An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema.

AIM: The aim of the study was to assess the safety and bioactivity of a single intravitreal injection of vascular endothelial growth factor (VEGF) Trap-Eye in subjects with diabetic macular oedema (DMO). METHODS: Five subjects with DMO, foveal thickness > or =250 microm measured by optical coherence tomography (OCT), and best-corrected visual acuity (BCVA) between 20/40 and 20/320, were enrolled. Each participant received a single intravitreal injection of 4.0 mg of VEGF Trap-Eye followed by a 6-week observation period. Outcome measures included safety and biological activity, including changes in BCVA and excess retinal thickness assessed by OCT. RESULTS: Injections of VEGF Trap-Eye were well tolerated with no ocular toxicity. One patient had an unrelated serious adverse event: hospitalisation for cellulitis of the left foot 27 days after injection of VEGF Trap-Eye. Median baseline BCVA was 36 ETDRS letters read at 4 m (not ETDRS visual acuity score; Snellen equivalent: 20/50) and median baseline excess central 1 mm foveal thickness (FTH) was 108 microm. At 4 weeks after injection, the median excess FTH was 59 microm and the median improvement in BCVA was nine letters. At 6 weeks after injection, four of the five patients showed improvement in excess FTH (median 74 microm; 31% reduction from baseline, p = 0.0625) and four of the five showed improvement in BCVA (median improvement of three letters). CONCLUSIONS: A single intravitreal injection of 4.0 mg of VEGF Trap-Eye was well tolerated and preliminary evidence of bioactivity was detected. These findings support additional studies investigating multiple injections of VEGF Trap-Eye in patients with DMO.

Posterior segment manifestations of active ocular syphilis, their response to a neurosyphilis regimen of penicillin therapy, and the influence of human immunodeficiency virus status on response.

OBJECTIVE: To determine the relative frequencies of signs in posterior segment ocular syphilis, the response to a neurosyphilis regimen of penicillin, and differences in findings between human immunodeficiency virus (HIV)-coinfected and -noncoinfected patients in a community setting. DESIGN: Retrospective, noncomparative, consecutive case series. PARTICIPANTS: Fourteen consecutive patients with posterior segment ocular syphilis over a 14-year period within or during the acquired immune deficiency syndrome era. INTERVENTION: Neurosyphilis intravenous penicillin regimen. MAIN OUTCOME MEASURES: Initial and final visual acuity; treponemal and nontreponemal serologic analyses; cerebrospinal fluid cell count, protein, and Venereal Disease Research Laboratory analyses; posterior segment signs; and relapses and recurrences. RESULTS: Blacks and males were predominantly affected. Five (36%) of patients were HIV coinfected, and ocular syphilis led to the HIV infection diagnosis in three. Four (29%) patients had received previous antibiotic therapy for primary or secondary syphilis, raising the suspicion of relapse. Two patients had negative nontreponemal serologic results. All patients responded rapidly to neurosyphilis therapy. One patient subsequently relapsed after neurosyphilis therapy, and a second was reinfected with recurrence of ocular involvement. One previously undescribed retinal manifestation was discovered: a sectorial retinochoroiditis with delayed retinal circulation in the involved area. CONCLUSIONS: Ocular syphilis is a form of neurosyphilis and requires neurosyphilis therapy regardless of when it develops after primary infection. Conventional syphilis staging is of little use in understanding ocular syphilis. A high suspicion for this diagnosis is appropriate, especially in poorer black males with posterior segment inflammatory disease. Human immunodeficiency virus coinfection with ocular syphilis is common, but does not affect response to a neurosyphilis regimen of penicillin in the short term. Awareness of the multiple presentations of posterior segment ocular syphilis will aid ophthalmologists in averting misdiagnosis or delayed diagnosis.

Fundus photographic, fluorescein angiographic, and indocyanine green angiographic signs in successful laser chorioretinal venous anastomosis for central retinal vein occlusion.

OBJECTIVE: To describe the fundus signs and angiographic signs that accompany development of a laser-induced chorioretinal venous anastomosis in central retinal vein occlusion and to describe the chronology of the signs. DESIGN: Noncomparative, consecutive case series. PARTICIPANTS: Fifteen eyes of 15 patients were treated. INTERVENTION: The argon laser was used in the original method of McAllister and Constable to form an anastomosis in five eyes, and the modified method of McAllister involving the argon laser followed by the YAG laser was used for ten eyes. MAIN OUTCOME MEASURES: Changes in vessel diameters, retinal blood flow, and morphology of anastomosis over time as documented photographically and angiographically. RESULTS: The earliest fluorescein angiographic sign of success is a hyperfluorescent spindle at 1 week. The earliest indocyanine green angiographic sign is direct connection of retinal venous and choroidal venous circulations at 2 weeks. The earliest fundus photographic and, hence, ophthalmoscopic sign is asymmetry in venous diameter at the disc at 3 weeks. No sign is present in all successful cases. The most commonly observed sign is fluorescein flow around a corner in a retrograde direction toward the anastomosis in 80% of cases. Drainage of only a fraction of the retina occurred in 93% of cases. Fifteen eyes with successful anastomoses had mean improvement of 2.3 +/- 2.4 (standard deviation [SD]) Snellen lines of best-corrected visual acuity compared to 0.2 +/- 2.3 (SD) lines for 9 eyes with unsuccessful anastomoses (P = 0.0439). CONCLUSION: Recognition of the variety and typical chronology of postoperative fundus and angiographic signs in laser-induced chorioretinal anastomosis will help prevent premature retreatment and guide appropriately timed additional treatment for failed initial attempts. Fluorescein angiography and indocyanine green angiography are necessary components of intensive postoperative follow-up of these patients. The follow-up care is more difficult than the technical aspects of the surgery itself. Successful anastomoses help by taking part of the flow away from the compromised central vein, not by providing global venous bypass. This technique remains controversial, unproven, and in need of a randomized clinical trial to determine its role in the management of nonischemic central retinal vein occlusion.

The effect of the surgeon and the laser wavelength on the response to focal photocoagulation for diabetic macular edema.

OBJECTIVE: To determine the effect of the surgeon and the wavelength of laser used on the response to focal photocoagulation for diabetic macular edema. DESIGN: Retrospective case-control study. PARTICIPANTS: Forty-four matched pairs of cases by two different retina surgeons in the study of surgeon influence were examined. Sixty-nine matched pairs of cases using dye yellow versus argon green laser treatment in the study of wavelength influence also were studied. In both studies, eyes were matched for the only patient-dependent variables affecting outcome: age, initial visual acuity, follow-up time, and diabetic control by diet versus any other method. INTERVENTION: Focal laser photocoagulation for clinically significant diabetic macular edema was performed. MAIN OUTCOME MEASURE: Visual acuity at 6 months follow-up was measured. RESULTS: For the study in which the only difference was the surgeon, at 6 months follow-up the mean difference in logarithm of the minimum angle of resolution (logMAR) visual acuity was -0.045, 95% confidence interval (-0.160, 0.070). For the study in which wavelength varied, at 6 months the mean difference in logMAR visual acuity was -0.048, 95% confidence interval (-0.147, 0.052). The power of the surgeon study to detect a difference in the logMAR visual acuity of 0.3 is 88% and of the wavelength study to detect this difference is 99%. CONCLUSION: In looking at the 6-month visual outcome after focal laser photocoagulation for clinically significant diabetic macular edema, different fellowship trained surgeons and the choice of green or yellow wavelength had no effect on the treatment outcome.

The risk of missing angle neovascularization by omitting screening gonioscopy in acute central retinal vein occlusion.

OBJECTIVE: The purpose of the study was to determine whether angle neovascularization can occur without pupillary margin neovascularization in central retinal vein occlusion (CRVO). DESIGN: The study design was a prospective study of the main question and a retrospective study of ancillary issues. PARTICIPANTS: The authors examined 105 eyes of 100 patients with CRVO having clinical evidence of ischemia between July 1, 1986, and March 18, 1996. INTERVENTION: The authors looked for iris and angle neovascularization with both undilated slit-lamp biomicroscopy and Zeiss four-mirror gonioscopy. MAIN OUTCOME MEASURES: The presence of anterior segment neovascularization was measured. RESULTS: Of 34 eyes developing anterior segment neovascularization, 4 (12%) developed angle neovascularization without pupillary margin neovascularization over a mean follow-up of 2.2 +/- 2.4 standard deviation years. CONCLUSIONS: Angle neovascularization can occur without pupillary margin involvement in CRVO, implying the necessity of screening gonioscopy and supporting the Central Vein Occlusion Study conclusion (based on a photographic technique not used clinically).

Laser chorioretinal venous anastomosis for nonischemic central retinal vein occlusion.

OBJECTIVE: This study aimed to test the efficacy and safety of laser chorioretinal anastomosis for central retinal vein occlusion (CRVO). DESIGN: The study design was a consecutive case series. PARTICIPANTS: Eight eyes of eight patients were treated. INTERVENTION: The argon laser was used in the method of McAllister and Constable to attempt to form an anastomosis. The patients were observed for 1 to 19 months (median, 11 months). MAIN OUTCOME MEASURES: Visual acuity, anastomosis success, and complications were measured. RESULTS: Twenty attempts to create anastomoses were made with 2 successful anastomoses but not of a therapeutic type. Three patients developed rubeosis, retinal neovascularization at the laser site, and vitreous hemorrhage. Traction retinal detachment occurred twice and neovascular glaucoma occurred once. Secondary panretinal photocoagulation, pars plana vitrectomy, and glaucoma seton were required in three patients, one patient, and one patient, respectively. Visual acuity improved in two patients independent of failed attempts at anastomosis creation and did not improve or worsened in six patients, including the two patients with the successfully created anastomoses. CONCLUSION: Laser chorioretinal anastomosis for nonischemic CRVO has greater risks and less success than the initial report suggested. Further refinement of the technique is needed before it is adopted extensively. Even when successful, macular pigment epithelial scarring can limit vision, implying a relatively short time window for its effective application in the face of severe macular edema. Successful laser chorioretinal anastomosis does not preclude development of anterior segment neovascularization.

The effect of patient characteristics on response to focal laser treatment for diabetic macular edema.

PURPOSE: The purpose of the study was to determine which patient characteristics influence response to focal photocoagulation for clinically significant diabetic macular edema (CSME). METHODS: A retrospective chart review was performed of 547 eyes from 361 patients who were observed for at least 1 year (mean, 2.6 +/- standard deviation 1.7 years) after surgery. Preoperative patient characteristics were tested for their significance in predicting outcome using multiple regression analysis. RESULTS: Increasing patient age has a negative effect on visual outcome (P = 0.0179). Patients with diet-controlled diabetes show improvement in mean vision, whereas patients whose diabetes is controlled with insulin, oral agents, or both show declines, and these differences are significant (P < 0.0001). Neither cataract surgery before or after focal photocoagulation nor simultaneous panretinal photocoagulation for patients having concomitant high-risk proliferative retinopathy had a significant effect on outcome. CONCLUSIONS: Younger patients with CSME and those with diet-controlled diabetes can be given more favorable prognoses. Patients with CSME and high-risk proliferative disease can have cost-effective simultaneous focal and panretinal photocoagulation without adversely affecting visual outcome.

Vitreous Hemorrhage complicating laser-induced chorioretinal anastomosis for central retinal vein occlusion.

PURPOSE: To report a severe complication of laser chorioretinal anastomosis for central retinal vein occlusion. METHOD: Case report. RESULTS: In the right eye of a 62-year-old woman with nonischemic central retinal vein occlusion, retinal neovascularization at the laser chorioretinal anastomosis site caused dense secondary vitreous hemorrhage. Vitreous hemorrhage prevented laser panretinal photocoagulation for subsequent iris neovascularization, necessitating vitrectomy surgery to clear the hemorrhage and allow the treatment. CONCLUSION: Laser chorioretinal anastomosis can result in severe vitreous hemorrhage and complicate efforts to manage later sequelae of central retinal vein occlusion.

Asymmetric retinopathy in patients with diabetes mellitus.

We reviewed retrospectively the records of 57 diabetic patients with asymmetric retinopathy persisting for two years or more (mean, 4.8 years) to identify intraocular risk and protective factors for the development of proliferative retinopathy. For each patient in this series, the more severely affected eye had proliferative retinopathy and the fellow eye had either background diabetic retinopathy or no retinopathy. Branch vein occlusion (P = .016) was identified as a statistically significant risk factor for proliferative retinopathy and chorioretinal scarring (P = .031) was found to be a statistically significant protective intraocular factor. In 34 patients with long-standing asymmetric retinopathy, no intraocular risk or protective factors were identified.

Reliability of brightness comparison testing in predicting afferent pupillary defects.

We tested the reliability of brightness comparison testing in predicting relative afferent pupillary defects (RAPDs) in 206 patients. For unselected patients, brightness comparison testing correctly predicted the RAPD in 62% of patients. For subgroups of patients with glaucoma and optic nerve lesions, correct predictions were made in 92% and 83% of patients, respectively. Sensitivity and specificity of brightness comparison testing with a 6-V test light were 85% and 49%, respectively. In subgroups of patients who are strongly suspected of having an RAPD but in whom pupillary testing is not possible, brightness comparison testing can reliably predict presence or absence of an RAPD.

Association of varicella zoster dermatitis with acute retinal necrosis syndrome.

The authors report seven patients in whom the acute retinal necrosis (ARN) syndrome developed shortly after cutaneous varicella zoster infection. The length of time between the skin infection and ARN varied from 5 days to 3 months. Both eyes were affected in one of seven cases. The ophthalmic branch of cranial nerve V ipsilateral to an affected eye was involved by the zoster dermatitis in only two of the seven cases. The association lends further support to the proposal that herpes zoster virus is a major cause of ARN. A history of recent zoster dermatitis should be sought in patients with ARN.

The test light affects quantitation of the afferent pupillary defect.

Nineteen patients with afferent pupillary defects (APDs) from a variety of lesions were examined using a brighter and dimmer test light. A denser neutral density filter was required to balance the afferent defect using the brighter test light in every case. For quantitation of an afferent defect to have meaning, the test light used must be specified. An indirect ophthalmoscope set to 6 V and held 1 foot from the eyes will allow easier detection of subtle relative APDs than it will if set to 3 V.

Ocular rosacea.

The demographic, clinical, and histopathologic characteristics of ocular rosacea are reviewed, with emphasis on examination of the skin in patients with external ocular disease. Since no single clinical or pathological hallmark of rosacea exists, a proposed point system for diagnosis is presented. Studies of pathogenesis reveal that no single unifying hypothesis accounts for all the expressions of ocular rosacea. Reports of treatment with tetracycline and other antibiotics demonstrate efficacy, although the mechanisms of action of these drugs are not known. More recently, other classes of drugs, including isotretinoin and hexachlorocyclohexane, have proven to be effective in dermatologic manifestations of rosacea, but effects on ocular manifestations are unknown.

An upper limit for the electrogenic Na-K pump contribution to maximum diastolic potential in feline cardiac Purkinje fibers in steady state.

We have estimated an upper limit for the electrogenic contribution of the Na-K pump to diastolic transmembrane potential. We simultaneously monitored the maximum diastolic potential and the extracellular space potassium activity during exposure to a very high concentration of ouabain. Exposure to ouabain caused a depolarization of approximately 3 mV (n = 33 experiments) over 34 +/- 3 s (mean +/- standard error) prior to any change in extracellular K activity. In four experiments, we monitored intracellular sodium activity and observed it to rise with approximately the same temporal lag (delay = 26 +/- 7 s). We also measured relative membrane conductance in one series of experiments and observed it to decrease to 91 +/- 2% of its control value by the time extracellular space K began to rise. Following the initial increase in extracellular space K activity the subsequent membrane depolarization is shown to be accurately predicted solely from the measured increase in extracellular space K activity as calculated from the Goldman equation. Limitations of the method and possible interpretations of the data are discussed. We interpret this ouabain-induced depolarization that occurs prior to the rise in external K to be an upper limit to the Na-K pump's electrogenic contribution to steady-state membrane potential.

Ocular rosacea in blacks.

In three black men (57, 64, and 61 years old) with the ocular manifestations of rosacea, the diagnosis was not initially suspected because the pathognomonic skin changes of rosacea were obscured by the skin hyperpigmentation. Ocular involvement ranged from blepharitis and conjunctival hyperemia to sight-threatening problems such as corneal neovascularization, thinning, ulceration, and perforation. Treatment with oral tetracycline and topical corticosteroids appeared to be as effective in these patients as in previously described white patients.