Henry D. Jampel

Vascular Endothelial Growth Factor in Ocular Fluid of Patients with Diabetic Retinopathy and Other Retinal Disorders

BACKGROUND Retinal ischemia induces intraocular neovascularization, which often leads to glaucoma, vitreous hemorrhage, and retinal detachment, presumably by stimulating the release of angiogenic molecules. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific angiogenic factor whose production is increased by hypoxia. METHODS We measured the concentration of VEGF in 210 specimens of ocular fluid obtained from 164 patients undergoing intraocular surgery, using both radioimmuno-assays and radioreceptor assays. Vitreous proliferative potential was measured with in vitro assays of the growth of retinal endothelial cells and with VEGF-neutralizing antibody. RESULTS VEGF was detected in 69 of 136 ocular-fluid samples from patients with diabetic retinopathy, 29 of 38 samples from patients with neovascularization of the iris, and 3 of 4 samples from patients with ischemic occlusion of the central retinal vein, as compared with 2 of 31 samples from patients with no neovascular disorders (P < 0.001, P < 0.001, and P = 0.006, respectively). The mean (+/- SD) VEGF concentration in 70 samples of ocular fluid from patients with active proliferative diabetic retinopathy (3.6 +/- 6.3 ng per milliliter) was higher than that in 25 samples from patients with nonproliferative diabetic retinopathy (0.1 +/- 0.1 ng per milliliter, P = 0.008), 41 samples from patients with quiescent proliferative diabetic retinopathy (0.2 +/- 0.6 ng per milliliter, P < 0.001), or 31 samples from nondiabetic patients (0.1 +/- 0.2 ng per milliliter, P = 0.003). Concentrations of VEGF in vitreous fluid (8.8 +/- 9.9 ng per milliliter) were higher than those in aqueous fluid (5.6 +/- 8.6 ng per milliliter, P = 0.033) in all 10 pairs of samples obtained simultaneously from the same patient; VEGF concentrations in vitreous fluid declined after successful laser photocoagulation. VEGF stimulated the growth of retinal endothelial cells in vitro, as did vitreous fluid containing measurable VEGF. Stimulation was inhibited by VEGF-neutralizing antibodies. CONCLUSIONS Our data suggest that VEGF plays a major part in mediating active intraocular neovascularization in patients with ischemic retinal diseases, such as diabetic retinopathy and retinal-vein occlusion.

Transforming growth factor-β in human aqueous humor

The transforming growth factor-βs are peptide growth factors known to play a central role in wound healing. Using a specific, in vitro assay of cell growth inhibition, we have detected transforming growth factor-β (TGF-β) in 24/24 aqueous humor specimens from eyes undergoing cataract extraction with intraocular lens implantation. The amount of TGF-β ranged from 2.3 to 8.1 ng/ml (mean ± SD = 4.5 ± 1.7 ng/ml), with 61% present in the active form.Subtyping of TGF-β was performed by addition of antibodies specific for the s1 and s2 isoforms to the growth inhibition assay, and confirmed with a sandwich enzyme-linked immunosorbent assay. None of the TGF-β detected was of the s1 isoform; in contrast, the s2 isoform was present in every sample, implying that it might have originated from ocular tissues. The presence of this potent modulator of tissue repair in aqueous humor suggests a role in the healing processes following intraocular surgery, including glaucoma filtration surgery.

Quantitative detection of glaucomatous damage at the posterior pole by retinal thickness mapping: A pilot study

OBJECTIVE The posterior pole ganglion cell bodies form a substantial fraction of the retinal thickness, prompting the authors to study the feasibility of detecting, by scanning retinal thickness analysis, retinal changes at the posterior pole due to glaucomatous damage. STUDY DESIGN Nonconsecutive case series. PARTICIPANTS One or both eyes of patients with chronic open-angle glaucoma who presented with either a superoinferior asymmetry in visual fields or a localized field loss or a nerve fiber layer defect visible on photography were recruited. Twenty-nine eyes of 18 patients were studied. INTERVENTIONS A laser slit was projected on the retina and scanned, in 400 msec, across a 2- x 2-mm area of the fundus, yielding optical cross-sections that were digitally recorded. Nine such scans covered the central 20 degrees of the fundus. The optical cross-sections were analyzed by an operator-free algorithm to yield a three-or two-dimensional color map. The asymmetry (difference) between the visual sensitivity of the upper and lower hemifields was compared with the asymmetry in retinal thickness deviation from normal. RESULTS Large losses (up to 34%) in retinal thickness were detected at the posterior pole of patients with glaucoma due to the loss of ganglion cells and nerve fibers. A statistically significant correlation was found between the asymmetry in visual sensitivity loss and the asymmetry in deviation from normal thickness (r = 0.72; P < 0.0005). CONCLUSIONS Mapping of the retinal thickness may provide a sensitive method for the detection and monitoring of early glaucomatous tissue loss in the posterior pole, which is unique due to the combination of (1) the direct measurement of neuroretinal loss in the central field of vision; (2) the mapping capability; and (3) the rapid image acquisition.

Effect of Brief Exposure to Mitomycin C on Viability and Proliferation of Cultured Human Tenon's Capsule Fibroblasts

PURPOSE The purpose of this study is to determine why a single intraoperative dose of mitomycin C (MMC) appears to promote the success of glaucoma filtration surgery. METHODS Human Tenons capsule fibroblasts were exposed to MMC and 5-fluorouracil (5-FU) in vitro at the concentrations and durations of exposure used clinically. Cell proliferation was assessed by quantification of 3H-thymidine uptake. Cell viability was studied using a sulfarhodamine B cell protein stain and by trypan blue exclusion. RESULTS Neither MMC (0.4 mg/ml) nor 5-FU (40 mg/ml) were cytocidal. Both 1- and 5-minute exposures to MMC were antiproliferative. A 1-minute exposure to 0.4 mg/ml inhibited 3H-thymidine uptake by 77%. For the 5-minute exposure, 3H-thymidine uptake was inhibited by 50% at 0.06 mg/ml and by 90% at 0.4 mg/ml. For 5-FU, 3H-thymidine uptake was inhibited by 50% at 10 mg/ml and by 64% at 40 mg/ml. CONCLUSIONS Mitomycin C probably does not improve the success of filtration surgery by killing fibroblasts. The ability of a brief exposure to MMC to improve filtration surgery may be due to an almost complete inhibition of proliferation. Alternatively, it may be due to sustained tissue binding, effects on other components of wound healing, such as cell migration and extracellular matrix production, or effects on the vasculature. A 1-minute exposure may be as effective as a 5-minute exposure.

Choroidal Thickness Measured by Spectral Domain Optical Coherence Tomography: Factors Affecting Thickness in Glaucoma Patients

PURPOSE To measure choroidal thickness and to determine parameters associated with it. DESIGN Cross-sectional study. PARTICIPANTS Seventy-four glaucoma patients and glaucoma suspects. METHODS Spectral domain optical coherence tomography (SD-OCT) scans were obtained to estimate average choroidal thickness in a group of glaucoma suspects and glaucoma patients. The average thickness was calculated from enhanced depth SD-OCT images and manually analyzed with Image J software. Open-angle glaucoma, open-angle glaucoma suspect, primary angle-closure glaucoma, primary angle closure, and primary angle-closure suspect were defined by published criteria. Glaucoma suspects had normal visual fields bilaterally. Glaucoma was defined by specific criteria for optic disc damage and visual field loss in ≥1 eye. The most affected eye was analyzed for comparisons across individuals, and right/left and upper half/lower half comparisons were made to compare thickness against degree of visual field damage. MAIN OUTCOME MEASURES Average macular and peripapillary choroidal thickness measured using SD-OCT. RESULTS The choroidal-scleral interface was visualized in 86% and 96% of the macular and peripapillary scans, respectively. In multivariable linear regression analysis, the macular choroid was significantly thinner in association with 4 features: Longer eyes (22 μm per mm longer [95% confidence interval (CI), -33, -11]), older individuals (31 μm thinner per decade older [95% CI, -44, -17]), lower diastolic ocular perfusion pressure (26 μm thinner per 10 mmHg lower [95% CI, 8, 44]), and thicker central corneas (6 μm per 10 μm thicker cornea [95% CI, -10, 0]). The choroid was not significantly thinner in glaucoma patients than in suspects (14 μm [95% CI, -54, 26]; P = 0.5). Peripapillary choroidal thickness was not significantly different between glaucoma and suspect patients. Thickness was not associated with damage severity as estimated by visual field mean deviation or nerve fiber layer thickness, including comparisons of right with left eye or upper with lower values. CONCLUSIONS Age, axial length, CCT, and diastolic ocular perfusion pressure are significantly associated with choroidal thickness in glaucoma suspects and glaucoma patients. Degree of glaucoma damage was not consistently associated with choroidal thickness. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Aqueous Shunts in Glaucoma: A Report by the American Academy of Ophthalmology

OBJECTIVE To provide an evidence-based summary of commercially available aqueous shunts currently used in substantial numbers (Ahmed [New World Medical, Inc., Rancho Cucamonga, CA], Baerveldt [Advanced Medical Optics, Inc., Santa Ana, CA], Krupin [Eagle Vision, Inc, Memphis, TN], Molteno [Molteno Ophthalmic Ltd., Dunedin, New Zealand]) to control intraocular pressure (IOP) in various glaucomas. METHODS Seventeen previously published randomized trials, 1 prospective nonrandomized comparative trial, 1 retrospective case-control study, 2 comprehensive literature reviews, and published English language, noncomparative case series and case reports were reviewed and graded for methodologic quality. RESULTS Aqueous shunts are used primarily after failure of medical, laser, and conventional filtering surgery to treat glaucoma and have been successful in controlling IOP in a variety of glaucomas. The principal long-term complication of anterior chamber tubes is corneal endothelial failure. The most shunt-specific delayed complication is erosion of the tube through overlying conjunctiva. There is a low incidence of this occurring with all shunts currently available, and it occurs most frequently within a few millimeters of the corneoscleral junction after anterior chamber insertion. Erosion of the equatorial plate through the conjunctival surface occurs less frequently. Clinical failure of the various devices over time occurs at a rate of approximately 10% per year, which is approximately the same as the failure rate for trabeculectomy. CONCLUSIONS Based on level I evidence, aqueous shunts seem to have benefits (IOP control, duration of benefit) comparable with those of trabeculectomy in the management of complex glaucomas (phakic or pseudophakic eyes after prior failed trabeculectomies). Level I evidence indicates that there are no advantages to the adjunctive use of antifibrotic agents or systemic corticosteroids with currently available shunts. Too few high-quality direct comparisons of various available shunts have been published to assess the relative efficacy or complication rates of specific devices beyond the implication that larger-surface-area explants provide more enduring and better IOP control. Long-term follow-up and comparative studies are encouraged.

Adherence with Topical Glaucoma Medication Monitored Electronically: The Travatan Dosing Aid Study

PURPOSE To assess patient adherence and behaviors with topical once-daily therapy for glaucoma. DESIGN Prospective, observational cohort study. PARTICIPANTS One hundred ninety-six patients with glaucoma who were being treated with a prostaglandin analog in 1 or both eyes at the Scheie or Wilmer Eye Institutes between August 2006 and June 2007. METHODS Detailed medical history was obtained from each patient. All subjects used the Travatan Dosing Aid (DA; Alcon, Fort Worth, TX) to administer travoprost as prescribed. Devices were collected at 3 months and the data of drop usage was downloaded using software provided with the dosing aid. Data were analyzed for the 8-week period starting 2 weeks after the enrollment visit and ending 2 weeks before the 3-month visit. MAIN OUTCOME MEASURES Assessment of adherence and patterns of drop usage as indicated by the DA. RESULTS A total of 282 subjects consented to be in the study and 86 (30%) withdrew before study completion or had device errors, leaving 196 subjects (70%) with evaluable data at 3 months. The overall mean (+/-standard deviation) adherence rate was 0.71 (+/-0.24), ranging from 0.02 to 0.97. One hundred nine of these patients (55.6%) took greater than 75% of the expected doses. Those with adherence of less than 50% of expected doses showed substantially increased dose taking immediately after the office visit and just before the return visit at 3 months (P = 0.03). The mean adherence rate estimates of the physician and patient self-report were 0.77 and 0.95, respectively. The agreement between the physician assessment and DA-recorded adherence rate showed poor correlation for individual cases (intraclass correlation coefficient, 0.09; 95% confidence interval, 0.00-0.19). CONCLUSIONS Nearly 45% of patients using an electronic monitoring device who knew they were being monitored and were provided free medication used their drops less than 75% of the time. Patients reported far higher medication use than their actual behavior. The ability of the physician to identify which persons are poorly adherent from their self-report or from other subjective clues is poor. FINANCIAL DISCLOSURE(S) Proprietary or commercial disclosure may be found after the references.

Surgical strategies for coexisting glaucoma and cataract. An evidence-based update

OBJECTIVE To assess short- and long-term control of intraocular pressure (IOP) with different surgical treatment strategies for coexisting cataract and glaucoma. DESIGN Systematic literature review and analysis. METHOD We performed a search of the published literature to identify all eligible articles pertaining to the surgical management of coexisting cataract and glaucoma in adults. One investigator abstracted the content of each article onto a custom-designed form. A second investigator corroborated the findings. The evidence supporting different approaches was graded by consensus as good, fair, weak, or insufficient. MAIN OUTCOME MEASURES Short-term (24 hours or fewer) and long-term (more than 24 hours) IOP control. RESULTS The evidence was good that long-term IOP is lowered more by combined glaucoma and cataract operations than by cataract operations alone. On average, the IOP was 3 to 4 mmHg lower in the combined groups with fewer medications required. The evidence was weak that extracapsular cataract extraction (ECCE) alone results in short-term increase in IOP and was insufficient to determine the short-term impact of phacoemulsification cataract extraction (PECE) on IOP in glaucoma patients. The evidence was weak that short-term IOP control was better with ECCE or PECE combined with an incisional glaucoma procedure compared with ECCE or PECE alone. The evidence was also weak (but consistent) that long-term IOP is lowered by 2 to 4 mmHg after ECCE or PECE. Finally, there was weak evidence that combined PECE and trabeculectomy produces slightly worse long-term IOP control than trabeculectomy alone, and there was fair evidence that the same is true for ECCE combined with trabeculectomy. CONCLUSIONS There is strong evidence for better long-term control of IOP with combined glaucoma and cataract operations compared with cataract surgery alone. For other issues regarding surgical treatment strategies for cataract and glaucoma, the available evidence is limited or conflicting.

Iris cross-sectional area decreases with pupil dilation and its dynamic behavior is a risk factor in angle closure.

PurposeTo estimate the change in iris cross-sectional (CS) area with pupil dilation using anterior segment optical coherence tomography comparing eyes with angle closure (AC) to open angle glaucoma (OAG). MethodsSixty-five patients from the Wilmer Glaucoma service, 36 with definite or suspected OAG and 29 with definite or suspected AC, underwent anterior segment optical coherence tomography imaging under 3 conditions (pupil constriction to light, physiologic dilation in the dark, and after pharmacologic dilation). The nasal and temporal iris CS areas were measured with custom software, 3 times in each of 4 meridians. The principal outcome variables were iris CS area and change in iris CS area/mm pupil diameter change. The relation of these parameters to potential variables that would influence iris area was estimated by multivariate regression. ResultsCS area was smaller in eyes with larger pupil diameter, those that had undergone trabeculectomy, and those of European-derived persons (P<0.05 for all in a univariate analysis). In a multivariate model with CS area as the dependent variable, larger pupil diameter (with a 0.19 mm2 decrease in CS area for each 1 mm of pupil enlargement, P=0.0002), and trabeculectomy remained significant factors. In a second multivariate model, AC irides had less change in CS area/mm pupil enlargement than OAG or OAG suspects (P=0.01). Change in iris CS area was essentially complete in 5 seconds (n=10 eyes). ConclusionsThe iris loses nearly half its volume from a pupil diameter of 3 to 7 mm, probably by eliminating extracellular fluid. Smaller iris CS area change with physiologic pupil dilation is a potential risk factor for AC. Dynamic iris CS area change deserves testing as a prospective indicator of AC.

Novel Glaucoma Procedures: A Report by the American Academy of Ophthalmology

OBJECTIVE To review the published literature and summarize clinically relevant information about novel, or emerging, surgical techniques for the treatment of open-angle glaucoma and to describe the devices and procedures in proper context of the appropriate patient population, theoretic effects, advantages, and disadvantages. DESIGN Devices and procedures that have US Food and Drug Administration clearance or are currently in phase III clinical trials in the United States are included: the Fugo blade (Medisurg Ltd., Norristown, PA), Ex-PRESS mini glaucoma shunt (Alcon, Inc., Hunenberg, Switzerland), SOLX Gold Shunt (SOLX Ltd., Boston, MA), excimer laser trabeculotomy (AIDA, Glautec AG, Nurnberg, Germany), canaloplasty (iScience Interventional Corp., Menlo Park, CA), trabeculotomy by internal approach (Trabectome, NeoMedix, Inc., Tustin, CA), and trabecular micro-bypass stent (iStent, Glaukos Corporation, Laguna Hills, CA). METHODS Literature searches of the PubMed and the Cochrane Library databases were conducted up to October 2009 with no date or language restrictions. MAIN OUTCOME MEASURES These searches retrieved 192 citations, of which 23 were deemed topically relevant and rated for quality of evidence by the panel methodologist. All studies but one, which was rated as level II evidence, were rated as level III evidence. RESULTS All of the devices studied showed a statistically significant reduction in intraocular pressure and, in some cases, glaucoma medication use. The success and failure definitions varied among studies, as did the calculated rates. Various types and rates of complications were reported depending on the surgical technique. On the basis of the review of the literature and mechanism of action, the authors also summarized theoretic advantages and disadvantages of each surgery. CONCLUSIONS The novel glaucoma surgeries studied all show some promise as alternative treatments to lower intraocular pressure in the treatment of open-angle glaucoma. It is not possible to conclude whether these novel procedures are superior, equal to, or inferior to surgery such as trabeculectomy or to one another. The studies provide the basis for future comparative or randomized trials of existing glaucoma surgical techniques and other novel procedures.