Mark I. Rosenblatt

Options and Adjuvants in Surgery for Pterygium: A Report by the American Academy of Ophthalmology

OBJECTIVE To assess the outcomes and safety of current surgical options and adjuvants in the treatment of primary and recurrent pterygium. METHODS Literature searches of the PubMed and the Cochrane Library databases were last conducted in January 2011 using keywords and were restricted to randomized controlled trials reporting on surgical intervention for pterygium. The searches were limited to articles published in English and yielded 120 citations. Citation abstracts, and if necessary the full text, were reviewed to identify randomized controlled trials that reported recurrence as an outcome measure and had a mean follow-up of at least 6 months. Fifty-one studies comparing bare sclera excision, conjunctival or limbal autograft, intraoperative mitomycin C, postoperative mitomycin C, and amniotic membrane transplantation for primary and recurrent pterygia fit these inclusion criteria. RESULTS Four studies demonstrated that the conjunctival or limbal autograft procedure is more efficacious than amniotic membrane placement. Use of conjunctival or limbal autografts or mitomycin C during or after pterygium excision reduced recurrence compared with bare sclera excision alone in most studies of primary or recurrent pterygium. The outcomes of conjunctival or limbal autograft were similar to outcomes for intraoperative mitomycin C in the few studies that directly compared the 2 techniques. There is evidence that increased concentration and duration of exposure to intraoperative mitomycin C is associated with increased efficacy. Of the adjuvants studied, only mitomycin C was associated with vision-threatening complications, including scleral thinning, ulceration, and delayed conjunctival epithelialization; there is some evidence of increasing complications with increased concentration and duration of exposure. There is conflicting evidence as to whether increasing age is protective against recurrence, but the morphologic features of the pterygium were shown to affect the recurrence rate. CONCLUSIONS Evidence indicates that bare sclera excision of pterygium results in a significantly higher recurrence rate than excision accompanied by use of certain adjuvants. Conjunctival or limbal autograft was superior to amniotic membrane graft surgery in reducing the rate of pterygium recurrence. Among other adjuvants, there is evidence that mitomycin C and conjunctival or limbal autografts reduce the recurrence rate after surgical excision of a pterygium. Furthermore, the data indicate that using a combination of conjunctival or limbal autograft with mitomycin C further reduces the recurrence rate after pterygium excision compared with conjunctival or limbal autograft or mitomycin C alone. Additional studies are necessary to determine the long-term effects, optimal route of administration, and dose and duration of treatment for mitomycin C. Factors such as availability of resources, primary or recurrent status of pterygium, age of patient, and surgeon or patient preference may influence the surgeons choice of adjuvant because there are insufficient data to recommend a specific adjuvant as superior. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Vascular endothelial growth factor mediates corneal nerve repair

PURPOSE To examine the expression of vascular endothelial growth factor (VEGF) and its receptors in the cornea and the trigeminal ganglion and to characterize the role of VEGF in mediating corneal nerve repair. METHODS Regeneration of the corneal subbasal nerve plexus after epithelial debridement was measured. The expression of VEGF and its receptors was examined in the trigeminal ganglia and in the cornea by RT-PCR, immunohistochemistry, and Western blotting. VEGF-mediated nerve growth was measured in a trigeminal ganglia explant assay. Anti-VEGF neutralizing antibody was used to examine the VEGF-dependent growth of neurons in vitro and regeneration of the corneal nerves in vivo. RESULTS After two distinct patterns of nerve regeneration, the subbasal nerves recovered to 65% of the preinjury density after 28 days. RT-PCR demonstrated gene expression of VEGF and VEGF receptors in the trigeminal ganglia. Immunohistochemistry showed staining for VEGF and its receptors in the trigeminal ganglia and for VEGFR1, VEGFR2, and neuropilin (NRP)-1 in the cornea. Western blot confirmed these results. In vitro, VEGF promoted the growth of explanted trigeminal ganglia by 91%. Blockage of VEGF signaling with anti-VEGF antibody reduced the growth of cultured neurons by 17% and the regeneration of subbasal neurons by 23%. CONCLUSIONS In addition to providing new information on the regeneration of murine corneal nerves, this study presents evidence that VEGF signaling influences the repair of corneal nerves by demonstrating that VEGF and VEGF receptors are present in the trigeminal ganglia and that abrogation of VEGF signaling reduces nerve growth in vitro and in vivo.

Effect of Hydration on Silk Film Material Properties

Effects of hydration on silk fibroin film properties were investigated for water-annealed and MeOH-treated samples. Hydration increased thickness by 60% for MeOH-immersed films, while water-annealed samples remained constant. MeOH-immersed films showed an 80% mass loss due to water, while water-annealed lost only 40%. O(2) permeability was higher in MeOH-immersed films with Dk values of 10(-10) (mL O(2) x cm) x (cm(-1) x s(-1) x mmHg(-1)), while those of water-annealed films reached only one fifth of this value. All films showed a decrease in Youngs modulus and increased plastic deformation by two orders of magnitude when submerged in saline solution. FT-IR showed that beta-sheet content in water-annealed films increased with increasing water vapor pressure, while MeOH-immersed films showed no change.

International Chronic Ocular Graft-vs-Host-Disease (GVHD) Consensus Group: Proposed Diagnostic Criteria for Chronic GVHD (Part I)

The International Chronic Ocular GVHD Consensus Group held 4 working meetings to define new diagnostic metrics for chronic ocular graft-versus-host disease (GVHD). After considering the factors currently used to diagnose chronic ocular GVHD, the Consensus Group identified 4 subjective and objective variables to measure in patients following allogeneic hematopoietic stem cell transplantation (HSCT): OSDI, Schirmers score without anesthesia, corneal staining, and conjunctival injection. Each variable was scored 0–2 or 0–3, with a maximum composite score of 11. Consideration was also given to the presence or the absence of systemic GVHD. On the basis of their composite score and the presence or absence of systemic GVHD, patients were assigned to one of three diagnostic categories: NO, PROBABLE, or DEFINITE ocular GVHD. New diagnostic criteria for chronic ocular GVHD are presented by the Consensus Group. Validation studies are needed to identify the best combination of the proposed metrics to maximize diagnostic sensitivity and specificity.

The TFOS International Workshop on Contact Lens Discomfort: Report of the Subcommittee on Neurobiology

This report characterizes the neurobiology of the ocular surface and highlights relevant mechanisms that may underpin contact lens-related discomfort. While there is limited evidence for the mechanisms involved in contact lens-related discomfort, neurobiological mechanisms in dry eye disease, the inflammatory pathway, the effect of hyperosmolarity on ocular surface nociceptors, and subsequent sensory processing of ocular pain and discomfort have been at least partly elucidated and are presented herein to provide insight in this new arena. The stimulus to the ocular surface from a contact lens is likely to be complex and multifactorial, including components of osmolarity, solution effects, desiccation, thermal effects, inflammation, friction, and mechanical stimulation. Sensory input will arise from stimulation of the lid margin, palpebral and bulbar conjunctiva, and the cornea.

Silk fibroin as a biomaterial substrate for corneal epithelial cell sheet generation.

PURPOSE To evaluate a silk fibroin (SF) biomaterial as a substrate for corneal epithelial cell proliferation, differentiation, and stratification in vitro compared with denuded human amniotic membrane (AM). METHODS Primary human and rabbit corneal epithelial cells and immortalized human corneal limbal epithelial cells were cultured on the SF and denuded AM, respectively. The biological cell behavior, including the morphology, proliferation, differentiation, and stratification, on the two substrates was compared and analyzed. RESULTS Corneal epithelial cells can adhere and proliferate on the SF and denuded AM with a cobblestone appearance, abundant microvilli on the surface, and wide connection with the adjacent cells. MTT assay showed that cell proliferation on denuded AM was statistically higher than that on SF at 24 and 72 hours after plating (P = 0.001 and 0.0005, respectively). Expression of ΔNp63a and keratin 3/12 was detected in primary cell cultures on the two substrates with no statistical difference. When cultured at the air-liquid interface for 7 days, cells on SF could form a comparable stratified graft with a 2- to 3-cell layering, which compared similarly to AM cultures. CONCLUSIONS SF, a novel biomaterial, could support corneal epithelial cells to proliferate, differentiate, and stratify, retaining the normal characteristic epithelium phenotype. Compared with AM, its unique features, including the transparency, ease of handling, and transfer, and inherent freedom from disease transmission, make it a promising substrate for corneal wound repair and tissue-engineering purposes.

VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions

Significance Peripheral nerve injury is a major neurological disorder that can cause multiple motor and sensory disturbances. In this study we found that VEGF-B can be used as a previously unidentified therapeutic for treating peripheral nerve injury. We demonstrated that VEGF-B stimulated nerve regeneration and enhanced the recovery of both tissue sensation and the ability of nerves to enhance healing of innervated tissue. The physiologic relevance of VEGF-B is demonstrated by our findings showing that mice lacking VEGF-B have impaired nerve regeneration and that nerve injury resulted in increased endogenous expression of VEGF-B. We discover that VEGF-B induces strong elongation and branching of neurons and requires specific transmembrane receptors as well as activation of a complex intracellular signaling. VEGF-B primarily provides neuroprotection and improves survival in CNS-derived neurons. However, its actions on the peripheral nervous system have been less characterized. We examined whether VEGF-B mediates peripheral nerve repair. We found that VEGF-B induced extensive neurite growth and branching in trigeminal ganglia neurons in a manner that required selective activation of transmembrane receptors and was distinct from VEGF-A–induced neuronal growth. VEGF-B–induced neurite elongation required PI3K and Notch signaling. In vivo, VEGF-B is required for normal nerve regeneration: mice lacking VEGF-B showed impaired nerve repair with concomitant impaired trophic function. VEGF-B treatment increased nerve regeneration, sensation recovery, and trophic functions of injured corneal peripheral nerves in VEGF-B–deficient and wild-type animals, without affecting uninjured nerves. These selective effects of VEGF-B on injured nerves and its lack of angiogenic activity makes VEGF-B a suitable therapeutic target to treat nerve injury.

Human corneal limbal epithelial cell response to varying silk film geometric topography in vitro

Silk fibroin films are a promising class of biomaterials that have a number of advantages for use in ophthalmic applications due to their transparent nature, mechanical properties and minimal inflammatory response upon implantation. Freestanding silk films with parallel line and concentric ring topographies were generated for in vitro characterization of human corneal limbal epithelial (HCLE) cell response upon differing geometric patterned surfaces. Results indicated that silk film topography significantly affected initial HCLE culture substrate attachment, cellular alignment, cell-to-cell contact formation, actin cytoskeleton alignment and focal adhesion (FA) localization. Most notably, parallel line patterned surfaces displayed a 36-54% increase on average in initial cell attachment, which corresponded to a more than 2-fold increase in FA localization when compared to other silk film surfaces and controls. In addition, distinct localization of FA formation was observed along the edges for all patterned silk film topographies. In conclusion, silk film feature topography appears to help direct corneal epithelial cell response and cytoskeleton development, especially with regard to FA distribution, in vitro.

Boston Keratoprosthesis: Outcomes and Complications: A Report by the American Academy of Ophthalmology

OBJECTIVE To review the published literature on safety and outcomes of the Boston type I keratoprosthesis (BI-KPro) for the surgical treatment of corneal opacification not amenable to human cadaveric corneal transplantation. METHODS Searches of peer-reviewed literature were conducted in PubMed and the Cochrane Library in December 2012, July 2013, and January 2014 without date restrictions. The searches were limited to studies published in English and yielded 587 citations. The abstracts of these articles were reviewed, 48 articles were selected for possible clinical relevance, and 22 were determined to be relevant for the assessment objectives. Nine studies were rated as level II evidence and 13 studies were rated as level III evidence. Excluded were level III evidence, case reports, review articles, letters, editorials, and case series with fewer than 25 eyes. RESULTS In 9 articles, a best-corrected Snellen visual acuity (BCSVA) of 20/200 or better occurred in 45% to 89% of eyes. Five articles described a BCSVA of 20/50 or better in 43% to 69% of eyes, and 4 articles found a BCSVA of 20/40 or better in 11% to 39% of eyes. Retention rates of the BI-KPro ranged from 65% to 100%. Reasons for loss of vision after BI-KPro implantation most commonly included corneal melts resulting from exposure keratopathy, endophthalmitis, and infectious keratitis or corneal ulceration. The 2 most common complications after surgery were retroprosthetic membrane formation (range, 1.0%-65.0%; mean ± standard deviation [SD], 30.0±19.0%) and elevated intraocular pressure (range, 2.4%-64.0%; mean ± SD, 27.5±18.1%). The 2 most common posterior segment complications were endophthalmitis (range, 0%-12.5%; mean ± SD, 4.6±4.6%) and vitritis (range, 0%-14.5%; mean ± SD, 5.6±4.7%). CONCLUSIONS The reviewed articles on BI-KPro use suggest that the device improves vision in cases of severe corneal opacification that were not amenable to corneal transplantation using human cadaveric keratoplasty techniques. A number of severe anterior and posterior segment complications can develop as follow-up continues, making ongoing close observation paramount for patients undergoing this surgery. These complications include infection, device extrusion, and permanent vision loss.

Hypertonic challenge to porcine vocal folds: effects on epithelial barrier function.

OBJECTIVE: Dehydration challenges can increase the chemical composition of surface fluid overlying vocal fold epithelia (hypertonic surface fluid). The vocal fold epithelium is posited to act as a barrier, shielding the lamina propria from perturbations in the airway lumen. However, the effects of hypertonic surface fluid on the barrier functions of vocal fold epithelia have not been quantified. We, therefore, sought to investigate whether hypertonic surface fluid compromises epithelial barrier function. We examined the effects of hypertonic surface fluid on vocal fold epithelial resistance, paracellular pathway morphology, and tight junction protein integrity. STUDY DESIGN: Ex vivo, between group design. SETTING: Laboratory. METHODS: Porcine vocal folds (n = 24) were exposed to hypertonic or isotonic challenge and examined by electrophysiology, transmission electron microscopy, and Western blot analyses. RESULTS: Hypertonic, but not isotonic, challenge significantly reduced transepithelial resistance. This decrease in resistance was observed immediately after the challenge and was consistent with the appearance of dilated paracellular pathway morphology. However, hypertonic challenge did not alter protein levels of occludin, zona occludens-1, E-cadherin, or β-catenin. CONCLUSION: Hypertonic surface fluid alters epithelial barrier function in the vocal folds. Specifically, exposure to hypertonic challenges increases epithelial permeability. Given the important role of the vocal fold epithelium in shielding the underlying mucosa from inhaled pathogens and pollutants, our data provide the impetus for future studies on pharmacological treatments aimed at restoring the hydration level and chemical composition of vocal fold surface fluid.