Don Calogero

The Food and Drug Administration's Proactive toxic anterior segment syndrome Program.

Toxic anterior segment syndrome (TASS) is a rare inflammatory condition usually observed within the first 48 hours after uncomplicated anterior segment surgery. Over the decades since its initial description, a number of TASS outbreaks have been reported. For a few of these outbreaks, the inciting factors were identified, but for the majority, the precipitating factors were often postulated but not confirmed. In light of the limitations identified in these outbreak investigations, the Food and Drug Administrations (FDAs) Center for Devices and Radiological Health staff has embarked on a number of activities aimed at mitigating medical device-related TASS outbreaks. Under the FDA-designed Proactive TASS Program (PTP), FDA scientists have conducted animal studies to better explore the inflammatory potential of suspected ophthalmic device contaminants implicated in prior cases of TASS. For contaminants displaying a TASS-like reaction in these animal models, the FDA scientists have developed analytic test methods to measure the level of those contaminants in or on ophthalmic devices. Moreover, FDA researchers have developed methods to better capture the clinical information necessary to assist investigations of potential future outbreaks. Last, the FDA has partnered with the Centers for Disease Control and Prevention to facilitate a potential TASS investigation, including expediting the analysis of potentially contaminated medical devices. The PTP is an example of the FDA proactively developing test methods and disease surveillance methods geared toward protecting the publics health.

An Investigation of Enzymatic Detergents as a Potential Cause of Toxic Anterior Segment Syndrome

OBJECTIVE To investigate whether enzymatic detergents used in cleaning ophthalmic surgical instruments can cause toxic anterior segment syndrome (TASS)-like responses in a rabbit model. DESIGN Randomized, investigator-masked, controlled experimental animal study. PARTICIPANTS Thirty-five New Zealand white rabbits. METHODS The rabbit eyes were randomized into 7 treatment groups to receive intracameral injection of 1 of 3 different doses of Medline Dual Detergent or Enzol Detergent, or sterile limulus amoebocyte lysate reagent water as a control. The eyes were evaluated for anterior segment inflammation at baseline and at 1, 3, 6, 24, 48, and 72 hours after treatment by slit-lamp biomicroscopy. MAIN OUTCOME MEASURES Anterior chamber (AC) inflammation, including cells, flare, fibrin, and iris injection; time course of inflammation; and residual detergent levels in luminated instruments. RESULTS Moderate to marked injection of the iris vessels was seen as early as 1 hour after treatment with the enzymatic detergents in 41 of 60 eyes, with the response being more severe in the Enzol Detergent-exposed eyes. Severe iris hemorrhages were accompanied by blood in the AC in 13 eyes, which usually persisted through 72 hours, with an associated increase in AC cell and flare. Corneal haze was present in 52 of 56 eyes 1 hour after treatment, but was mild and resolved within 24 hours in all but the Enzol 4.5%-exposed eyes. Median AC cell and flare peaked at 6 hours and resolved by 48 hours. CONCLUSIONS Enzymatic detergents caused a severe but unusual response from the iris when injected intracamerally into rabbit eyes. This response has not been reported in humans with TASS. The time course of inflammation was faster (peak at 6 hours) and resolved more quickly (within 48 hours) than TASS. Simulated cleaning and extraction studies indicate that the level of residual detergent to which a patient could be exposed is significantly less than the lowest dose used in this study. Because that low dose caused no significant observations other than injection of the iris vessels, these results do not support residual enzymatic detergents on surgical instruments as a cause for TASS.

Detecting endotoxin contamination of ophthalmic viscosurgical devices: intracameral versus intravitreal assays in rabbits.

OBJECTIVE To compare the sensitivities of intracameral and intravitreal assays in the rabbit model to determine the relative adequacy of these methods in detecting bacterial endotoxin contamination of ophthalmic viscosurgical devices (OVDs). DESIGN Experimental, randomized animal study. PARTICIPANTS Twenty New Zealand white rabbits. METHODS Rabbits were randomized into 4 groups to receive a cohesive or a dispersive OVD via intracameral or intravitreal injection. All 40 treated eyes (10 eyes of 5 animals in each group) received bilateral injection of OVD spiked with bacterial endotoxin at 7.0 endotoxin units/ml. All eyes were evaluated by slit-lamp biomicroscopy for inflammatory response at 3, 6, 9, 24, 48, and 72 hours after exposure. Eyes that received intravitreal injection were also dilated at 24, 48, and 72 hours and were re-examined by slit-lamp biomicroscopy and by indirect ophthalmoscopy. MAIN OUTCOME MEASURES Conjunctival inflammation, anterior chamber (AC) flare, cells and fibrin, vitreous haze and cells, iridal hyperemia, corneal clouding, lens opacities, and onset times. RESULTS Intracamerally injected eyes frequently showed conjunctival congestion, AC cells and flare, iridal hyperemia, and fibrin within 6 hours. Up to 80% showed AC cells and flare at 9 hours, and up to 70% showed fibrin at 24 hours. These signs diminished within 48 hours. Fibrin and cells also were seen on the lens surface of most of the eyes. Intravitreally injected eyes showed no signs of inflammation within 24 hours, other than some conjunctival inflammation. After the 24-hour time point, in addition to some conjunctival inflammation, some other signs of inflammation were observed infrequently in the intravitreally injected eyes, including minor vitreous cell reaction in 2 eyes. Although there was 1 dispersive OVD-treated eye with cells and fibrin on the lens capsule at 48 hours, no aqueous cells or flare were seen in the AC of any intravitreally injected eyes at any time during the course of the study. CONCLUSIONS The rabbit intravitreal assay, when limited to 72 hours, does not seem to have adequate sensitivity to detect endotoxin reliably in OVDs.

Evaluation of intraocular reactivity to metallic and ethylene oxide contaminants of medical devices in a rabbit model.

OBJECTIVE To evaluate the intraocular reactivity to metallic and ethylene oxide (EO) contaminants of ophthalmic devices in rabbits. DESIGN Two experimental animal studies. PARTICIPANTS Thirty-five New Zealand white rabbits. METHODS A metallic exposure study and an EO exposure study were performed. In the first study, both eyes of 25 rabbits were equally allocated to intracameral injections of alumina 0.2 μg, alumina 20 μg, copper sulfate 0.4 μg, copper sulfate 20 μg, or an aqueous control. In the second study, 10 rabbits were allocated (5 per group) to receive intracamerally an ophthalmic viscosurgical device (OVD) exposed to EO or not exposed to EO (control). All eyes were examined by slit lamp at baseline and 3, 6, 9, 24, 48, and 72 hours after exposure, with dilated indirect ophthalmoscopy being performed at 24 and 72 hours. Tonometry was performed only in the first study. MAIN OUTCOME MEASURES Grade of corneal clouding, anterior chamber (AC) flare, AC cells, AC fibrin, iridal hyperemia, cell and fibrin on the lens surface, vitreous haze and cells, lens opacities, intraocular pressure, and onset time. RESULTS For metallic compounds at the studys low doses, mean inflammatory grades were 0.2 or less above the control for all responses at all time points. For the high-dose alumina, mean inflammatory grades peaked at 6 to 9 hours at 0.5 to 0.7 above the control responses for conjunctival congestion, iris hyperemia, AC cells, flare, and fibrin and declined over the remaining time points. For the high-dose copper sulfate, mean inflammatory grades peaked between 3 and 24 hours at 1.2 to 1.8 above the control responses for conjunctival congestion, iris hyperemia, AC cells, flare, fibrin, and corneal clouding, then subsequently declined. The intraocular pressure changes appeared significant for only high-dose copper sulfate, with mean declines of 4.3 to 7.5 mmHg at 6 to 72 hours. No clinically meaningful differences in ocular inflammation were observed between the OVD exposed to EO and the OVD not exposed to EO. CONCLUSIONS Alumina and copper sulfate did not cause clinically meaningful ocular inflammation at the low study levels (levels expected with ophthalmic devices). Ethylene oxide exposure of an OVD was not associated with inflammation.

Rabbit Ocular Reactivity to Bacterial Endotoxin Contained in Aqueous Solution and Ophthalmic Viscosurgical Devices

OBJECTIVE To describe the ocular reactivity of the rabbit to bacterial endotoxin contained in an aqueous medium and in a cohesive and a dispersive ophthalmic viscosurgical device (OVD). DESIGN Experimental, randomized animal study. PARTICIPANTS Seventy-five New Zealand white rabbits. METHODS This study was performed using 75 rabbits to evaluate the ocular reactivity to bacterial endotoxin contained in Dulbeccos phosphate-buffered saline (DPBS), a cohesive OVD, and a dispersive OVD. For each test material, 25 rabbits were randomized into 5 groups and were exposed to the test material containing 0.75 endotoxin units (EU), 0.25 EU, 0.08 EU, and 0.02 EU of endotoxin or the vehicle control. The rabbits in each group received bilateral intracameral injection of 0.05 ml of the same test material. All eyes were examined by slit-lamp biomicroscopy at baseline, 3, 6, 9, 24, 48, and 72 hours after injection. At 24 and 72 hours, slit-lamp biomicroscopy (and additionally indirect ophthalmoscopy) was performed through dilated pupils. MAIN OUTCOME MEASURES Corneal clouding, anterior chamber (AC) flare, cells and fibrin, vitreous haze and cells, cells and fibrin on lens surface, lens opacities, and onset time. RESULTS The inflammation seen after exposure to the 3 endotoxin-spiked materials followed the same general time course. Anterior chamber cells, flare, iris hyperemia, and conjunctival congestion were seen as early as 3 hours. They started to diminish after 6 hours (DPBS eyes) and 9 hours (OVDs) and were not detectable at 48 and 72 hours, respectively. The AC inflammation was more severe in the OVD eyes than in the DPBS eyes. Anterior chamber fibrin was seen in the OVD eyes only, which persisted through 72 hours in many eyes. A trend toward a dose-response relationship was seen for AC cells and flare and the presence of cells and fibrin on the lens surface in all 3 treatment groups in the first 24 hours. CONCLUSIONS Inflammation was seen after intracameral injection of as little as 0.02 and 0.08 EU in OVD and DPBS eyes, respectively. Observed responses to intracamerally injected endotoxin in OVDs were more severe and of longer duration than those in aqueous medium.

Testing the dioptric power accuracy of exact-power-labeled intraocular lenses

PURPOSE: To test the accuracy of exact‐power‐labeled intraocular lenses (IOLs) in a limited independent study. SETTING: U.S. Food and Drug Administration Optical Testing Lab. METHODS: Hydrophilic acrylic IOLs were measured using a new confocal laser method for dioptric power measurement per International Organization for Standards standard 11979‐2 and American National Standards Institute standard Z80.7. Some of the IOLs were measured at 22°C and 35°C. RESULTS: For the 18 IOLs tested, the mean difference between the manufacturers exact labeled power (DEL) and the power measured in the study (DM) was 0.18 diopter (D) ± 0.12 (SD) and between DM and the usual normal rounded‐off (0.50 D steps) dioptric power (DUL) labeling, 0.23 ± 0.09 D (difference 0.05 D). For 15.00 to 20.0 D IOLs, the mean difference between DM and DEL was 0.08 ± 0.05 D and between DM and DUL, 0.17 ± 0.06 D (difference 0.09 D). For IOLs of 20.00 D or greater, the mean difference between DM and DEL was 0.24 ± 0.11 D and between DM and DUL, 0.27 D ± 0.08 D (difference 0.03 D). When the IOL hydration temperature increased from 22°C to 35°C (4 IOLs tested), the IOL power increase on average was approximately 0.13 D. CONCLUSIONS: The small improvement in power‐prediction accuracy for exact‐power‐labeled IOLs decreased in IOLs of 20.00 D or greater. For IOLs of 15.00 to 20.00 D, the increased accuracy (±0.09 D) was statistically significant and could increase predictability of postoperative refractions. Acrylic dioptric power was directly proportional to temperature.

Rabbit Intraocular Reactivity to Endotoxin Measured by Slit-Lamp Biomicroscopy and Laser Flare Photometry

OBJECTIVE To evaluate the ocular reactivity of the rabbit to an intracameral injection of a dispersive ophthalmic viscosurgical device (OVD) containing various levels of bacterial endotoxin using slit-lamp biomicroscopy and laser flare photometry. DESIGN Experimental, randomized, masked animal study. PARTICIPANTS Thirty Dutch-Belted rabbits. METHODS The rabbits were randomized into 6 groups to receive 0.05 ml of a hydroxypropyl methylcellulose-based dispersive OVD to which had been added one of 5 different doses of bacterial endotoxin ranging from 0.02 to 1.4 endotoxin units (EUs) or a vehicle control to both eyes. The eyes were evaluated for anterior segment inflammation at baseline and 3, 6, 9, 24, 48, and 72 hours after injection using slit-lamp biomicroscopy and laser flare photometry. MAIN OUTCOME MEASURES Corneal clarity and anterior chamber (AC) inflammation. RESULTS All the corneas remained clear throughout the study. Anterior chamber cells were seen at 6, 9, and 24 hours in 60% to 100% of the eyes intracamerally injected with endotoxin-containing OVD, and the response declined rapidly after 24 hours. A dose-response effect was seen between the concentration of endotoxin and the AC cell response. The aqueous flare response in eyes injected with the 2 highest doses of endotoxin was significantly greater (P<0.05) than that of controls. The amounts of fibrin observed in the AC were random, with no apparent dose-response effect seen. The flare values as obtained by laser flare photometry were consistent with the slit-lamp biomicroscopy flare findings up to grade 3+. However, the increase in laser flare value seemed to level off in eyes with more than 3+ flare. Neither measure of flare correlated with endotoxin level. CONCLUSIONS Among the parameters evaluated in this study, the AC cell response, evaluated by slit-lamp biomicroscopy and graded using a standard grading system, was found to be the most reliable indicator of the amount of endotoxin in the dispersive OVD. The use of laser flare photometry alone does not seem to be useful in detecting an ocular response to endotoxin contamination in OVDs.

Noncontact common-path Fourier domain optical coherence tomography method for in vitro intraocular lens power measurement

We propose a novel common-path Fourier domain optical coherence tomography (CP-FD-OCT) method for noncontact, accurate, and objective in vitro measurement of the dioptric power of intraocular lenses (IOLs) implants. The CP-FD-OCT method principle of operation is based on simple two-dimensional scanning common-path Fourier domain optical coherence tomography. By reconstructing the anterior and posterior IOL surfaces, the radii of the two surfaces, and thus the IOL dioptric power are determined. The CP-FD-OCT design provides high accuracy of IOL surface reconstruction. The axial position detection accuracy is calibrated at 1.22 μm in balanced saline solution used for simulation of in situ conditions. The lateral sampling rate is controlled by the step size of linear scanning systems. IOL samples with labeled dioptric power in the low-power (5D), mid-power (20D and 22D), and high-power (36D) ranges under in situ conditions are tested. We obtained a mean power of 4.95/20.11/22.09/36.25 D with high levels of repeatability estimated by a standard deviation of 0.10/0.18/0.2/0.58 D and a relative error of 2/0.9/0.9/1.6%, based on five measurements for each IOL respectively. The new CP-FD-OCT method provides an independent source of IOL power measurement data as well as information for evaluating other optical properties of IOLs such as refractive index, central thickness, and aberrations.

Quantification of glistenings in intraocular lenses using a ballistic-photon removing integrating-sphere method

An alternative method for quantification of glistenings in intraocular lenses (IOLs) using an integrating sphere with an adjustable back aperture to remove ballistic photons is presented. Glistenings in soft IOLs have been known for more than a decade; however, their severity and visual impact are still under investigation. A number of studies have been made to quantitatively describe glistenings in IOLs. Quantization and precise grading of IOLs will provide needed information to evaluate the severity and visual impact of glistenings in patients. We investigated the use of a simple modification of an integrating-sphere method to eliminate ballistic photons to quantitatively measure scattered light from glistenings in IOLs. The method described in this paper provides a simple and effective way to quantitatively characterize glistenings in vitro. It may be especially useful to quantify scattering associated with low-grade glistenings where the density of the scattering centers is low. Finally, the modified integrating-sphere method may also be generally applicable to quantitatively characterize scattering from other optical media.

Assessing the effect of laser beam width on quantitative evaluation of optical properties of intraocular lens implants

Abstract. The design and manufacture of intraocular lenses (IOLs) depend upon the identification and quantitative preclinical evaluation of key optical properties and environmental parameters. The confocal laser method (CLM) is a new technique for measuring IOL optical properties, such as dioptric power, optical quality, refractive index, and geometrical parameters. In comparison to competing systems, the CLM utilizes a fiber-optic confocal laser design that significantly improves the resolution, accuracy, and repeatability of optical measurements. Here, we investigate the impact of changing the beam diameter on the CLM platform for the evaluation of IOL dioptric powers. Due to the Gaussian intensity profile of the CLM laser beam, the changes in focal length and dioptric power associated with changes in beam diameter are well within the tolerances specified in the ISO IOL standard. These results demonstrate some of the advanced potentials of the CLM toward more effectively and quantitatively evaluating IOL optical properties.