Evaluation of the IOP-Lowering Effect of a Multi-Pressure Dial at Different Negative Pressure Settings.

Purpose: To evaluate the intraocular pressure (IOP)-lowering effect of a multi-pressure dial (MPD) at targeted negative pressure settings. Methods: Prospective, intrasubject controlled study of 65 healthy subjects randomized to receive no negative pressure for 60 minutes or negative pressure application at designated levels of 25%, 50%, and 75% of baseline IOP for 20 minutes each. The main outcome measure was mean IOP with application of negative pressure. Results: In the study eye group, from a baseline IOP of 15.8 ± 3.6 mm Hg, the mean IOP was 13.5 ± 3.4, 11.5 ± 3.1, and 10.2 ± 2.7 mm Hg with negative pressure settings of 25%, 50% and 75%, respectively. In the control eye group, from a baseline IOP of 15.5 ± 3.0 mm Hg, the mean IOP values at the same time points, without negative pressure, were 15.6 ± 3.0, 15.5 ± 2.5 and 15.3 ± 2.4 mm Hg. The difference between the mean IOPs of the two groups was significantly different at all negative pressure settings (P < 0.001) in comparison with baseline. There was one minor adverse event, a corneal abrasion, that was unrelated to device wear. Conclusions: Negative pressure application to the periocular space with a multi-pressure dial can produce titratable IOP reduction while the device is worn with active negative pressure. To our knowledge, this technology represents the first nonpharmacologic, nonlaser, nonsurgical method for IOP reduction. Translational Relevance: This represents the first study demonstrating the IOP-lowering ability of the multi-pressure dial, a device that uses a novel IOP-lowering strategy by delivering negative pressure to the periocular region.

Short-Term Steady-State Pattern Electroretinography Changes Using a Multi-Pressure Dial in Ocular Hypertensive, Glaucoma Suspect, and Mild Open-Angle Glaucoma Patients: A Randomized, Controlled, Prospective, Pilot Study.

INTRODUCTION: This study evaluates the effects of the multi-pressure dial (MPD) on steady-state pattern electroretinography (ss-pERG) parameters. The study is a randomized, controlled, prospective, pilot trial in a private practice setting with ocular hypertensive (OHT), glaucoma suspect, and open-angle glaucoma (OAG) subjects. METHODS: This study included nine patients (64 ± 9.0 years, nine female) with OHT, glaucoma suspect, or mild OAG. One eye of each subject was randomized to receive negative periocular pressure, while the contralateral eye served as the intrasubject control through the goggle without negative pressure. The Diopsys High Contrast Sensitivity ss-pERG protocol was conducted on both eyes of each subject while wearing the MPD device. Application of negative periocular pressure was set at 50% of baseline intraocular pressure for each study eye. RESULTS: Following 2 h of negative periocular pressure application, the difference in MagnitudeD (MagD) from baseline for eyes randomized to receive negative periocular pressure (+ 0.17 versus - 0.26) was statistically significant (p = 0.023). Over the same period, the change in MagD/Magnitude (MagD/Mag ratio) from baseline for eyes randomized to receive negative periocular pressure was also higher (+ 0.14 versus - 0.16), compared to the control eyes, approached significance (p = 0.059). CONCLUSIONS: Following 2 h of MPD wear, the measured MagD and MagD/Mag ratio improved compared to control, suggesting that negative periocular pressure application to the anterior globe can lead to short-term improvement in one measure of retinal ganglion cell function.

Trabecular microbypass stent implantation in pseudoexfoliative glaucoma: long-term results.

PURPOSE: To evaluate the long-term safety and efficacy of an iStent trabecular microbypass stent in combination with cataract surgery in pseudoexfoliative glaucoma (PXG). SETTING: Private practice, Sioux Falls, South Dakota, USA. DESIGN: Retrospective, consecutive case series. METHODS: Eyes with a preoperative diagnosis of PXG implanted with a single iStent trabecular microbypass stent with concomitant cataract surgery were included. Performance outcome measures included intraocular pressure (IOP) and number of glaucoma medications. Safety outcomes included intraoperative or postoperative complications and the need for secondary procedures. RESULTS: The series included 117 eyes. IOP was reduced by 25% to 15.3 ± 3.7 mm Hg at 5 years postoperatively from 20.5 ± 6.6 mm Hg at baseline. The statistically significant (P < .01) 36% reduction in medication use through 36 months was not sustained, and medication use was unchanged from baseline (1.4 ± 1.0) at 5 years postoperatively (1.3 ± 1.1) (P > .05). At 5 years, 52% of eyes had an IOP of 15 mm Hg or lesser, increased from 22% at baseline. There were no severe postoperative complications; 5 eyes (4%) underwent an additional glaucoma procedure. CONCLUSIONS: Implantation of a trabecular microbypass stent with concomitant cataract surgery provided a sustained reduction in IOP up to 5 years postoperatively. The long-term safety profile of the device in this population was excellent with a low rate of postoperative IOP spikes and low percentage of eyes undergoing a secondary procedure.

Short-Term Safety Evaluation of a Multi-Pressure Dial: A Prospective, Open-label, Non-randomized Study.

INTRODUCTION: Prospective, open-label, non-randomized, single site study to assess the safety and tolerability of a multi-pressure dial. METHODS: 30 healthy subjects received application of negative pressure (-15 mmHg) in one eye for 30 minutes and ambient atmospheric pressure in the contralateral eye. To evaluate safety, the primary outcome measures included best corrected visual acuity (BCVA), intraocular pressure (IOP) changes from baseline, slit-lamp and dilated fundus examination findings, and rate of adverse events. Exploratory analyses included in this study also evaluated changes from baseline measurement in tear break-up time (TBUT) and RNFL thickness measured by OCT. In addition to baseline screening, subjects underwent testing and negative pressure application on day 0 and returned 1 week after the initial visit for clinical testing. The follow-up visit did not include use of the multi-pressure dial (MPD) but repeated baseline testing and evaluated for adverse events. RESULTS: No adverse events were reported in the study. After short-term wear of the MPD on day 0, there was a minimal but statistically significant increase of half a line (LogMAR) in BCDVA for study eyes; this increase was not present at 1 week. There were no observed changes in cup-disk ratio and TBUT 1 week after the initial testing. There was a statistically significant pressure reduction in both study and fellow eyes at 1 week following the study, but clinical significance has yet to be determined. CONCLUSION: The MPD, which consists of a pair of goggles connected to a handheld, programmable pump, was well tolerated by subjects enrolled in the study. Key safety parameters remained stable after short-term exposure. The favorable safety results of this study support the safety profile of the MPD and promote further investigation of the device as a potential treatment of glaucoma. FUNDING: Equinox Ophthalmic, Inc. (Newport Beach, CA).

Intravitreal Versus Subretinal Tissue Plasminogen Activator Injection for Submacular Hemorrhage.

BACKGROUND AND OBJECTIVE: The objective of this study was to compare visual acuity outcomes between the following procedures used to treat submacular hemorrhages: pneumatic displacement followed by intravitreal tissue plasminogen activator (tPA) if needed (pneumatic ± tPA) and pars plana vitrectomy (PPV) with subretinal tPA (PPV + tPA). PATIENTS AND METHODS: This is a retrospective chart review of submacular hemorrhages treated with either pneumatic ± tPA or PPV + tPA. RESULTS: Eighteen patients had pneumatic ± tPA, and 14 patients had PPV + tPA. The percentage of patients achieving three lines or greater of vision improvement 1 year postoperatively was 46% and 18% in these groups, respectively (P = .194). CONCLUSION: The difference in visual acuity was not statistically significant; however, the lack of a statistical difference is important as pneumatic ± tPA is a less-invasive, less costly procedure that can be done in a clinical setting. [Ophthalmic Surg Lasers Imaging Retina. 2017;48:26-32.].

CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice.

Cytokines play an emerging role as neurotransmitters, neuromodulators, and neurohormones in the brain. This paradigm shift in cytokine function offers a new framework to understand their roles in ameliorating neurodegenerative disorders, such as Alzheimer's disease (AD). Molecular adjuvant therapy of AD animal models with glatiramer acetate induces anti-inflammatory responses and therapeutic effects. Although these effects are potentially mediated through anti-inflammatory cytokine signaling, the exact molecular identities and pathways are poorly understood. Here, we show that virus-mediated expression of the mouse interleukin (IL)-4 gene in beta-amyloid precursor protein + presenilin-1 (APP+PS1) bigenic mice attenuates AD pathogenesis. Introduction of an adeno-associated viral (AAV) vector encoding IL-4 into the hippocampus resulted in sustained expression of IL-4, reduced astro/microgliosis, amyloid-beta peptide (Abeta) oligomerization and deposition, and enhanced neurogenesis. Moreover, increased levels of IL-4 improved spatial learning, promoted phosphorylation of N-methyl-D-aspartate receptor subunit 2B at Tyr 1472, and enhanced its cell surface retention both in vivo and in vitro. Our data suggest that neuronal anti-inflammatory cytokine signaling may be a potential alternative target for non-Abeta-mediated treatment of AD.

AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice.

Accumulation of aggregated amyloid-beta (Abeta) peptide was studied as an initial step for Alzheimer's disease (AD) pathogenesis. Following amyloid plaque formation, reactive microglia and astrocytes accumulate around plaques and cause neuroinflammation. Here brain chemokines play a major role for the glial accumulation. We have previously shown that transgenic overexpression of chemokine CCL2 in the brain results in increased microglial accumulation and diffuse amyloid plaque deposition in a transgenic mouse model of AD expressing Swedish amyloid precursor protein (APP) mutant. Here, we report that adeno-associated virus (AAV) serotype 1 and 2 hybrid efficiently deliver 7ND gene, a dominant-negative CCL2 mutant, in a dose-response manner and express >1,000-fold higher recombinant CCL2 than basal levels after a single administration. AAV1/2 hybrid virus principally infected neurons without neuroinflammation with sustained expression for 6-months. 7ND expressed in APP/presenilin-1 (APP/PS1) bigenic mice reduced astro/microgliosis, beta-amyloidosis, including suppression of both fibrillar and oligomer Abeta accumulation, and improved spatial learning. Our data support the idea that the AAV1/2 system is a useful tool for CNS gene delivery, and suppression of CCL2 may be a therapeutic target for the amelioration of AD-related neuroinflammation.