Ramez I. Haddadin

SPARC-null mice exhibit lower intraocular pressures.

PURPOSE SPARC is a matricellular protein that is highly expressed in remodeling tissues, including the trabecular meshwork and ciliary body. The hypothesis for the study was that SPARC contributes to the regulation of intraocular pressure (IOP). The IOPs of SPARC-null mice, their corresponding wild-type (WT), and heterozygous animals were compared. METHODS Diurnal and nocturnal IOPs of C57Bl/6x129SvJ WT, SPARC-null, and heterozygous mice were measured. Fluorophotometric measurements were made to assess aqueous turnover. Central corneal thickness (CCT) was measured using histology, ultrasound biomicroscopy, and optical coherence tomography. Iridocorneal angles were examined using light microscopy (LM). RESULTS During the day, the mean IOP of SPARC-null mice (n = 142, 16.9 +/- 2.4 mm Hg) was lower than that of both WT mice (n = 104, 19.9 +/- 2.9 mm Hg; P < 10(-12)), and heterozygotes (n = 38, 19.3 +/- 2.5 mm Hg; P < 10(-4)). At night, SPARC-null mice also exhibited a blunted increase in IOP in comparison to WT and heterozygous mice. CCTs were not significantly different between WT and SPARC-null mice. Heterozygous mice tended to have thicker corneas (3.4%). Fluorophotometric measurements suggest that aqueous turnover rates in SPARC-null mice are equal to if not greater than rates in WT mice. LM of the SPARC-null iridocorneal angle revealed morphology that is indistinguishable from WT. CONCLUSIONS SPARC-null mice have lower IOPs than do their WT counterparts with equal CCTs. The rate of aqueous turnover suggests that the mechanism is enhanced outflow resistance.

Matricellular proteins in the trabecular meshwork

The trabecular meshwork is one of the primary tissues of interest in the normal regulation and dysregulation of intraocular pressure (IOP) that is a causative risk factor for primary open-angle glaucoma. Matricellular proteins generally function to allow cells to modulate their attachments with and alter the characteristics of their surrounding extracellular matrix (ECM). In non-ocular tissues, matricellular proteins generally increase fibrosis. Since ECM turnover is very important to the outflow facility, matricellular proteins may have a significant role in the regulation of IOP. The formalized study of matricellular proteins in trabecular meshwork is in its infancy. SPARC, thrombospondins-1 and -2, and tenascins-C and -X, and osteopontin have been localized to varying areas within the trabecular meshwork. Preliminary evidence indicates that SPARC and thrombospondin-1 play a role in the regulation of IOP and possibly the pathophysiology of glaucoma. These data show promise that matricellular proteins are involved in IOP dysregulation and are potential therapeutic targets. Further study is needed to clarify these roles.

The effects of tenascin C knockdown on trabecular meshwork outflow resistance

PURPOSE Tenascin C (TNC) is a matricellular glycoprotein whose expression in adult tissue is indicative of tissue remodeling. The purpose of the current study was to determine the localization of TNC in trabecular meshwork (TM) tissue and to analyze the effects of TNC on intraocular pressure (IOP). METHODS Human TM frontal sections were immunostained with anti-TNC and imaged by confocal microscopy. TNC mRNA and protein levels were quantitated in anterior segments perfused at physiological and elevated pressure. Short, hairpin RNA (shRNA) silencing lentivirus targeting full-length TNC (shTNC) was applied to anterior segment perfusion organ cultures. The IOPs and central corneal thickness (CCT) of wild-type, TNC(-/-), and tenascin X (TNX(-/-)) knockout mice were measured. RESULTS TNC was distributed in the juxtacanalicular (JCT) region of adult human TM, predominantly in the basement membrane underlying the inner wall of Schlemms canal. Application of shTNC lentivirus to human and porcine anterior segments in perfusion culture did not significantly affect outflow rate. Although TNC was upregulated in response to pressure, there was no difference in outflow rate when shTNC-silenced anterior segments were subjected to elevated pressure. Furthermore, IOPs and CCTs were not significantly different between TNC(-/-) or TNX(-/-) and wild-type mice. CONCLUSIONS TNC does not appear to contribute directly to outflow resistance. However, TNC immunolocalization in the JCT of adult human eyes suggests that certain areas of the TM are being continuously remodeled with or without an IOP increase.

Disruption of the Blood-Aqueous Barrier and Lens Abnormalities in Mice Lacking Lysyl Oxidase-Like 1 (LOXL1)

PURPOSE Exfoliation syndrome (ES) is commonly associated with glaucoma, premature cataracts, and other ocular and systemic pathologies. LOXL1 gene variants are significantly associated with ES; however, the role of the protein in ES development remains unclear. The purpose of this study was to characterize the ocular phenotype in Loxl1(-/-) (null) mice. METHODS Loxl1 null mice and strain-matched controls (C57BL) were evaluated by clinical and histologic analyses. RESULTS Anterior segment histology showed a pronounced vesiculation of the anterior lens in the null mice. The lesions were subcapsular and in direct apposition with the posterior iris surface. Fluorescein angiography showed increased diffusion of fluorescein into the anterior chamber of the null mice compared with age-matched controls (P = 0.003, two-tailed, unequal variance t-test), suggesting compromise of the blood-aqueous barrier. Intraocular pressure measurements were within the normal range (16.5 ± 2.0 mm Hg) in null mice up to 1 year of age. Immunohistochemistry showed decreased elastin in the iris and ciliary body in the null mouse compared with controls. CONCLUSIONS Elimination of LOXL1 in mice impairs the blood-aqueous humor barrier in the ocular anterior segment and causes lens abnormalities consistent with cataract formation, but does not result in deposition of macromolecular material or glaucoma. These results show that mice lacking LOXL1 have some ES features but that complete disease manifestation requires other factors that could be genetic and/or environmental.

Achieving Target Refraction after Cataract Surgery

PURPOSE To evaluate the difference between target and actual refraction after phacoemulsification and intraocular lens implantation at an academic teaching institutions Comprehensive Ophthalmology Service. DESIGN Retrospective study. PARTICIPANTS We examined 1275 eye surgeries for this study. METHODS All consecutive cataract surgeries were included if they were performed by an attending or resident surgeon from January through December 2010. Postoperative refractions were compared with preoperative target refractions. Patients were excluded if they did not have a preoperative target refraction documented or if they did not have a recorded postoperative manifest refraction within 90 days. MAIN OUTCOME MEASURES The main outcome measure was percentage of cases achieving a postoperative spherical equivalent ± 1.0 diopter (D) of target spherical equivalent. RESULTS We performed 1368 cataract surgeries from January through December of 2010. Of these, 1275 (93%) had sufficient information for analysis. Of the included cases, 94% (1196 of 1275) achieved ± 1.0 D of target refraction by 90 days after cataract surgery. CONCLUSIONS This paper establishes a new benchmark for a teaching hospital, where 94% of patients achieved within 1.0 D of target refraction after cataract surgery. The refractive outcomes after cataract surgery at this academic teaching institution were higher than average international benchmarks.

Corneal Transplantation and Glaucoma

Abstract Glaucoma is the leading cause of irreversible vision loss post-keratoplasty and an important cause of graft failure. With newer techniques, such as lamellar, endothelial, and laser-assisted keratoplasty as well as keratoprosthesis gaining popularity, clinicians will need to consider the incidence, risks, evaluation, and management of glaucoma for each type of keratoplasty when determining which type of transplant may be most appropriate. A comprehensive literature search of glaucoma in the setting of corneal transplantation was performed and serves as the basis for this review. Preexisting glaucoma and aphakia are notable risk factors. Patients that are candidates for deep anterior lamellar keratoplasty may benefit from reduced rates of post-keratoplasty glaucoma. Although glaucoma also complicates eyes with Descemet stripping endothelial keratoplasty, the severity is less and the intraocular pressure is more easily controlled when compared to penetrating keratoplasty. Endothelial keratoplasty creates unique perioperative issues mostly related to management of anterior chamber air bubbles.

Management of corneal lacerations and perforations.

Corneal trauma can cause significant ocular morbidity and visual difficulty. Prompt diagnosis and management is required to prevent these complications. Although open globe injuries are uncommon, corneal lacerations and perforations represent 6.8% to 14.7% of ocular traumatic injuries presenting in an emergency medical setting. Corneal lacerations can be full or partial thickness. In this report, a corneal perforation, which is different from globe perforation, involving an entry and exit wound, represents full-thickness injury with tissue loss. Several retrospective studies report common characteristics and demographics of patients presenting with such injuries. A Chinese study of 715 traumatic corneal perforations reported the trauma most often occurred by penetrating wounds followed by explosion injuries. The patients were mostly farm workers and physical laborers. Most studies of ocular emergencies report a male preponderance, with peak age between 15 and 30 years. Pediatric corneal injuries represent a significant challenge in diagnosis and management and are unfortunately common in the pediatric emergency setting. In a Taiwanese study reviewing 18 years of 156 pediatric eye injuries, 40.4% were diagnosed with corneal lacerations. Another study reported that corneal laceration was the most frequent finding in pediatric perforating eye injuries. The most frequent long-term complications were corneal leukomas and anterior synechiae in these patients.

Corneal trauma following keratoplasty.

In 2006, there were 574,000 emergency room (ER) visits for eye injuries, representing 1.4% of all ER visits (National Healthy Statistics Reports, http://www.cdc.gov/nchs/data/nhsr/nhsr007.pdf). The United States Eye Injury Registry reports eye injury as the second most common cause of visual impairment in the United States, after cataract. They estimate that 500,000 years of vision are lost annually in the United States because of eye injuries. Patients with corneal transplants are particularly vulnerable to eye injury, as corneal wound healing does not restore the original tensile strength of the cornea. In 2009, 42,606 keratoplasties were performed. Penetrating keratoplasties (PK) and endothelial keratoplasties (EK), both forms of corneal transplantation, were by far the most common procedures at 23,269 and 18,221, respectively (Eye Bank Association of America, Eye Banking Statistical Report, http://www.restoresight.org). Traumatic wound dehiscence is considered an uncommon but potentially devastating consequence of eye injury after PK. With newer techniques such as lamellar, endothelial, and laser-assisted keratoplasties gaining popularity, clinicians will need to consider the susceptibilities to and consequences of trauma for each type of keratoplasty when counseling patients both prekeratoplasty and prognostically after injury has already occurred.

Diagnosis and management of herpes zoster ophthalmicus

Herpes zoster (HZ) occurs from reactivation of endogenous latent varicella-zoster virus (VZV) within sensory ganglia. VZV is a neurotropic herpes virus that affects sensory neurons following childhood infection with varicella (chickenpox). When reactivation of the virus occurs in the ophthalmic division of the trigeminal nerve, the infection is called herpes zoster ophthalmicus (HZO). Despite advances in antiviral therapy and vaccines, HZO remains a significant source of morbidity. This article discusses the background, clinical manifestations, and management of herpes zoster ophthalmicus.

Laser/Light Application in Ophthalmology: Control of Intraocular Pressure

The term “glaucoma” refers to a group of disorders that share common phenotypes. There are over 20 different subtypes of glaucoma. The glaucomas are defined by a characteristic loss of retinal ganglion cell axons leading to a progressive optic neuropathy that is related to intraocular pressure (IOP). If untreated, glaucoma can cause visual disability and even blindness. Although elevated intraocular pressure (IOP) is no longer formally part of the definition, it is recognized as the major risk factor for progression of the disease.