative medical testing should be avoided in patients with cataracts throughout the interval between ocular biometry and cataract surgery.
Choi HJ, Wang R, Jakobs T. Single-Cell Dissociation and Characterization in the Murine Retina and Optic Nerve. Methods Mol Biol. 2018;1695:311–334.
Recent technological advances have extended the range of analytic tools to very small samples. It is now possible to assay the transcriptome, and in some cases even the proteome, of single cells reliably. This allows addressing novel questions, such as the genotype/phenotype relationships of single neurons, heterogeneity within individual cells of the same type, or the basis of differential vulnerability to injury. An important prerequisite for these kinds of studies is the ability to isolate well-defined individual cells without contamination by adjacent tissue. In the retina and optic nerve, cells of different types and functions are closely intermingled, limiting the use of standard methods such as laser capture microdissection. Here, we describe a simple method to isolate morphologically intact cells from the retina and the optic nerve and discuss considerations in recognizing and isolating different cell types after dissociation.
Chou J, Cousins C, Miller J, Song B, Shen L, Kass M, Wiggs J, Pasquale L. Fundus Densitometry Findings Suggest Optic Disc Hemorrhages in Primary Open-Angle Glaucoma Have an Arterial Origin. Am J Ophthalmol. 2018;187:108–116.
PURPOSE: To analyze optic disc hemorrhages (DH) associated with primary open-angle glaucoma by quantifying their geometric profile and comparing their densitometry with hemorrhages from retinal vein occlusions (RVO) and retinal macroaneurysms (MA), which have venous and arterial sources of bleeding, respectively. DESIGN: Retrospective cross-sectional study. METHODS: Setting: Massachusetts Eye & Ear. POPULATION: Fundus images of DH (n = 40), MA (n = 14), and RVO (n = 25) were identified. Patient clinical backgrounds and demographics were obtained. MAIN OUTCOME MEASURES: Grayscale pixel intensity units of hemorrhages and adjacent arteriole and venule over the same background tissue were measured. Densitometry differentials (arteriole or venule minus hemorrhage [ΔA and ΔV, respectively]) were calculated. The ratios of length (radial) to midpoint width for DH were calculated. Mean ΔA and ΔV between groups were compared with t tests. Multiple linear regression assessed the relation of retinal hemorrhage diagnosis to ΔA and ΔV and of DH shape to ΔA and ΔV. RESULTS: Mean (± standard deviation) ΔA and ΔV for DH (6.9 ± 7.1 and -4.7 ± 8.0 pixel intensity units, respectively) and MA (5.3 ± 5.9 and -6.0 ± 4.6, respectively) were comparable (P ≥ .43). Mean ΔA (14.6 ± 7.7) and ΔV (6.4 ± 6.3) for RVO were significantly higher compared to DH and MA (P < .0001) and remained significant in multivariable analyses. A unit increase in DH length-to-width ratio was associated with 1.2 (0.5) and 1.3 (0.5) pixel intensity unit (standard error) decrease in ΔA and ΔV, respectively (P ≤ .014). CONCLUSIONS: DH have densitometry profiles comparable to MA and different from RVO, suggesting that DH in glaucoma have an arterial origin.
Cruzat A, Gonzalez-Andrades M, Mauris J, AbuSamra D, Chidambaram P, Kenyon K, Chodosh J, Dohlman C, Argüeso P. Colocalization of Galectin-3 With CD147 Is Associated With Increased Gelatinolytic Activity in Ulcerating Human Corneas. Invest Ophthalmol Vis Sci. 2018;59(1):223–230.
Purpose: Galectin-3 is a carbohydrate-binding protein known to promote expression of matrix metalloproteinases, a hallmark of ulceration, through interaction with the extracellular matrix metalloproteinase inducer CD147. The aim of this study was to investigate the distribution of galectin-3 in corneas of patients with ulcerative keratitis and to determine its relationship to CD147 and the presence of gelatinolytic activity. Methods: This was an observational case series involving donor tissue from 13 patients with active corneal ulceration and 6 control corneas. Fixed-frozen sections of the corneas were processed to localize galectin-3 and CD147 by immunofluorescence microscopy. Gelatinolytic activity was detected by in situ zymography. Results: Tissue from patients with active corneal ulceration showed a greater galectin-3 immunoreactivity in basal epithelia and stroma compared with controls. Immunofluorescence grading scores revealed increased colocalization of galectin-3 and CD147 in corneal ulcers at the epithelial-stromal junction and within fibroblasts. Quantitative analysis using the Manders' colocalization coefficient demonstrated significant overlap in corneas from patients with ulcerative keratitis (M1 = 0.29; M2 = 0.22) as opposed to control corneas (M1 = 0.01, P < 0.01; M2 = 0.02, P < 0.05). In these experiments, there was a significant positive correlation between the degree of galectin-3 and CD147 colocalization and the presence of gelatinolytic activity. Conclusions: Our results indicate that concomitant stimulation and colocalization of galectin-3 with CD147 are associated with increased gelatinolytic activity in the actively ulcerating human cornea and suggest a mechanism by which galectin-3 may contribute to the degradation of extracellular matrix proteins during ulceration.
Dudek A, Pillay S, Puschnik A, Nagamine C, Cheng F, Qiu J, Carette J, Vandenberghe L. An Alternate Route for Adeno-associated Virus (AAV) Entry Independent of AAV Receptor. J Virol. 2018;92(7).
Determinants and mechanisms of cell attachment and entry steer adeno-associated virus (AAV) in its utility as a gene therapy vector. Thus far, a systematic assessment of how diverse AAV serotypes engage their proteinaceous receptor AAVR (KIAA0319L) to establish transduction has been lacking, despite potential implications for cell and tissue tropism. Here, a large set of human and simian AAVs as well as -reconstructed ancestral AAV capsids were interrogated for AAVR usage. We identified a distinct AAV capsid lineage comprised of AAV4 and AAVrh32.33 that can bind and transduce cells in the absence of AAVR, independent of the multiplicity of infection. Virus overlay assays and rescue experiments in nonpermissive cells demonstrate that these AAVs are unable to bind to or use the AAVR protein for entry. Further evidence for a distinct entry pathway was observed , as AAVR knockout mice were equally as permissive to transduction by AAVrh32.33 as wild-type mice upon systemic injection. We interestingly observe that some AAV capsids undergo a low level of transduction in the absence of AAVR, both and , suggesting that some capsids may have a multimodal entry pathway. In aggregate, our results demonstrate that AAVR usage is conserved among all primate AAVs except for those of the AAV4 lineage, and a non-AAVR pathway may be available to other serotypes. This work furthers our understanding of the entry of AAV, a vector system of broad utility in gene therapy. Adeno-associated virus (AAV) is a nonpathogenic virus that is used as a vehicle for gene delivery. Here, we have identified several situations in which transduction is retained in both cell lines and a mouse model in the absence of a previously defined entry receptor, AAVR. Defining the molecular determinants of the infectious pathway of this highly relevant viral vector system can help refine future applications and therapies with this vector.
Ebrahimiadib N, Hernandez M, Modjtahedi B, Roohipoor R, Foster S. Atopy in Patients With Ocular Cicatricial Pemphigoid. Cornea. 2018;37(4):436–441.
PURPOSE: To evaluate the presence of atopy in patients with ocular cicatricial pemphigoid (OCP). METHOD: Patient encounters between August 2005 and November 2016 at the Massachusetts Eye Research and Surgery Institute (MERSI) were searched to identify those with biopsy-proven OCP who had concurrent evidence of atopy. RESULTS: There were 230 patients with biopsy-proven OCP. Thirty-three of them were found to have clinical symptoms of atopy (asthma, hay fever, and eczema) and of these, 23 had evidence of atopy in their conjunctival biopsy specimens. All patients were administered immunomodulatory therapy for treatment of their OCP with 20 patients requiring additional antiallergy treatment to control residual atopic ocular symptoms. Among patients who used antiallergy medications, 80% showed improvement in residual symptoms. Rituximab and/or intravenous immunoglobulin is a preferred OCP medication for patients with OCP with some evidence of atopy. CONCLUSIONS: Clinicians should consider the coexistence of atopy in patients with OCP, especially in those with persistent symptoms after initiation of immunomodulatory therapy.
Eslani M, Putra I, Shen X, Hamouie J, Tadepalli A, Anwar K, Kink J, Ghassemi S, Agnihotri G, Reshetylo S, Mashaghi A, Dana R, Hematti P, Djalilian A. Cornea-Derived Mesenchymal Stromal Cells Therapeutically Modulate Macrophage Immunophenotype and Angiogenic Function. Stem Cells. 2018;36(5):775–784.
Macrophages are crucial drivers of inflammatory corneal neovascularization and thus are potential targets for immunomodulatory therapies. We hypothesized that therapeutic use of cornea-derived mesenchymal stromal cells (cMSCs) may alter the function of macrophages. We found that cMSCs can modulate the phenotype and angiogenic function of macrophages. In vitro, cMSCs induce apoptosis of macrophages while preferentially promoting a distinct CD14 CD16 CD163 CD206 immunophenotype that has significantly reduced angiogenic effects based on in vitro angiogenesis assays. In vivo, application of cMSCs to murine corneas after injury leads to reduced macrophage infiltration and higher expression of CD206 in macrophages. Macrophages cocultured ("educated") by cMSCs express significantly higher levels of anti-angiogenic and anti-inflammatory factors compared with control macrophages. In vivo, injured corneas treated with cMSC-educated macrophages demonstrate significantly less neovascularization compared with corneas treated with control macrophages. Knocking down the expression of pigment epithelial derived factor (PEDF) in cMSCs significantly abrogates its modulating effects on macrophages, as shown by the reduced rate of apoptosis, decreased expression of sFLT-1/PEDF, and increased expression of vascular endothelial growth factor-A in the cocultured macrophages. Similarly, cMSCs isolated from PEDF knockout mice are less effective compared with wild-type cMSCs at inhibiting macrophage infiltration when applied to wild-type corneas after injury. Overall, these results demonstrate that cMSCs therapeutically suppress the angiogenic capacity of macrophages and highlight the role of cMSC secreted PEDF in the modulation of macrophage phenotype and function. Stem Cells 2018;36:775-784.
Feinstein M, Moussa K, Han Y. Ab Interno Tube Occlusion for Postoperative Hypotony in a Patient With an Ahmed Glaucoma Drainage Device. J Glaucoma. 2018;27(3):e61-e63.
PURPOSE: To report a case of Ahmed glaucoma valve-induced hypotony that was successfully managed with postoperative intraluminal stenting of the aqueous shunt tube. PATIENT AND METHODS: We describe a 68-year-old man with advanced uveitic glaucoma with an intraocular pressure (IOP) of 25 mm Hg in the left eye. The patient initially responded well to an Ahmed glaucoma valve implant, but at 10 weeks postimplantation, the patient underwent cataract surgery and developed persistent hypotony, choroidal folds, and decreased vision. RESULTS: Before partial occlusion of the aqueous shunt tube, the patient had an IOP of 3 mm Hg and a best-corrected visual acuity (BCVA) of 20/60. Following intraluminal stenting of the aqueous shunt tube with 4-0 polypropylene suture (Prolene; Ethican), IOP rose from 7 to 10 mm Hg, BCVA improved to 20/30, and the choroidal folds resolved; IOP and BCVA remained stable through 1 year of follow-up and no additional surgical or pharmacological interventions were required. CONCLUSIONS: Aqueous shunt-induced hypotony can be successfully managed with intraluminal stenting and should be considered before tubal ligation or shunt removal.
Fernandez-Godino R, Bujakowska K, Pierce E. Changes in extracellular matrix cause RPE cells to make basal deposits and activate the alternative complement pathway. Hum Mol Genet. 2018;27(1):147–159.
The design of efficient therapies for age-related macular degeneration (AMD) is limited by our understanding of the pathogenesis of basal deposits, which form between retinal pigment epithelium (RPE) and Bruch's membrane (BrM) early in disease, and involve activation of the complement system. To investigate the roles of BrM, RPE and complement in an AMD, we generated abnormal extracellular matrix (ECM) using CRISPR-edited ARPE-19 cells. We introduced to these cells the p.R345W mutation in EFEMP1, which causes early-onset macular degeneration. The abnormal ECM binds active complement C3 and causes the formation of basal deposits by normal human fetal (hf)RPE cells. Human fetal RPE (hfRPE) cells grown on abnormal ECM or BrM explants from AMD donors show chronic activation of the alternative complement pathway by excessive deposition of C3b. This process is exacerbated by impaired ECM turnover via increased matrix metalloproteinase-2 activity. The local cleavage of C3 via convertase-independent mechanisms can be a new therapeutic target for early AMD.
Ferrara M, Eggenschwiler L, Stephenson A, Montieth A, Nakhoul N, Araùjo-Miranda R, Foster S. The Challenge of Pediatric Uveitis: Tertiary Referral Center Experience in the United States. Ocul Immunol Inflamm. 2018;:1–8.
PURPOSE: To describe the distribution, clinical findings, visual outcomes, treatment, and complications of children with uveitis at a tertiary referral ophthalmic center. METHODS: Retrospective cohort study. We reviewed the medical records of all patients ≤16 years with uveitis referred to Massachusetts Eye Research and Surgery Institution from March 2005 to July 2016. RESULTS: Of 286 included children, 62.24% were female. Mean age of onset was 8.4 years. The uveitis was mainly anterior (61.9%), recurrent (68.53%), bilateral (81.82%), and noninfectious (96.5%). Idiopathic cases accounted for 51.4%. The most frequent systemic association was juvenile idiopathic arthritis (34.96%). The majority of patients (78.32%) experienced complications. All patients, except one, needed systemic therapy. CONCLUSION: Pediatric uveitis is challenging to diagnose and manage, with frequent and potentially severe complications. Most cases were bilateral, recurrent, and idiopathic. Prompt referral to uveitis-specialized centers and an appropriate systemic therapy are mandatory for good visual outcomes.
Houston K, Peli E, Goldstein R, Bowers A. Driving With Hemianopia VI: Peripheral Prisms and Perceptual-Motor Training Improve Detection in a Driving Simulator. Transl Vis Sci Technol. 2018;7(1):5.
Purpose: Drivers with homonymous hemianopia (HH) were previously found to have impaired detection of blind-side hazards, yet in many jurisdictions they may obtain a license. We evaluated whether oblique 57Δ peripheral prisms (p-prisms) and perceptual-motor training improved blind-side detection rates. Methods: Patients with HH (n = 11) wore p-prisms for 2 weeks and then received perceptual-motor training (six visits) detecting and touching stimuli in the prism-expanded vision. In a driving simulator, patients drove and pressed the horn upon detection of pedestrians who ran toward the roadway (26 from each side): (1) without p-prisms at baseline; (2) with p-prisms after 2 weeks acclimation but before training; (3) with p-prisms after training; and (4) 3 months later. Results: P-prisms improved blind-side detection from 42% to 56%, which further improved after training to 72% (all P < 0.001). Blind-side timely responses (adequate time to have stopped) improved from 31% without to 44% with p-prisms (P < 0.001) and further improved with training to 55% (P = 0.02). At the 3-month follow-up, improvements from training were maintained for detection (65%; P = 0.02) but not timely responses (P = 0.725). There was wide between-subject variability in baseline detection performance and response to p-prisms. There were no negative effects of p-prisms on vehicle control or seeing-side performance. Conclusions: P-prisms improved detection with no negative effects, and training may provide additional benefit. Translational Relevance: In jurisdictions where people with HH are legally driving, these data aid in clinical decision making by providing evidence that p-prisms improve performance without negative effects.
Kaochar S, Dong J, Torres M, Rajapakshe K, Nikolos F, Davis C, Ehli E, Coarfa C, Mitsiades N, Poulaki V. ICG-001 Exerts Potent Anticancer Activity Against Uveal Melanoma Cells. Invest Ophthalmol Vis Sci. 2018;59(1):132–143.
Purpose: Uveal melanoma (UM) is uniformly refractory to all available systemic chemotherapies, thus creating an urgent need for novel therapeutics. In this study, we investigated the sensitivity of UM cells to ICG-001, a small molecule reported to suppress the Wnt/β-catenin-mediated transcriptional program. Methods: We used a panel of UM cell lines to examine the effects of ICG-001 on cellular proliferation, migration, and gene expression. In vivo efficacy of ICG-001 was evaluated in a UM xenograft model. Results: ICG-001 exerted strong antiproliferative activity against UM cells, leading to cell cycle arrest, apoptosis, and inhibition of migration. Global gene expression profiling revealed strong suppression of genes associated with cell cycle proliferation, DNA replication, and G1/S transition. Gene set enrichment analysis revealed that ICG-001 suppressed Wnt, mTOR, and MAPK signaling. Strikingly, ICG-001 suppressed the expression of genes associated with UM aggressiveness, including CDH1, CITED1, EMP1, EMP3, SDCBP, and SPARC. Notably, the transcriptomic footprint of ICG-001, when applied to a UM patient dataset, was associated with better clinical outcome. Lastly, ICG-001 exerted anticancer activity against a UM tumor xenograft in mice. Conclusions: Using in vitro and in vivo experiments, we demonstrate that ICG-001 has strong anticancer activity against UM cells and suppresses transcriptional programs critical for the cancer cell. Our results suggest that ICG-001 holds promise and should be examined further as a novel therapeutic agent for UM.
Kheirkhah A, Satitpitakul V, Syed Z, Muller R, Goyal S, Tu E, Dana R. Factors Influencing the Diagnostic Accuracy of Laser-Scanning In Vivo Confocal Microscopy for Acanthamoeba Keratitis. Cornea. 2018;37(7):818–823.
PURPOSE: To determine the factors that influence the sensitivity and specificity of laser-scanning in vivo confocal microscopy (IVCM) for diagnosing Acanthamoeba keratitis (AK). METHODS: This retrospective, controlled study included 28 eyes of 27 patients with AK and 34 eyes of 34 patients with bacterial keratitis (as the control group). All patients had undergone corneal imaging with a laser-scanning IVCM (Heidelberg Retina Tomograph 3 with the Rostock Cornea Module). The IVCM images were independently evaluated by 2 experienced and 2 inexperienced masked observers. Sensitivity and specificity of IVCM for diagnosing AK and the effects of various clinical and imaging parameters on the sensitivity were then investigated. RESULTS: Overall, IVCM had average sensitivity and specificity of 69.7% ± 2.5% and 97.1% ± 4.2% for experienced observers and 59.0% ± 7.6% and 92.7% ± 10.4% for inexperienced observers, respectively. However, the sensitivity did not show any significant association with the duration of disease, size of ulcer, depth of involvement, culture results, or cyst morphology. Although interobserver agreement was good (κ = 0.60, P < 0.001) for the experienced observers, it was only at a moderate level (κ = 0.48, P < 0.001) for the inexperienced observers. CONCLUSIONS: IVCM has a moderate sensitivity and a high specificity for diagnosis of AK. Although clinical parameters do not affect this diagnostic accuracy, a higher sensitivity is seen when images are interpreted by experienced observers.
Kobashi H, Kamiya K, Shimizu K. Impact of Forward and Backward Scattering and Corneal Higher-Order Aberrations on Visual Acuity after Penetrating Keratoplasty. Semin Ophthalmol. 2018;:1–9.
PURPOSE: To assess the relationship of forward and backward scattering and corneal higher-order aberrations (HOAs) with corrected distance visual acuity (CDVA) after penetrating keratoplasty (PK). METHODS: This retrospective study comprised 25 eyes of 25 consecutive patients who underwent PK using the VisuMax femtosecond laser system and age-matched 25 eyes of 25 healthy subjects. We quantitatively assessed objective scattering index (OSI) using the double-pass instrument (OQAS II, Visiometrics), corneal densitometry (CD) and corneal HOAs with the Scheimpflug rotating camera (Pentacam HR, Oculus) 1 year postoperatively. RESULTS: The OSI, CD, and corneal HOAs were significantly larger in the PK group than those in the control group (p ≤ 0.011). We found significant correlations of logMAR CDVA with the OSI (r = 0.477, p = 0.016), and with the anterior, posterior, and total corneal HOAs of the central 4-mm zone (anterior: r = 0.573, p = 0.003, posterior: r = 0.596, p = 0.002, total: r = 0.472, p = 0.017), but no significant association with the CD of the 0-2 mm zone at any layers (anterior: r = 0.236, p = 0.257, center: r = 0.139, p = 0.506, posterior: r = 0.073, p = 0.728, total: r = 0.212, p = 0.308). Similar results were obtained when the analysis was repeated with corneal HOAs of the central 6-mm zone and CDs in 2-6 mm zone. CONCLUSIONS: Our pilot study demonstrated that the postoperative CDVA was significantly correlated with OSI and corneal HOAs, but not with backward scattering in post-PK eyes, suggesting that OSI as well as corneal HOAs plays an essential role in postoperative visual performance after PK.
Kosmidou C, Efstathiou N, Hoang M, Notomi S, Konstantinou E, Hirano M, Takahashi K, Maidana D, Tsoka P, Young L, Gragoudas E, Olsen T, Morizane Y, Miller J, Vavvas D. Issues with the Specificity of Immunological Reagents for NLRP3: Implications for Age-related Macular Degeneration. Sci Rep. 2018;8(1):461.
Contradictory data have been presented regarding the implication of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in age-related macular degeneration (AMD), the leading cause of vision loss in the Western world. Recognizing that antibody specificity may explain this discrepancy and in line with recent National Institutes of Health (NIH) guidelines requiring authentication of key biological resources, the specificity of anti-NLRP3 antibodies was assessed to elucidate whether non-immune RPE cells express NLRP3. Using validated resources, NLRP3 was not detected in human primary or human established RPE cell lines under multiple inflammasome-priming conditions, including purported NLRP3 stimuli in RPE such as DICER1 deletion and Alu RNA transfection. Furthermore, NLRP3 was below detection limits in ex vivo macular RPE from AMD patients, as well as in human induced pluripotent stem cell (hiPSC)-derived RPE from patients with overactive NLRP3 syndrome (Chronic infantile neurologic cutaneous and articulate, CINCA syndrome). Evidence presented in this study provides new data regarding the interpretation of published results reporting NLRP3 expression and upregulation in RPE and addresses the role that this inflammasome plays in AMD pathogenesis.
Lin SC, Pasquale L, Singh K, Lin S. The Association Between Body Mass Index and Open-angle Glaucoma in a South Korean Population-based Sample. J Glaucoma. 2018;27(3):239–245.
PURPOSE: The purpose of this article is to investigate the association between body mass index (BMI) and open-angle glaucoma (OAG) in a sample of the South Korean population. MATERIALS AND METHODS: The sample consisted of a cross-sectional, population-based sample of 10,978 participants, 40 years of age and older, enrolled in the 2008 to 2011 Korean National Health and Nutrition Examination Survey. All participants had measured intraocular pressure <22 mm Hg and open anterior chamber angles. OAG was defined using disc and visual field criteria established by the International Society for Geographical and Epidemiological Ophthalmology. Multivariable analyses were performed to determine the association between BMI and OAG. These analyses were also performed in a sex-stratified and age-stratified manner. RESULTS: After adjusting for potential confounding variables, lower BMI (<19 kg/m) was associated with greater risk of OAG compared with normal BMI (19 to 24.9 kg/m) [odds ratio (OR), 2.28; 95% confidence interval (CI), 1.22-4.26]. In sex-stratified analyses, low BMI remained adversely related to glaucoma in women (OR, 3.45; 95% CI, 1.42-8.38) but not in men (OR, 1.72; 95% CI, 0.71-4.20). In age-stratified analyses, lower BMI was adversely related to glaucoma among subjects 40- to 49-year old (OR, 5.16; 95% CI, 1.86-14.36) but differences in glaucoma prevalence were not statistically significant between those with low versus normal BMI in other age strata. CONCLUSIONS: Lower BMI was associated with increased odds of OAG in a sample of the South Korean population. Multivariate analysis revealed the association to be statistically significant in women and those in the youngest age stratum.
Ma L, Jakobiec F, Wolkow N, Dryja T, Borodic G. Multiple Eyelid Cysts (Apocrine and Eccrine Hidrocystomas, Trichilemmal Cyst, and Hybrid Cyst) in a Patient With a Prolactinoma. Ophthalmic Plast Reconstr Surg. 2018;34(3):e83-e85.
A 53-year-old man presented with smooth-domed, variegated cysts (polycystic disease) of all 4 eyelids, worse on the left side. Some of the cysts were clear, while others were creamy-white colored. In addition, multiple, very fine vesicopapules were noted along the eyelid margins. Histopathologic examination revealed a trichilemmal cyst, several pure apocrine hidrocystomas displaying multiple chambers, a hybrid cyst, and many small eccrine cysts of the deep dermis. The apocrine lesions, including the small ones at the eyelid margins, predominated. Smooth muscle actin sometimes positively stained outer myoepithelial cells in some of the apocrine cysts, which helped to distinguish them from eccrine cysts. Most noteworthy was the fact that the patient had been diagnosed with a prolactinoma 20 years earlier. There is only 1 previous report of multiple apocrine cysts and an antecedent prolactinoma in the dermatologic literature. This syndrome should be separated from that of Schöpf-Schulz-Passarge, which manifests multiple small eyelid apocrine cysts and other ectodermal dysplasias without any association with neoplasia, and from that of focal dermal hypoplasia (Goltz-Gorlin) syndrome with apocrine cysts but again without neoplasia.
M Mallery R, Poolman P, J Thurtell M, Full J, Ledolter J, Kimbrough D, Frohman E, Frohman T, Kardon R. Visual Fixation Instability in Multiple Sclerosis Measured Using SLO-OCT. Invest Ophthalmol Vis Sci. 2018;59(1):196–201.
Purpose: Precise measurements of visual fixation and its instability were recorded during optical coherence tomography (OCT) as a marker of neural network dysfunction in multiple sclerosis (MS), which could be used to monitor disease progression or response to treatment. Methods: A total of 16 MS patients and 26 normal subjects underwent 30 seconds of scanning laser ophthalmoscope (SLO)-based eye tracking during OCT scanning of retinal layer thickness. Study groups consisted of normal eyes, MS eyes without prior optic neuritis (MS wo ON), and MS eyes with prior optic neuritis (MS + ON). Kernel density estimation quantified fixation instability from the distribution of fixation points on the retina. In MS wo ON eyes, fixation instability was compared to other measures of visual and neurologic function. Results: Fixation instability was increased in MS wo ON eyes (0.062 deg2) compared to normal eyes (0.030 deg2, P = 0.015). A further increase was seen for MS + ON eyes (0.11 deg2) compared to MS wo ON (P = 0.04) and normal (P = 0.006) eyes. Fixation instability correlated weakly with ganglion cell layer (GCL) volume and showed no correlation with low-contrast letter acuity, EDSS score, or SDMT score. Conclusions: Fixation instability reflects the integrity of a widespread neural network germane to visual processing and ocular motor control, and is disturbed in MS. Further study of visual fixation, including the contribution of microsaccades to fixation instability, may provide insight into the localization of fixation abnormalities in MS and introduce innovative and easily measured outcomes for monitoring progression and treatment response.
Moein HR, Kheirkhah A, Müller R, Cruzat A, Pavan-Langston D, Hamrah P. Corneal nerve regeneration after herpes simplex keratitis: A longitudinal in vivo confocal microscopy study. Ocul Surf. 2018;16(2):218–225.
PURPOSE: To evaluate the long-term alterations of corneal nerves in patients with herpes simplex virus (HSV) keratitis using in vivo confocal microscopy (IVCM). DESIGN: Prospective, longitudinal, cross sectional. METHODS: This study included 16 patients with a history of HSV keratitis and 15 age-matched normal controls. Slit-scanning IVCM was performed in all subjects at baseline and then after a mean follow-up of 37.3 ± 1.7 months in the patient group. Corneal subbasal nerve density and corneal sensation were compared between groups at baseline and follow-up. RESULTS: At baseline, the mean subbasal nerve density was significantly lower in both affected eyes (1.4 ± 0.6 mm/mm) and contralateral unaffected eyes (6.4 ± 0.7 mm/mm) compared with the controls (14.1 ± 1.6 mm/mm; all P  .001). At the end of follow-up, the mean nerve density in affected eyes increased to 2.8 ± 0.7 mm/mm (P = .006), with no significant change in contralateral unaffected eyes (6.5 ± 1.0 mm/mm, P = .72). However, both eyes had lower nerve density than controls (all P  .001). Corneal sensation was significantly lower in affected eyes (2.6 ± 0.6 cm) than in the control group (6.0 ± 0.0, P  .001) and showed no significant change at the end of follow-up (2.5 ± 0.6 cm, P = .80). Corneal sensation in contralateral unaffected eyes was not different in comparison with controls at both baseline and follow up (all p > .05). CONCLUSIONS: Our results demonstrate that although corneal nerve regeneration occurs in patients with HSV keratitis, this change is not clinically significant and does not results in changes of corneal sensation. Therefore, these patients need to be followed closely for complications of neurotrophic keratopathy and might benefit from neuro-regenerative therapies.
Spors B, Seemann J, Homer N, Fay A. Lymphatic malformation with acquired Horner syndrome in an infant. J Neurointerv Surg. 2018;10(3):e2.
An infant presented with right upper eyelid ptosis and was subsequently diagnosed with acquired Horner syndrome. Further evaluation revealed a right-sided cervicothoracic lymphatic malformation. At 13 weeks of age, the child underwent percutaneous intracystic sclerotherapy with a mixture of sodium tetradecyl sulphate and ethanol. Twenty-one weeks after initial treatment, ophthalmic examination showed complete resolution of the blepharoptosis and pupillary miosis. Percutaneous sclerotherapy not only effectively treated the space-occupying lymphatic malformation but also reversed the Horner syndrome that was presumably induced by neural tension (more likely) or compression.
Stahl A, Krohne T, Eter N, Oberacher-Velten I, Guthoff R, Meltendorf S, Ehrt O, Aisenbrey S, Roider J, Gerding H, Jandeck C, Smith L, Walz J, Group CARDSERP (CARE RS. Comparing Alternative Ranibizumab Dosages for Safety and Efficacy in Retinopathy of Prematurity: A Randomized Clinical Trial. JAMA Pediatr. 2018;172(3):278–286.
Importance: Anti-vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient. Objective: To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab. Design, Setting, and Participants: This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized. Interventions: All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. Main Outcomes and Measures: The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee. Results: Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group. Conclusions and Relevance: This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab. Trial Registration: clinicaltrials.gov Identifier: NCT02134457 and clinicaltrialsregister.eu Identifier: 2013-002539-13.
Sun D. Visualizing Astrocytes of the Optic Nerve. Methods Mol Biol. 2018;1695:269–286.
Astrocytes make up approximately 30% of all the cells in the mammalian central nervous system. They are not passive, as once thought, but are integral to brain physiology and perform many functions that are important for normal neuronal development and metabolism, synapse formation, synaptic transmission, and in repair following injury/disease. Astrocytes also communicate with neurons, blood vessels, and other types of glial cells. Astrocytes within the optic nerve head region play a key role in glaucomatous axon degeneration. In this chapter, we describe ways in which astrocytes of the optic nerve head can be visualized, beginning with basic immunohistochemical staining methods, to single-cell dye injections and then to transgenic animals. We will also discuss the pros and cons of each method. Many of the methods were initially developed to visualize brain astrocytes; in some cases, the method has translated well to astrocytes of the optic nerve, and in others, it remains unclear.
Tao Y, Huang M, Shu Y, Ruprecht A, Wang H, Tang Y, Vandenberghe L, Wang Q, Gao G, Kong WJ, Chen ZY. Delivery of Adeno-Associated Virus Vectors in Adult Mammalian Inner-Ear Cell Subtypes Without Auditory Dysfunction. Hum Gene Ther. 2018;29(4):492–506.
Hearing loss, including genetic hearing loss, is one of the most common forms of sensory deficits in humans with limited options of treatment. Adeno-associated virus (AAV)-mediated gene transfer has been shown to recover auditory functions effectively in mouse models of genetic deafness when delivered at neonatal stages. However, the mouse cochlea is still developing at those time points, whereas in humans, the newborn inner ears are already fully mature. For effective gene therapy to treat genetic deafness, it is necessary to determine whether AAV-mediated therapy can be equally effective in the fully mature mouse inner ear without causing damage to the inner ear. This study tested several AAV serotypes by canalostomy in adult mice. It is shown that most AAVs transduce the sensory inner hair cells efficiently, but are less efficient at transducing outer hair cells. A subset of AAVs also transduces non-sensory cochlear cell types. Neither the surgical procedure of canalostomy nor the AAV serotypes damage hair cells or impair normal hearing. The studies indicate that canalostomy can be a viable route for safe and efficient gene delivery, and they expand the repertoire of AAVs to target diverse cell types in the adult inner ear.