Model of zonular forces on the lens capsule during accommodation.

How the human eye focuses for near; i.e. accommodates, is still being evaluated after more than 165 years. The mechanism of accommodation is essential for understanding the etiology and potential treatments for myopia, glaucoma and presbyopia. Presbyopia affects 100% of the population in the fifth decade of life. The lens is encased in a semi-elastic capsule with attached ligaments called zonules that mediate ciliary muscle forces to alter lens shape. The zonules are attached at the lens capsule equator. The fundamental issue is whether during accommodation all the zonules relax causing the central and peripheral lens surfaces to steepen, or the equatorial zonules are under increased tension while the anterior and posterior zonules relax causing the lens surface to peripherally flatten and centrally steepen while maintaining lens stability. Here we show with a balloon capsule zonular force model that increased equatorial zonular tension with relaxation of the anterior and posterior zonules replicates the topographical changes observed during in vivo rhesus and human accommodation of the lens capsule without lens stroma. The zonular forces required to simulate lens capsule configuration during in vivo accommodation are inconsistent with the general belief that all the zonules relax during accommodation.

Concerning Syfovre Approval for Geographic Atrophy.

This Viewpoint discusses concerns about Syfovre being approved as a treatment to slow the rate of geographic atrophy.

Finite element analysis of zonular forces.

To determine the effect of zonular forces on lens capsule topography, a finite element (FE) analyses of lens capsules with no lens stroma and constant and variable thickness with anterior capsulotomies of 1.5 mm-6.5 mm were evaluated when subjected to equatorial (Ez), anterior (Az) and posterior (Pz) zonular forces. The lens capsule was considered in the unaccommodated state when the total initial zonular force was 0.00075 N or 0.3 N. From the total 0.00075 N zonular force, the Ez force was increased in 0.000125 N steps for a maximum force of 0.03 N and simultaneously the Az plus Pz force was reduced in 0.000125 N steps to zero. In addition, the force of all the zonules was reduced from 0.00075 N and separately from 0.3 N in 0.000125 N steps to zero. Only when Ez force was increased as Az and Pz force was reduced did the capsule topography simulate in vivo observations with the posterior capsule pole bowing posteriorly. The posterior bowing was directly related to Ez force and capsulotomy size. Whether the total force of all the zonules in the unaccommodated state was 0.00075 N or 0.3 N and reduced in steps to zero, the lens capsule topography did not emulate the in vivo observations. The FE analysis demonstrated that Ez tension increases while the Az and Pz tension decreases and that all the zonules do not relax during ciliary muscle contraction.

Ocular Penetrance and Safety of the Dopaminergic Prodrug Etilevodopa.

Purpose: Animal models have demonstrated the role of dopamine in regulating axial elongation, the critical feature of myopia. Because frequent delivery of dopaminergic agents via peribulbar, intravitreal, or intraperitoneal injections is not clinically viable, we sought to evaluate ocular penetration and safety of the topically applied dopaminergic prodrug etilevodopa. Methods: The ocular penetration of dopamine and dopaminergic prodrugs (levodopa and etilevodopa) were quantified using an enzyme-linked immunosorbent assay in enucleated porcine eyes after a single topical administration. The pharmacokinetic profile of the etilevodopa was then assessed in rats. A four-week once-daily application of etilevodopa as a topical eye drop was conducted to establish its safety profile. Results: At 24 hours, the studied prodrugs showed increased dopaminergic derivatives in the vitreous of porcine eyes. Dopamine 0.5% (P = 0.0123) and etilevodopa 10% (p = 0.370) achieved significant vitreous concentrations. Etilevodopa 10% was able to enter the posterior segment of the eye after topical administration in rats with an intravitreal half-life of eight hours after single topical administration. Monthly application of topical etilevodopa showed no alterations in retinal ocular coherence tomography, electroretinography, caspase staining, or TUNEL staining. Conclusions: At similar concentrations, no difference in ocular penetration of levodopa and etilevodopa was observed. However, etilevodopa was highly soluble and able to be applied at higher topical concentrations. Dopamine exhibited both high solubility and enhanced penetration into the vitreous as compared to other dopaminergic prodrugs. Translational Relevance: These findings indicate the potential of topical etilevodopa and dopamine for further study as a therapeutic treatment for myopia.

An anchoring molecule increases intravitreal retention of antibody-based therapeutics used in the treatment of ocular diseases.

Intravitreal delivery of antibody-based therapeutics has revolutionized the treatment of intraocular vascular diseases involving the retina and choroid. Unfortunately, limited durability requires frequent retreatment placing an enormous burden on patients. We sought to solve this problem with a novel approach that uses an anchoring molecule characterized by two key molecular properties: (1) non-covalent binding to an antibody-based therapeutic, and (2) retention in the vitreous cavity. As an initial proof-of-principle, we chose an anchoring molecule composed of agarose microbeads functionalized with an Fc-binding domain. Bevacizumab was chosen as the antibody-based therapeutic. In vitro experiments demonstrated that bevacizumab was maximally bound to this anchoring molecule within 1 h, and was competitively released upon exposure to either polyclonal human (p < 0.0001) or rat (p = 0.0017) immunoglobulins. In silico modeling predicted prolonged intravitreal retention of an antibody-based therapeutic in the presence of this anchoring molecule, which was confirmed by in vivo experiments with this initial anchoring molecule in rats. This anchoring molecule increased the intraocular half-life of bevacizumab from 5.8 days to over 18 days and maintained therapeutic concentrations for over 80 days. Despite showing no evidence of direct cellular toxicity, this anchoring molecule collected in the anterior vitreous, partially obscuring retinal visualization and eliciting a mild chronic microglial/macrophage inflammatory response. These studies provide a plausible approach to the development of novel non-covalent methods of binding, retention, and release of antibody-based therapeutics in the vitreous.

Surgical timing and presence of a vitreoretinal fellow on postoperative adverse events following pars plana vitrectomy.

INTRODUCTION: To evaluate the adverse event rate following pars plana vitrectomy as a function of surgical start time and the presence of a vitreoretinal fellow. METHODS: Single-institution retrospective cohort study of patients undergoing pars plana vitrectomy from 1 January 2016 to 31 December 2016 at Stanford University School of Medicine (Palo Alto, CA, USA). Records were reviewed for surgical start time, the presence of vitreoretinal fellow, and postoperative adverse events defined as any finding deviating from the expected postoperative course requiring observation or intervention. RESULTS: A total of 310 pars plana vitrectomies were performed. There was no statistical difference in the rate of any adverse event when comparing cases starting after 16:01 (9/13, 69.2%) and after 12:01 (42/99, 42.4%) to a morning start time (69/198, 34.9%, adjusted p = 0.083). There was a statistically significant increase in the risk of postoperative vitreous hemorrhage with afternoon and evening cases as compared to morning cases (adjusted p = 0.021). In addition, there was no difference in any adverse event with a fellow present (93/244, 38.1%) compared to without (27/66, 40.9%, adjusted p = 0.163). There was a higher risk of postoperative hypotony when a fellow was involved (6.6% vs 0%, p = 0.028), though this difference disappeared after adjusting for confounders (adjusted p = 0.252). There was no difference in the length of surgery with and without a fellow (49 vs 54 min, respectively; p = 0.990). DISCUSSION: Afternoon start time and the presence of a fellow were not independent risk factors for postoperative adverse events.

Posterior Scleritis.

The patient is a 19-year-old female who presented with 3 weeks of right eye pain, eyelid swelling, blurry vision, and headache. Visual acuity was counting fingers at 1 foot. Intraocular pressure was normal, and there was diffuse scleral injection on anterior examination. She had a mild anterior chamber reaction with 15 cells/high-powered field and a mild vitreous inflammatory reaction. Fundus examination revealed diffuse choroidal thickening with multilobulated serous retinal detachments worse inferiorly (Figures 1 and 2). Fluorescein angiography demonstrated severe optic disc leakage. Ultrasonography demonstrated diffuse choroidal thickening, a serous retinal detachment, and a prominent "T-sign" (Figure 3). The patient was diagnosed with posterior scleritis and treated with 80 mg of oral prednisone. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:660.].

Image registration of the human accommodating eye demonstrates equivalent increases in lens equatorial radius and central thickness.

AIM: To compare the results of in vivo human high resolution image registration studies of the eye during accommodation to the predictions of mathematical and finite element models of accommodation. METHODS: Data from published high quality image registration studies of pilocarpine induced accommodative changes of equatorial lens radius (ELR) and central lens thickness (CLT) were statistically analyzed. RESULTS: The mean changes in ELR and CLT were 6.76 µm/diopter and 6.51 µm/diopter, respectively. The linear regressions, reflecting the association between ELR and accommodative amplitude (AAELR) was: slope=6.58 µm/diopter, r2 =0.98, P<0.0001 and between CLT and AACLT was: slope=6.75 µm/diopter, r2 =0.83, P<0.001. On the basis of these relationships, the CLT slope and the AAELR were used to predict the measured change in ELR (ELRpredicted). There was no statistical difference between ELRpredicted and the measured ELR as demonstrated by a Student's paired t-test: P=0.96 and linear regression analysis: slope=0.97, r2 =0.98, P<0.00001. CONCLUSION: Image registration with invariant positional references demonstrates that ELR and CLT equivalently minimally increase ∼7.0 µm/diopter during accommodation. The small equivalent increases in ELR and CLT are associated with a large accommodative amplitude. These findings are consistent with the predictions of mathematical and finite element models that specified the stiffness of the lens nucleus is the same or greater than the lens cortex and that accommodation involves a small force (<5 g).

Reductions in final visual acuity occur even within the first 3 days after a macula-off retinal detachment.

PURPOSE: To determine if final visual acuity (VA) is affected by duration of macular detachment (DMD) within the first week of macula-off retinal detachment (RD). METHODS: This is a retrospective study of eyes that underwent repair within 7 days with vitrectomy or vitrectomy with scleral buckle for macula-off RD at Stanford University Hospital between 1 May 2007 and 1 May 2017. A generalised linear model was constructed using DMD, postoperative lens status, preoperative VA, patient age and surgeon as the independent variables and the final VA as the dependent variable. The main outcome measure was the final VA. RESULTS: Seventy-nine eyes met the entry criteria. Group 1 included 52 eyes with RD repaired within 3 days of DMD, and group 2 included 27 eyes repaired between 4 and 7 days of DMD. The average final VA in group 1 eyes was logarithm of the minimum angle of resolution (logMAR) 0.21 (Snellen 20/33) and in group 2 eyes was logMAR 0.54 (Snellen 20/69). In group 1 and group 2 eyes, preoperative VA (p=0.017and p=0.007), DMD (p=0.004 and p=0.041) and final lens status (p<0.0001 and p<0.001) predicted postoperative VA. Post-hoc analysis showed significant differences in final VA between detachments of 1day vs 3 days (p=0.0009). CONCLUSION: DMD affects the final VA even among patients whose DMD is <3 days. Based on these results, interventions that shorten DMD, including those occurring within the first 3days, may result in improved long-term VA outcomes.

A Spectrum of Regression Following Intravitreal Bevacizumab in Retinopathy of Prematurity.

PURPOSE: To describe an improved understanding of the regression patterns following off-label intravitreal bevacizumab (IVB) treatment for retinopathy of prematurity (ROP). DESIGN: Retrospective cohort study. METHODS: All infants treated with IVB for type 1 ROP at a single institution from June 2013 to March 2018 were retrospectively reviewed and the amount of retinal nonperfusion on fluorescein angiogram was calculated. RESULTS: In the 92 eyes of 46 patients analyzed, only 3 eyes (3.3%) reached full vascular maturity. Of the 89 eyes not reaching maturity, 39 eyes (43.8%) had vascular arrest alone (VAA), 34 eyes (38.2%) had vascular arrest with persistent tortuosity (VAT), and 16 eyes (18.0%) had ROP reactivation. Those eyes that reactivated were more likely to be initially classified as having aggressive posterior ROP (P = .004) and of Asian ethnicity (P = .008). There were greater areas of ischemia in eyes with reactivation as compared to VAT and VAA (112.1 mm2 vs 72.5 mm2 vs 56.6 mm2, respectively, P = .007). Younger gestational age at birth was found to be an independent predictor of persistent tortuosity (VAT vs VAA) in a logistic regression model. CONCLUSIONS: Incomplete vascularization following IVB is very common and is associated with a younger gestational age at birth, Asian ethnicity, and aggressive posterior ROP. The presence of tortuosity following IVB may be indicative of persistently elevated vascular endothelial growth factor levels and an early indicator of potential reactivation.

Mechanisms of electrical vasoconstriction.

BACKGROUND: Electrical vasoconstriction is a promising approach to control blood pressure or restrict bleeding in non-compressible wounds. We explore the neural and non-neural pathways of electrical vasoconstriction in-vivo. METHODS: Charge-balanced, asymmetric pulses were delivered through a pair of metal disc electrodes. Vasoconstriction was assessed by measuring the diameter of rat saphenous vessels stimulated with low-voltage (20 V, 1 ms) and high-voltage (150 V, 10 µs) stimuli at 10 Hz for 5 min. Activation pathways were explored by topical application of a specific neural agonist (phenylephrine, alpha-1 receptor), a non-specific agonist (KCl) and neural inhibitors (phenoxybenzamine, 25 mg/ml; guanethidine, 1 mg/ml). Acute tissue damage was assessed with a membrane permeability (live-dead) fluorescent assay. The Joule heating in tissue was estimated using COMSOL Multiphysics modeling. RESULTS: During stimulation, arteries constricted to 41 ± 8% and 37 ± 6% of their pre-stimulus diameter with low- and high-voltage stimuli, while veins constricted to 80 ± 18% and 40 ± 11%, respectively. In arteries, despite similar extent of constriction, the recovery time was very different: about 30 s for low-voltage and 10 min for high-voltage stimuli. Neural inhibitors significantly reduced low-voltage arterial constriction, but did not affect high-voltage arterial or venous constriction, indicating that high-voltage stimuli activate non-neural vasoconstriction pathways. Adrenergic pathways predominantly controlled low-voltage arterial but not venous constriction, which may involve a purinergic pathway. Viability staining confirmed that stimuli were below the electroporation threshold. Modeling indicates that heating of the blood vessels during stimulation (< 0.2 °C) is too low to cause vasoconstriction. CONCLUSIONS: We demonstrate that low-voltage stimuli induce reversible vasoconstriction through neural pathways, while high-voltage stimuli activate non-neural pathways, likely in addition to neural stimulation. Different stimuli providing precise control over the extent of arterial and venous constriction as well as relaxation rate could be used to control bleeding, perfusion or blood pressure.

Outcomes of Intravitreal Bevacizumab and Diode Laser Photocoagulation for Treatment-Warranted Retinopathy of Prematurity.

BACKGROUND AND OBJECTIVE: To investigate the outcomes of infants with treatment-warranted retinopathy of prematurity (TW-ROP) who received intravitreal bevacizumab (Avastin; Genentech, South San Francisco, CA) (IVB) injections as compared to diode laser photocoagulation (DLP). PATIENTS AND METHODS: Data from the Stanford University Network for Diagnosis of Retinopathy of Prematurity database and inpatients at Stanford Children's Hospital were retrospectively reviewed for premature newborns with TW-ROP treated with DLP or 0.625 mg of IVB. Patient characteristics, hospital course, and neurodevelopmental outcomes were compared. RESULTS: In all, 49 eyes from 25 patients were included; 10 infants (20 eyes) received DLP and 15 infants (29 eyes) received IVB. The IVB infants had significantly fewer diagnoses at the time of discharge and fewer readmissions after initial hospital discharge than the DLP infants (four versus six diagnoses, P = .004; zero versus one readmission, P = .038). At an average of 20 months corrected age, there was no significant difference in neurodevelopmental delay (adjusted odds ratio = 0.87; 95% CI, 0.08-9.46). CONCLUSION: Systemic morbidity may be similar among infants treated initially with bevacizumab compared to DLP. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:126-131.].

Maximum human objectively measured pharmacologically stimulated accommodative amplitude.

PURPOSE: To measure the maximum, objectively measured, accommodative amplitude, produced by pharmacologic stimulation. METHODS: Thirty-seven healthy subjects were enrolled, with a mean age of 20.2±1.1 years, corrected visual acuity of 20/20, and mean spherical equivalent refraction (SER) =-0.83±1.60 diopters. For each subject, the right pupil was dilated with phenylephrine 10%. After 30 minutes, the pupil was measured, the left eye was patched, and the right eye was autorefracted. Pilocarpine 4% was then instilled in the right eye, followed by phenylephrine. At 45 minutes after the pilocarpine, autorefraction and pupil size were again measured. RESULTS: Mean pupil size pre- and postpilocarpine was 8.0±0.8 mm and 4.4±1.9 mm, respectively. Pre- and postpilocarpine, the mean SER was -0.83±1.60 and -10.55±4.26 diopters, respectively. The mean pilocarpine-induced accommodative amplitude was 9.73±3.64 diopters. Five subjects had accommodative amplitudes ≥14.00 diopters. Accommodative amplitude was not significantly related to baseline SER (p-value =0.24), pre- or postpilocarpine pupil size (p-values =0.13 and 0.74), or change in pupil size (p-value =0.37). Iris color did not statistically significantly affect accommodative amplitude (p-value =0.83). CONCLUSION: Following topically applied pilocarpine, the induced objectively measured accommodation in the young eye is greater than or equal to the reported subjectively measured voluntary maximum accommodative amplitude.