Alternatives to Topical Glaucoma Medication for Glaucoma Management.

Topical glaucoma medications have favorable safety and efficacy, but their use is limited by factors such as side effects, nonadherence, costs, ocular surface disease, intraocular pressure fluctuations, diminished quality of life, and the inherent difficulty of penetrating the corneal surface. Although traditionally these limitations have been accepted as an inevitable part of glaucoma treatment, a rapidly-evolving arena of minimally invasive surgical and laser interventions has initiated the beginnings of a reevaluation of the glaucoma treatment paradigm. This reevaluation encompasses an overall shift away from the reactive, topical-medication-first default and a shift toward earlier intervention with laser or surgical therapies such as selective laser trabeculoplasty, sustained-release drug delivery, and micro-invasive glaucoma surgery. Aside from favorable safety, these interventions may have clinically important attributes such as consistent IOP control, cost-effectiveness, independence from patient adherence, prevention of disease progression, and improved quality of life.

Gel Stent Versus Trabeculectomy: The Randomized, Multicenter, Gold-Standard Pathway Study (GPS) of Effectiveness and Safety at 12 Months.

PURPOSE: To compare effectiveness and safety of the gel stent to trabeculectomy in open-angle glaucoma (OAG). DESIGN: Prospective, randomized, multicenter, noninferiority study. METHODS: Patients with OAG and intraocular pressure (IOP) 15 to 44 mm Hg on topical IOP-lowering medication were randomized 2:1 to gel stent implantation or trabeculectomy. Primary end point (surgical success): percentage of patients at month 12 achieving ≥20% IOP reduction from baseline without medication increase, clinical hypotony, vision loss to counting fingers, or secondary surgical intervention (SSI) in a noninferiority test with 24% margins. Secondary end points (month 12) included mean IOP and medication count, postoperative intervention rate, visual recovery, and patient-reported outcomes (PROs). Safety end points included adverse events (AEs). RESULTS: At month 12, the gel stent was statistically noninferior to trabeculectomy (between-treatment difference [Δ], -6.1%; 95% CI, -22.9%, 10.8%); 62.1% and 68.2% achieved the primary end point, respectively (P=.487); mean IOP and medication count reductions from baseline were significant (P<.001); and the IOP change-related Δ (2.8 mm Hg) favored trabeculectomy (P=.024). The gel stent resulted in fewer eyes requiring in-office postoperative interventions (P=.024 after excluding laser suture lysis), faster visual recovery (P≤.048), and greater 6-month improvements in visual function problems (ie, PROs; P≤.022). The most common AEs were reduced visual acuity at any time (gel stent, 38.9%; trabeculectomy, 54.5%) and hypotony (IOP <6 mm Hg at any time) (gel stent, 23.2%; trabeculectomy, 50.0%). CONCLUSIONS: At month 12, the gel stent was statistically noninferior to trabeculectomy, per the percentage of patients achieving ≥20% IOP reduction from baseline without medication increase, clinical hypotony, vision loss to counting fingers, or SSI. Trabeculectomy achieved a statistically lower mean IOP, numerically lower failure rate, and numerically lower need for supplemental medications. The gel stent resulted in fewer postoperative interventions, better visual recovery, and fewer AEs.

A mysterious myopic surprise.

A 73-year-old man with an ocular history of inactive age-related macular degeneration and chronic angle-closure glaucoma (CACG) in both eyes recently underwent femtosecond laser-assisted cataract surgery/phacoemulsification and intraocular lens (IOL) implantation with simultaneous Hydrus microstent (Ivantis, Inc.) implantation in the left eye. Although there was some reported subincisional iris prolapse due to intraoperative floppy iris, the case was otherwise uneventful according to the referring surgeon. Two months postoperatively, he was referred to our office for a myopic surprise of approximately 2.0 diopters (D) in the left eye (Figure 1JOURNAL/jcrs/04.03/02158034-202202000-00022/figure1/v/2022-01-26T192641Z/r/image-tiff). Of note, he has a distant history of acute ACG and complicated cataract surgery in the right eye with a failed trabeculectomy. He subsequently had laser peripheral iridoplasty to pull the iris away from the angle in the right eye (Figure 2JOURNAL/jcrs/04.03/02158034-202202000-00022/figure2/v/2022-01-26T192641Z/r/image-tiff). His topical intraocular pressure (IOP)-lowering medications at presentation included dorzolamide-timolol 1 drop twice daily in the left eye and 1 drop of timolol in the right eye once daily. His past medical history is significant for hypertension and benign prostatic hyperplasia, and his oral medications include Tamsulosin (Flomax), Irbasartan (Avapro), and Atenolol. On examination, he had an UCDVA of 20/20 in the right eye and 20/80 in the left eye, and a BCDVA of 20/20 in the right eye and 20/25 in the left eye. His manifest refraction was plano in the right eye and 1.50 -0.75 × 90 in the left eye. IOP measured 19 mm Hg in the right eye and 26 mm Hg in the left eye. Pupil examination revealed a nonreactive pupil in the right eye and a round sluggish pupil in the left eye without an obvious relative afferent pupillary defect. Extraocular motility and confrontational visual fields were full in both eyes. On slitlamp examination, pertinent findings included the following: 1+ corneal guttata without edema in both eyes; anterior chambers were shallow but adequate in both eyes with scattered peripheral anterior synechiae in the right eye and a uniformly shallow but adequate chamber in the left eye; there was no cell or flare in either eye. Iris findings included a surgical pupil with a fibrotic pupillary membrane, laser iridoplasty scars with scattered temporal transillumination defects (TIDs) in the right eye, and 2.5 clock hours of TIDs and a patent peripheral iridotomy at 1 o'clock in the left eye; lens examination revealed centered posterior chamber IOLs with open posterior capsules in both eyes and lens pitting in the left eye. Pertinent findings on dilated fundus examination included a cup-to-disc ratio of 0.3 in both eyes with good neuroretinal rims and macular examination revealed medium-sized drusen with pigment clumping in both eyes and no active choroidal neovascular membranes. The remainder of the examination was unremarkable. What is the etiology of this myopic surprise? What diagnostic testing will help confirm the diagnosis and what are the best management options for this patient?

Diagnostic Performance of Macular Versus Peripapillary Vessel Parameters by Optical Coherence Tomography Angiography for Glaucoma.

PURPOSE: To compare the diagnostic ability of the vessel parameters in macular and peripapillary regions measured using spectral-domain optical coherence tomography angiography (SD-OCTA) in differentiating primary open-angle glaucoma (POAG) from healthy eyes. METHODS: POAG patients and healthy subjects underwent 6 × 6-mm scans centered on the macula and optic nerve head. Commercially available automatic segmentation created en face images from SD-OCTA of the superficial retinal layer (SRL) of the macular (m) and peripapillary (cp) regions. Vessel area density (VAD), vessel skeleton density (VSD), vessel complexity index (VCI), and flux were calculated. Area under curve (AUC) statistics controlled for age and intereye correlation. RESULTS: Of 126 eyes from 79 patients who underwent SD-OCTA macula and peripapillary imaging, 50 eyes from 35 POAG patients and 37 healthy eyes from 25 control subjects had good quality imaging and were studied. Diagnostic accuracies of four perfusion parameters, VAD, VSD, VCI, and flux, were significantly greater in the peripapillary compared with the macular regions. For VAD, the cpAUC was 0.84 and mAUC was 0.73 (AUC difference: P = 0.026). For VSD, the cpAUC was 0.84 and mAUC was 0.72 (ΔP = 0.015). For VCI, the cpAUC was 0.80 and mAUC was 0.70 (ΔP = 0.045). For flux, the cpAUC = 0.87 and mAUC was 0.76 (ΔP = 0.0091). CONCLUSIONS: Peripapillary perfusion parameters performed better than macular perfusion parameters for glaucoma diagnosis, supporting the idea that glaucomatous superficial retinal vascular changes are more pronounced in the peripapillary region. TRANSLATIONAL RELEVANCE: The diagnostic accuracy of OCTA perfusion parameters of the superficial retinal microcirculation was greater for the peripapillary region than the macular region in the diagnosis of glaucoma.

Biomechanical Responses of Lamina Cribrosa to Intraocular Pressure Change Assessed by Optical Coherence Tomography in Glaucoma Eyes.

Purpose: The purpose of this study was to measure change in anterior lamina cribrosa depth (ALD) globally and regionally in glaucoma eyes at different intraocular pressures (IOP). Methods: Twenty-seven glaucoma patients were imaged before and after IOP-lowering procedures using optical coherence tomography. The anterior lamina was marked in approximately 25 locations in each of six radial scans to obtain global and regional estimates of ALD. ALD and its change with IOP were compared with optic disc damage, nerve fiber layer thickness, and visual field loss. Results: Variables associated with deeper baseline ALD included larger cup/disc ratio, thinner rim area, larger cup volume, thinner central corneal thickness, and male sex (all P ≤ 0.02). When IOP was lowered, ALD position became more anterior, more posterior, or was unchanged. The mean ALD change after lowering was 27 ± 142 µm (P = 0.3). The mean absolute value of ALD change was 112 ± 90 µm (P = 0.002). Change in ALD was greater in eyes with lower IOP in paired comparisons (P = 0.006) but was not associated with the magnitude of IOP lowering between imaging sessions (P = 0.94). Eyes with no significant change in ALD tended to have more visual field loss than those with significant anterior ALD displacement (P = 0.07). Areas within each optic nerve head that corresponded to zones with thicker nerve fiber layer had greater ALD positional change (P = 0.0007). Conclusions: The lamina can move either anteriorly or posteriorly with IOP decrease, with greater displacement at lower IOP. Glaucoma eyes and regions within glaucoma eyes associated with greater glaucoma damage exhibited smaller responses.

Diabetic Risk Factors Promote Islet Amyloid Polypeptide Misfolding by a Common, Membrane-mediated Mechanism.

The current diabetes epidemic is associated with a diverse set of risk factors including obesity and exposure to plastics. Notably, significant elevations of negatively charged amphiphilic molecules are observed in obesity (e.g. free fatty acids and phosphatidic acid) and plastics exposure (monophthalate esters). It remains unclear whether these factors share pathogenic mechanisms and whether links exist with islet amyloid polypeptide (IAPP) misfolding, a process central to ß-cell dysfunction and death. Using a combination of fluorescence, circular dichroism and electron microscopy, we show that phosphatidic acid, oleic acid, and the phthalate metabolite MBzP partition into neutral membranes and enhance IAPP misfolding. The elevation of negative charge density caused by the presence of the risk factor molecules stabilizes a common membrane-bound α-helical intermediate that, in turn, facilitates IAPP misfolding. This shared mechanism points to a critical role for the membrane-bound intermediate in disease pathogenesis, making it a potential target for therapeutic intervention.

Fibril structure of human islet amyloid polypeptide.

Misfolding and amyloid fibril formation by human islet amyloid polypeptide (hIAPP) are thought to be important in the pathogenesis of type 2 diabetes, but the structures of the misfolded forms remain poorly understood. Here we developed an approach that combines site-directed spin labeling with continuous wave and pulsed EPR to investigate local secondary structure and to determine the relative orientation of the secondary structure elements with respect to each other. These data indicated that individual hIAPP molecules take up a hairpin fold within the fibril. This fold contains two ß-strands that are much farther apart than expected from previous models. Atomistic structural models were obtained using computational refinement with EPR data as constraints. The resulting family of structures exhibited a left-handed helical twist, in agreement with the twisted morphology observed by electron microscopy. The fibril protofilaments contain stacked hIAPP monomers that form opposing ß-sheets that twist around each other. The two ß-strands of the monomer adopt out-of-plane positions and are staggered by about three peptide layers (∼15 Å). These results provide a mechanism for hIAPP fibril formation and could explain the remarkable stability of the fibrils. Thus, the structural model serves as a starting point for understanding and preventing hIAPP misfolding.

The effect of curcumin on human islet amyloid polypeptide misfolding and toxicity.

Type 2 diabetes involves aberrant misfolding of human islet amyloid polypeptide (h-IAPP) and resultant pancreatic amyloid deposits. Curcumin, a biphenolic small molecule, has offered potential benefits in other protein misfolding diseases, such as Alzheimer's disease. Our aim was to investigate whether curcumin alters h-IAPP misfolding and protects from cellular toxicity at physiologically relevant concentrations. The effect of curcumin on h-IAPP misfolding in vitro was investigated by electron paramagnetic resonance spectroscopy, ThT fluorescence and electron microscopy. Our in vitro studies revealed that curcumin significantly reduces h-IAPP fibril formation and aggregates formed in the presence of curcumin display alternative morphology and structure. We then tested a potential protective effect of curcumin against h-IAPP toxicity on ß-cells. Micromolar concentrations of curcumin partially protect INS cells from exogenous IAPP toxicity. This protective effect, however, is limited to a narrow concentration range, as curcumin becomes cytotoxic at micromolar concentrations. In different models of endogenous over-expression of h-IAPP (INS cells and h-IAPP transgenic rat islets), curcumin failed to protect ß-cells from h-IAPP-induced apoptosis. While curcumin has the ability to inhibit amyloid formation, the present data suggest that, without further modification, it is unlikely to be therapeutically useful in protection of ß-cells in type 2 diabetes.

Annexin A5 directly interacts with amyloidogenic proteins and reduces their toxicity.

Protein misfolding is a central mechanism for the development of neurodegenerative diseases and type 2 diabetes mellitus. The accumulation of misfolded alpha-synuclein protein inclusions in the Lewy bodies of Parkinson's disease is thought to play a key role in pathogenesis and disease progression. Similarly, the misfolding of the beta-cell hormone human islet amyloid polypeptide (h-IAPP) into toxic oligomers plays a central role in the induction of beta-cell apoptosis in the context of type 2 diabetes. In this study, we show that annexin A5 plays a role in interacting with and reducing the toxicity of the amyloidogenic proteins, h-IAPP and alpha-synuclein. We find that annexin A5 is coexpressed in human beta-cells and that exogenous annexin A5 reduces the level of h-IAPP-induced apoptosis in human islets by approximately 50% and in rodent beta-cells by approximately 90%. Experiments with transgenic expression of alpha-synuclein in Caenorhabditis elegans show that annexin A5 reduces alpha-synuclein inclusions in vivo. Using thioflavin T fluorescence, electron microscopy, and electron paramagnetic resonance, we provide evidence that substoichiometric amounts of annexin A5 inhibit h-IAPP and alpha-synuclein misfolding and fibril formation. We conclude that annexin A5 might act as a molecular safeguard against the formation of toxic amyloid aggregates.

Nebivolol inhibits vascular smooth muscle cell proliferation by mechanisms involving nitric oxide but not cyclic GMP.

The objective of this study was to elucidate the mechanisms by which nebivolol, a cardio-selective beta-adrenergic receptor antagonist, inhibits rat aortic smooth muscle cell (RASMC) proliferation. Nebivolol was compared with DETA-NO and S-nitroso-N-acetylpenicillamine (SNAP), two nitric oxide (NO) donor agents, and alpha-difluoromethylornithine (DFMO), a known inhibitor of ornithine decarboxylase (ODC). All four test agents inhibited RASMC proliferation in a concentration-dependent manner, with nebivolol being the most potent (IC(50) = 4.5 microM), whereas atenolol, another relatively selective beta(1)-blocker, was inactive. DFMO, nebivolol, and DETA-NO interfered with cell proliferation in a cell-density-dependent manner, the lower the cell density the greater the inhibition of cell proliferation. The cytostatic effects of nebivolol and DETA-NO were completely independent of cyclic GMP, as neither ODQ (cytosolic guanylyl cyclase inhibitor) nor zaprinast (cyclic GMP phosphodiesterase inhibitor) affected the antiproliferative action of nebivolol or DETA-NO. The cytostatic effects of nebivolol, SNAP, and DFMO were largely prevented by the addition of excess putrescine, but not ornithine, to cell cultures. Moreover, nebivolol caused a marked reduction in the intracellular levels of putrescine, spermidine, and spermine. Like DFMO, nebivolol and DETA-NO interfered with the G(1)-phase to S-phase cell cycle transition in RASMC. These observations confirm previous findings that DFMO and NO interfere with RASMC proliferation by inhibiting ODC and polyamine production and provide evidence that nebivolol works by the same mechanism.