Scott W. Cousins

Identification of alpha-melanocyte stimulating hormone as a potential immunosuppressive factor in aqueous humor

The aqueous humor of the eye contains factors that regulate immunological responses within the immunosuppressive ocular microenvironment. Besides TGF-beta, the proteins in the low molecular weight (< 3500 Da) fraction of normal aqueous humor are also immunosuppressive. The low molecular weight fraction of aqueous humor inhibits IFN-gamma production and proliferation of antigen-stimulated lymph node cells. Neuropeptides are one possible family of low molecular weight factors in aqueous humor. Through the utilization of an antigen capturing enzyme-assay, the immunosuppressive neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) was detected in normal aqueous humor of humans, rabbits, and mice. The mean concentration of alpha-MSH in normal aqueous humor of humans was 20 +/- 3 pM, of rabbits 11 +/- 1 pM, of BALB/c mice 16 +/- 3 pM, and of C57BL/6 mice 14 +/- 3 pM. These physiological concentrations of alpha-MSH inhibited the production of IFN-gamma by antigen-stimulated lymph node cells. In contrast to the low molecular weight fraction, alpha-MSH did not inhibit proliferation. There was a 26% recovery of IFN-gamma production when alpha-MSH was absorbed from the low molecular weight fraction. The results demonstrate neuropeptides to be constitutive components of normal aqueous humor and that factors with the capability of differential regulation of effector T-cell activity may be present within the immunosuppressive ocular microenvironment.

Risks of Mortality, Myocardial Infarction, Bleeding, and Stroke Associated With Therapies for Age-Related Macular Degeneration

OBJECTIVE To examine associations between therapies for age-related macular degeneration and risks of all-cause mortality, incident myocardial infarction, bleeding, and incident stroke. METHODS We conducted a retrospective cohort study of 146,942 Medicare beneficiaries 65 years or older with a claim for age-related macular degeneration between January 1, 2005, and December 31, 2006. On the basis of claims for the initial treatment, we assigned beneficiaries to 1 of 4 groups. The active control group included patients who received photodynamic therapy. The other groups included patients who received intravitreous pegaptanib octasodium, bevacizumab, or ranibizumab. We censored data from patients when they received a therapy different from the initial therapy. The main outcome measures were associations between photodynamic, pegaptanib, bevacizumab, and ranibizumab therapies and the risks of all-cause mortality, incident myocardial infarction, bleeding, and incident stroke. RESULTS After adjustment for baseline characteristics and comorbid conditions, we found significant differences in the rates of mortality and myocardial infarction by treatment group. Specifically, the hazard of mortality was significantly lower with ranibizumab therapy than with photodynamic therapy (hazard ratio, 0.85; 99% confidence interval, 0.75-0.95) or pegaptanib use (0.84; 0.74-0.95), and the hazard of myocardial infarction was significantly lower with ranibizumab use than with photodynamic therapy (0.73; 0.58-0.92). There were no significant differences in the hazard of mortality or myocardial infarction between bevacizumab use and the other therapies. We found no statistically significant relationship between treatment group and bleeding events or stroke. CONCLUSION Bevacizumab and ranibizumab use was not associated with increased risks of mortality, myocardial infarction, bleeding, or stroke compared with photodynamic therapy or pegaptanib use.

Endophthalmitis after penetrating trauma : risk factors and visual acuity outcomes

PURPOSE To identify clinical characteristics that were associated with an increased incidence of endophthalmitis in eyes with penetrating ocular trauma. METHODS In part 1, a retrospective analysis was performed on 258 consecutive patients with penetrating ocular trauma presenting to the Bascom Palmer Eye Institute between October 1987 and January 1991. In part 2 of the study, 28 consecutive patients with culture-proven endophthalmitis were identified from the Clinical Microbiology Registry from April 1987 through September 1987 and February 1991 through August 1993. Clinical variables were evaluated in each part for association with an increased risk of endophthalmitis. RESULTS In part 1 of the study, endophthalmitis developed in 13 (5%) of the 258 patients. Endophthalmitis did not occur in eyes that had blunt injury. In those eyes with a lacerating injury, there was an increased relative risk of infection in eyes with disruption of the crystalline lens. This risk factor was found statistically significant by univariate and multivariate analysis. In part 2 of the study, lens disruption was present in 24 (86%) of 28 patients with culture-proven endophthalmitis. Of the 41 patients with infection from part I and part II, 22 (54%) achieved visual acuity of 20/ 400 or greater. Endophthalmitis caused by coagulase-negative staphylococci had the best visual outcome, with 7 (64%) of 11 patients obtaining visual acuity of 20/ 400 or greater. CONCLUSION Lens disruption in eyes with penetrating trauma is a significant risk factor for the development of endophthalmitis. The prognosis for useful vision in eyes with posttraumatic endophthalmitis is best when infection is caused by less virulent organisms.

Immunoregulatory mechanisms of the eye

Immune-privileged sites, such as the the internal compartments of the eye, and perhaps the brain, are physiological adaptations that act to modify systemic immune responses such that effector mechanisms that invoke locally destructive inflammation are suppressed. In the case of the eye, the parenchymal cells of the iris and ciliary body create an intraocular microenvironment that alters both the induction and expression of immunity to antigens placed within the eye. The immunosuppressive properties of the intraocular microenvironment are mediated by cytokines, especially transforming growth factor-beta (TGF beta). This cytokine has been demonstrated to endow intraocular antigen-presenting cells with the capacity to induce an atypical or deviant form of immunity to intraocular antigens which is selectively deficient in T cells that mediate delayed hypersensitivity. Moreover, TGF beta, along with other intraocular factors, can impair the intraocular expression of pre-existing cell-mediated immunity by inhibiting antigen-driven activation of primed T cells. The strategies employed by the eye to engender specialized immune responses appropriate to its physiological functions are discussed in terms of other privileged sites such as the brain.

Immune privilege and suppression of immunogenic inflammation in the anterior chamber of the eye.

Immunologic privilege of the anterior chamber has been associated with the capacity to induce a unique form of deviant systemic immunity after anterior chamber (AC) immunization. However, the capacity of privilege to suppress expression of immunity in the AC has not been examined. We studied the ability of the AC to sustain immunogenic inflammation after direct antigen challenge (delayed hypersensitivity-DH) in C57BL/6 mice primed to M tuberculosis (MT) antigens. Compared to subcutaneous and subconjunctival sites where primed mice demonstrated vigorous and significant DH, the anterior chambers of these mice failed to develop signs of inflammation unless toxic doses of antigen were injected. In an attempt to promote intraocular DH, the ACs of MT-primed mice were pre-treated with subinflammatory intracameral injections of IFN-gamma, a cytokine that antagonizes TGF-beta, recruits antigen presenting cells (APC) from the blood and activates resident APC precursors. It was observed that AC injection of IFN-gamma, followed 3 days later by AC challenge with 200 ng of MT, resulted in severe intraocular inflammation only in primed (but not naive) mice. We conclude that the normal mouse AC resists DH unless its immunosuppressive microenvironment is abolished, as in these experiments by IFN-gamma. We propose that impaired expression of cell-mediated immunity is an important component of immune privilege of the AC.

Intravitreal sustained-release cyclosporine in the treatment of experimental uveitis

OBJECTIVE Uveitis often is a chronic disease requiring long-term medical therapy. Despite treatment, the disease may be difficult to control and may produce serious, vision-threatening ocular complications. In this study, the authors determined whether an intravitreal cyclosporine-sustained delivery device was effective in the treatment of ocular inflammation in a rabbit model of uveitis. METHODS New Zealand White rabbits were immunized subcutaneously with Mycobacterium tuberculosis H37Ra antigen. Fourteen days later, sustained-release cyclosporine devices were implanted into the vitreous cavity of the right eye of experimental rabbits. Control animals received sham devices. Seven days after device implantation, rabbits were challenged with an intravitreal injection of tuberculin antigen. To simulate chronic inflammation with exacerbations, some animals were rechallenged with intravitreal antigen on day 21 after device implantation. Inflammation was assessed clinically by a masked observer who graded anterior chamber cells, flare, corneal neovascularization, iris congestion, and vitreous opacity daily until day 7 and on day 13 after the initial intravitreous challenge, and on days 1 and 2 after the rechallenge. Retinal function was evaluated by electroretinography. Animals were killed 3, 6, 8, and 14 days after the initial intravitreal challenge and on the second day after rechallenge for aqueous leukocyte count, protein measurement, and histologic examination. The number of aqueous and peripheral blood proliferating lymphocytes and the subset of CD4+ T cells were determined by flow cytometry. High-performance liquid chromatography was used to measure cyclosporine A levels in vitreous and peripheral blood. Light microscopy was used to evaluate the eyes histopathologically. RESULTS By clinical criteria, treated eyes had significantly less inflammation than untreated eyes. The number of aqueous cells and protein concentration determined quantitatively paralleled the clinical assessment of anterior chamber cells and flare. The electroretinography B-wave was depressed significantly in untreated eyes compared with that of treated eyes (P < 0.02). Histopathologic examination results showed marked inflammation and tissue disorganization in untreated eyes, whereas cyclosporine-treated eyes had preserved architecture and greatly reduced inflammatory cells. Intravitreal cyclosporine remained at therapeutic levels for at least 6 months after intravitreal device implantation, whereas blood levels were low to nondetectable. CONCLUSIONS The intravitreal cyclosporine A device effectively suppresses ocular inflammation in a rabbit model of uveitis. This device may be useful in the treatment of patients with severe chronic uveitis who are intolerant to currently available therapies.

Pseudophakic Retinal Detachments in the Presence of Various IOL Types

A series of 600 pseudophakic retinal detachments in 578 patients undergoing surgical repair between 1974 and 1984 was reviewed. Patients with previous retinal surgery of less than six months follow-up were excluded. The series included 395 iris-fixated (IF) lenses, 130 anterior chamber (AC) lenses, and 75 posterior chamber (PC) lenses. The overall success rate for retinal detachment was 88% but was significantly better in the PC lens group and significantly worse in the AC lens group. Forty-one percent of all cases achieved 20/40 visual acuity or better, although the AC lens group did worse (28%), while the PC lens group did significantly better (48%). Risk factors that were predictive of failure also were identified. Many of these factors occurred more frequently in the AC lens group and probably are related to the overall worse outcome in eyes with AC lens implants. The implications of these results for retinal and cataract surgeons are discussed.

Fully automated detection of diabetic macular edema and dry age-related macular degeneration from optical coherence tomography images

We present a novel fully automated algorithm for the detection of retinal diseases via optical coherence tomography (OCT) imaging. Our algorithm utilizes multiscale histograms of oriented gradient descriptors as feature vectors of a support vector machine based classifier. The spectral domain OCT data sets used for cross-validation consisted of volumetric scans acquired from 45 subjects: 15 normal subjects, 15 patients with dry age-related macular degeneration (AMD), and 15 patients with diabetic macular edema (DME). Our classifier correctly identified 100% of cases with AMD, 100% cases with DME, and 86.67% cases of normal subjects. This algorithm is a potentially impactful tool for the remote diagnosis of ophthalmic diseases.

Endotoxin-induced uveitis in the rat: observations on altered vascular permeability, clinical findings, and histology.

A single intraperitoneal dose of endotoxin (lipopolysaccharide or LPS) induces an acute inflammatory response in the uveal tract of rats. This inflammation is characterized by a breakdown of the blood/aqueous barrier within 3 hr after the LPS and the subsequent development of clinical disease and a cellular infiltrate. Early change in vascular permeability, clinical, and pathological changes were dose dependent with the two highest doses (100 micrograms or 500 micrograms) producing more severe pathology. Clinical and histopathologic abnormalities peaked at 24 hr and were resolving by 48 hr. Although clinical and histologic changes correlated well, the degree of breakdown of the blood/aqueous barrier at 3 hr failed to predict the extent of the cellular exudate measured by either clinical or histologic criteria. In addition, pharmacologic suppression of the early vascular permeability changes with indomethacin, cyproheptadine, or both agents failed to protect the animals consistently from subsequently developing significant clinical disease or cellular infiltrates on histopathology. LPS-induced uveitis in the rat provides a simple, reproducible model for ocular inflammation without requiring direct eye manipulation. The mediators responsible for the early vascular permeability in this model appear to be distinct from the mediators primarily responsible for the subsequent cellular exudate.

The Combined Effect of Visual Impairment and Cognitive Impairment on Disability in Older People

OBJECTIVES: To determine the risk of disability in individuals with coexisting visual and cognitive impairment and to compare the magnitude of risk associated with visual impairment, cognitive impairment, or the multimorbidity.