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Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. Using genome-wide association single-nucleotide polymorphism data from the Glaucoma Genes and Environment study and National Eye Institute Glaucoma Human Genetics Collaboration comprising 3,108 cases and 3,430 controls, we assessed biologic pathways as annotated in the KEGG database for association with risk of POAG. After correction for genic overlap among pathways, we found 4 pathways, butanoate metabolism (hsa00650), hematopoietic cell lineage (hsa04640), lysine degradation (hsa00310) and basal transcription factors (hsa03022) related to POAG with permuted p

AimsVascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG.MethodsWe used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG.ResultsThe vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P

Purpose: Tonography is the standard method for non-invasive measurement of aqueous humor outflow facility. However, assessment of tonography tracing quality is currently subjective, and acceptance of poor-quality data or inappropriately discarding valid data can bias results. The purpose of this study was to develop an objective method for assessing the quality of tonography tracings., Methods: Pneumatonography tracings were obtained from glaucoma and ocular hypertension patients as part of an ongoing multicenter study of aqueous humor dynamics. Intraocular pressure (IOP) was captured digitally at 40 Hz over 2 minutes. Root mean square error (RMSE) of a linear best-fit line was obtained for each tracing. Each tracing was also graded by seven experienced tonographers using a scale of 1 (worst) to 10 (best) for quality (Expert score). A Reference set of 35 tracings was used to determine the relationship between RMSE values and Expert scores using a logarithmic curve. This relationship was used to calculate a predicted score in a second Test set of 20 tracings. A logarithmic curve was used to account for the fixed range of Expert scores and unbounded upper range for RMSE values. The differences between the predicted scores and the Expert scores were evaluated using Bland-Altman analysis., Results: There was a very strong correlation between predicted and Expert scores (R = 0.94). The mean difference between Expert and predicted scores was -1.01 ± 0.84, and the limits of agreement were between -2.65 and +0.63., Conclusions: Objective assessment of pneumatonography tracings can be performed using RMSE of a fitted line and calculation of a predicted quality score that closely matches scores given by expert graders., Translational Relevance: Tonography tracing quality can now be objectively assessed.

Purpose: Evaluate the relationship between CYP3A4 phenotype, the gene encoding the enzyme that metabolizes exogenous steroids, and the rate of steroid-induced intraocular pressure (IOP) response., Materials and Methods: Lymphocyte-derived DNA sequencing of CYP3A4 from 10073 patients was completed using the PGRN-Seq assay. Subjects with CYP3A4 intermediate metabolizer or slower phenotypes were identified and compared with controls matched by age, race, and sex. All subjects had at least 3 eye exams with at least an exam while on topical/systemic/local steroid in any body location except the eye. Patients with pre-existing glaucoma or glaucoma suspects were excluded., Results: Of the 10,073 patients, there were 63 patients who had CYP3A4 poor or intermediate metabolizer phenotype. Of the 63 patients, 22 had documented steroid use. Fifty-nine percent (13/22) of patients with CYP3A4 poor/intermediate metabolizer had a steroid-induced IOP response of 3 mm Hg or more, significantly higher compared with 23% (5/22) of matched controls ( P =0.031). Although more poor/intermediate metabolizers were steroid responders, the average IOP elevation in steroid responders in both groups was similar (5.0±2.5 mm Hg in CYP3A4 poor/intermediate metabolizers compared with 4.1±2.1 mm Hg in controls, P =0.327). Family history of glaucoma was similar in both groups (7/22 vs. 8/22, P =1.0)., Conclusion: Reduced CYP3A4 phenotypes may help identify patients at a higher risk of steroid-induced IOP elevation., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This research aims to develop a noninvasive ultrasound vibro-elastography technique for assessing ocular lesions including intraocular melanoma and nevus lesions., Method: Wave speed (WS) was noninvasively measured in the lesions at three different frequencies (i.e., 100 Hz, 150 Hz, and 200 Hz). The nearby normal tissue of choroid and sclera was also analyzed as controls. Viscoelasticity of these tissues was analyzed using the wave speed dispersion curve and the Voigt model., Results: In this pilot study of 10 cases (5 melanomas vs. 5 nevus) with ages (mean ± SD) of (53.2 ± 6.82) vs. (72.2 ± 7.71) yo, the WS (m/s), elasticity (kPa) and viscosity (Pa.s) of lesion (melanoma vs. nevus) locations of the eye (i.e., WS @100 Hz: 3.63 vs. 3.09 (m/s), @150 Hz: 4.10 vs. 3.66 (m/s), @200 Hz: 4.78 vs. 4.07 (m/s); elasticity: 9.59 vs. 6.89 (kPa); viscosity: 12.46 vs. 9.26(Pa.s)) were analyzed. There were significant differences of WS ratio (WS close to the surface and WS inside the tumor) between the nevus and melanoma of all three frequencies (i.e., nevus vs. melanoma; @100 Hz: 1.59 vs. 2.95, p = 0.0285; @150 Hz: 1.58 vs. 3.53, p = 0.0054; @200 Hz: 1.70 vs. 3.31, p = 0.0124). The melanoma lesions are stiffer than the nevus lesions. It also shows that the lesion tissues are stiffer than the control tissues. However, there were no significant differences in WS, elasticity, viscosity among melanoma lesions, nevus lesions, and control tissues., Conclusions: We demonstrate for the first time that noninvasive ultrasound vibro-elastography can be used for assessing ocular lesions. The results show that lesion tissues are stiffer than control tissues. They also show that melanoma lesions are stiffer than the nevus lesions. We plan to study more ocular lesion patients and improve the specificity and sensitivity of wave speed or viscoelasticity between lesions and controls., Significance: Ultrasound vibro-elastography is an innovative and noninvasive technique for assessing ocular lesions., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Xiaoming Zhang reports was provided by Mayo Clinic in Rochester. Xiaoming Zhang reports a relationship with Mayo Clinic in Rochester that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Minimally invasive glaucoma surgery (MIGS) offers options for glaucoma treatment that have generally improved safety profiles compared with filtering surgery. MIGS vary in design and procedure, but all angle-based MIGS function by bypassing or removing aqueous humor outflow resistance at the level of the trabecular meshwork. This can lower intraocular pressure but also remove the blood-aqueous barrier. Most studies of MIGS report on relatively short-term safety, but awareness of potential long-term complications is critical for optimal patient management. This case report describes a patient with recurrent and refractory delayed onset spontaneous hyphema after OMNI procedure. To the best of our knowledge, this is the first case report describing this complication of the OMNI surgical system., Competing Interests: Conflict of Interest: None, (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Intraocular pressure is currently the only known reliable, modifiable risk factor for the development and progression of glaucoma. Other risk factors for glaucoma include increasing age, myopia, decreased central corneal thickness, and low corneal hysteresis (CH) measurements. Photoablative keratorefractive surgery including laser assisted in situ keratomileusis (LASIK) has become a common way to treat refractive error, with over 25 million procedures performed in the United States alone. Though myopic LASIK has been associated with a decrease in CH measurements, relatively little is known about the risk of LASIK on glaucoma onset and progression. Here we present an observational study of 4 consecutive relatively young and otherwise healthy glaucoma patients with a history of myopic LASIK who showed progression of paracentral visual field deficits at intraocular pressures of 12 mm Hg or less while being carefully monitored. Therefore, these patients required lower targets of intraocular pressure, in the single-digit range, to slow or halt progression. In this cohort, the average corneal hysteresis was more than 2 standard deviations below normal values. This series suggests that additional study into the association of LASIK and glaucoma is warranted, including the potential risk contribution of diminished CH. These studies may be particularly relevant as patients who underwent LASIK procedures in the early 2000s may now be at increased risk of glaucoma due to the risk factor of age., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Prcis: Damage to disposable selective laser trabeculoplasty (SLT) lenses correlated with the amount of total laser energy. Furthermore, greater lens damage was associated with diminished patient treatment response., Purpose: Disposable SLT lenses have been observed to be damaged during use by laser, potentially affecting therapeutic response. This study sought to identify factors associated with the magnitude of lens damage and its effect on treatment outcomes., Patient and Methods: We analyzed 113 eyes from 82 patients who underwent SLT between 2020 and 2021 at an American academic medical center. For each procedure, we recorded baseline patient characteristics, procedure settings, physician age (as a possible factor causing laser defocus due to accommodation), and area of lens damage. Treatment response was calculated as the difference between preoperative and postoperative intraocular pressure (IOP)., Results: Area of lens damage was associated with greater total laser energy ( r =0.34, P <0.001) and greater mean energy per application ( r =0.37, P <0.001). IOP reduction decreased with increasing lens damage ( r =-0.19, P =0.022). Lens damage was not associated with patient characteristics indicative of glaucoma severity or user settings (physician age and slit lamp used). Greater IOP reduction was associated with higher preop IOP ( r =0.46, P <0.001) and a smaller cup-to-disc ratio ( r =0.22, P =0.036). IOP reduction was not associated with retinal nerve fiber layer thickness, patient age, or the number of glaucoma medications., Conclusions: Increased laser damage to disposable SLT lenses was associated with diminished treatment effect. The amount of damage was correlated with total and average laser energy, but not patient or physician factors. Overall, these findings call for reconsideration of using disposable SLT lenses as part of routine practice., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To determine the trans-lamina cribrosa pressure difference (TLCPD) in a cohort of normal community-based patients and the relationship to primary open-angle glaucoma (POAG) and normal-tension glaucoma (NTG)., Design: Retrospective cohort study of the Mayo Clinic Study of Aging., Participants: The Mayo Clinic Study of Aging is a prospective study evaluating the normal aging population., Methods: Mayo Clinic Study of Aging patients who underwent routine lumbar puncture (LP) studies with eye examinations were reviewed. The trans-lamina cribrosa pressure difference was calculated in 2 contexts of intraocular pressure (IOP): (1) maximum IOP at eye visit closest in time to the LP (closest-in-time TLCPD); and (2) IOP before IOP-lowering treatment (pretreatment IOP and pretreatment TLCPD) in POAG and NTG patients. Glaucoma patients without POAG or NTG were excluded. Regression analyses were performed to determine the relationship with glaucoma., Main Outcome Measures: IOP, intracranial pressure, TLCPD, POAG, normal-tension glaucoma (NTG) diagnosis, glaucoma parameters., Results: Five hundred forty-eight patients were analyzed. Of these, there were 38 treated glaucoma patients (14 POAG and 24 NTG) and 510 nonglaucomatous patients. Cerebral spinal fluid (CSF) opening pressure was 155.0 ± 42.2 mmH 2 O in nonglaucomatous patients, 144.0 ± 34.0 mmH 2 O in POAG (P = 0.15 vs. nonglaucomatous patients), and 136.6 ± 29.3 mmH 2 O in NTG (P = 0.017 vs. nonglaucomatous patients). Intraocular pressure was 15.47 ± 2.9 mmHg in nonglaucomatous patients, 26.6 ± 3.7 mmHg in POAG, and 17.4 ± 3.4 mmHg in NTG. The closest-in-time TLCPD in the nonglaucomatous cohort was 4.07 ± 4.22 mmHg, which was lower than both the POAG cohort (7.19 ± 3.6 mmHg) and the NTG cohort (5.79 ± 4.5 mmHg, P = 0.04). Pretreatment TLCPD for the overall glaucoma cohort was 10.57 ± 6.1 mmHg. The POAG cohort had a higher pretreatment TLCPD (16.05 ± 5.2 mmHg) than the NTG cohort (7.37 ± 4.1 mmHg; P < 0.0001). Closest-in-time TLCPD for the nonglaucoma cohort (4.07± 4.2 mmHg) was significantly lower than pretreatment TLCPDs for both POAG (16.05 ± 5.2 mmHg; P < 0.0001) and NTG (7.37 ± 4.1 mmHg; P < 0.0001) cohorts., Conclusions: This study establishes the baseline TLCPD in a large cohort of normal, community-based patients. The differences in regression analysis between TLCPD and IOP suggests NTG pathophysiology is partially driven by TLCPD, but is also likely multifactorial., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the intraocular pressure (IOP) reduction of various trabecular procedures (a form of minimally invasive glaucoma surgery [MIGS]) combined with cataract surgery compared with cataract surgery alone, to compare the safety of the various trabecular procedures, and to highlight patient characteristics that may favor one trabecular procedure over another., Methods: A search of English-language peer-reviewed literature in the PubMed database was initially conducted in February 2021 and updated in April 2023. This yielded 279 articles. Twenty studies met initial inclusion and exclusion criteria and were assessed for quality by the panel methodologist. Of these, 10 were rated level I, 3 were rated level II, and 7 were rated level III. Only the 10 level I randomized controlled trials (RCTs) were included in this assessment, and all were subject to potential industry-sponsorship bias., Results: The current analysis focuses on the amount of IOP reduction (in studies that involved medication washout) and on IOP reduction with concurrent medication reduction (in studies that did not involve medication washout). Based on studies that performed a medication washout, adding a trabecular procedure to cataract surgery provided an additional 1.6 to 2.3 mmHg IOP reduction in subjects with hypertensive, mild to moderate open-angle glaucoma (OAG) at 2 years over cataract surgery alone, which itself provided approximately 5.4 to 7.6 mmHg IOP reduction. In other words, adding a trabecular procedure provided an additional 3.8% to 8.9% IOP reduction over cataract surgery alone, which itself provided 21% to 28% IOP reduction. There was no clear benefit of one trabecular procedure over another. Patient-specific considerations that can guide procedure selection include uveitis predisposition, bleeding risk, metal allergy, and narrowing of Schlemm's canal. There are no level I data on the efficacy of trabecular procedures in subjects with pretreatment IOP of 21 mmHg or less., Conclusions: Trabecular procedures combined with cataract surgery provide an additional mild IOP reduction over cataract surgery alone in hypertensive OAG subjects. Additional research should standardize outcome definitions, avoid industry sponsorship bias, and study the efficacy of these procedures in normotensive OAG., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: To determine the appropriateness of ophthalmology recommendations from an online chat-based artificial intelligence model to ophthalmology questions., Patients and Methods: Cross-sectional qualitative study from April 1, 2023, to April 30, 2023. A total of 192 questions were generated spanning all ophthalmic subspecialties. Each question was posed to a large language model (LLM) 3 times. The responses were graded by appropriate subspecialists as appropriate, inappropriate, or unreliable in 2 grading contexts. The first grading context was if the information was presented on a patient information site. The second was an LLM-generated draft response to patient queries sent by the electronic medical record (EMR). Appropriate was defined as accurate and specific enough to serve as a surrogate for physician-approved information. Main outcome measure was percentage of appropriate responses per subspecialty., Results: For patient information site-related questions, the LLM provided an overall average of 79% appropriate responses. Variable rates of average appropriateness were observed across ophthalmic subspecialties for patient information site information ranging from 56% to 100%: cataract or refractive (92%), cornea (56%), glaucoma (72%), neuro-ophthalmology (67%), oculoplastic or orbital surgery (80%), ocular oncology (100%), pediatrics (89%), vitreoretinal diseases (86%), and uveitis (65%). For draft responses to patient questions via EMR, the LLM provided an overall average of 74% appropriate responses and varied by subspecialty: cataract or refractive (85%), cornea (54%), glaucoma (77%), neuro-ophthalmology (63%), oculoplastic or orbital surgery (62%), ocular oncology (90%), pediatrics (94%), vitreoretinal diseases (88%), and uveitis (55%). Stratifying grades across health information categories (disease and condition, risk and prevention, surgery-related, and treatment and management) showed notable but insignificant variations, with disease and condition often rated highest (72% and 69%) for appropriateness and surgery-related (55% and 51%) lowest, in both contexts., Conclusion: This LLM reported mostly appropriate responses across multiple ophthalmology subspecialties in the context of both patient information sites and EMR-related responses to patient questions. Current LLM offerings require optimization and improvement before widespread clinical use., Competing Interests: POTENTIAL COMPETING INTERESTS The authors report no competing interests.

Purpose: To evaluate the current published literature on the utility of the 10-2 visual field (VF) testing strategy for the evaluation and management of early glaucoma, defined here as mean deviation (MD) better than -6 decibels (dB)., Methods: A search of the peer-reviewed literature was last conducted in June 2023 in the PubMed database. Abstracts of 986 articles were examined to exclude reviews and non-English-language articles. After inclusion and exclusion criteria were applied, 26 articles were selected, and the panel methodologist rated them for strength of evidence. Thirteen articles were rated level I, and 8 articles were rated level II. The 5 level III articles were excluded. Data from the 21 included articles were abstracted and reviewed., Results: The central 12 locations on the 24-2 VF test grid lie within the central 10 degrees covered by the 10-2 VF test. In early glaucoma, defects detected within the central 10 degrees generally agree between the 2 tests. Defects within the central 10 degrees of the 24-2 VF test can predict defects on the 10-2 VF test, although the 24-2 may miss defects detected on the 10-2 VF test. In addition, results from the 10-2 VF test show better association with findings from OCT scans of the macular ganglion cell complex. Modifications of the 24-2 test that include extra test locations within the central 10 degrees improve detection of central defects found on 10-2 VF testing., Conclusions: Evidence to date does not support routine testing using 10-2 VF for patients with early glaucoma. However, early 10-2 VF testing may provide sufficient additional information for some patients, particularly those with a repeatable defect within the central 12 locations of the standard 24-2 VF test or who have inner retinal layer thinning on OCT scans of the macula., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the recently published literature on the efficacy and safety of the use of aqueous shunts with extraocular reservoir for the management of adult open-angle glaucomas (OAGs)., Methods: A search of peer-reviewed literature was last conducted in April 2023 of the PubMed database and included only articles published since the last aqueous shunt Ophthalmic Technology Assessment, which assessed articles published before 2008. The abstracts of these 419 articles were examined, and 58 studies were selected for full-text analysis. After inclusion and exclusion criteria were applied, 28 articles were selected and assigned ratings by the panel methodologist according to the level of evidence. Twenty-five articles were rated level I and 3 articles were rated level II. There were no level III articles., Results: Implantation of aqueous shunts with extraocular reservoir can lower intraocular pressure (IOP) by between one-third and one-half of baseline IOP, depending on whether it is undertaken as the primary or secondary glaucoma surgery. Success rates for aqueous shunts were found to be better than for trabeculectomies in eyes with prior incisional surgery. Conversely, in eyes without prior incisional surgery, implantation of aqueous shunts was found to have an overall lower success rate as the primary glaucoma procedure compared with trabeculectomy. Although both valved and nonvalved aqueous shunts with extraocular reservoir were effective, the nonvalved device generally achieved slightly lower long-term IOPs with fewer glaucoma medications and less need for additional glaucoma surgery. Both devices slow the rates of visual field progression with efficacy comparable with that of trabeculectomy. Early aqueous humor suppression after aqueous shunt implantation is recommended for the management of the postoperative hypertensive phase and long-term IOP control. No strong evidence supports the routine use of mitomycin C with aqueous shunt implantation for OAG., Conclusions: Implantation of aqueous shunts with extraocular reservoir, including valved or nonvalved devices, has been shown to be an effective strategy to lower IOP. Strong level I evidence supports the use of aqueous shunts with extraocular reservoir by clinicians for the management of adult OAG., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Uveitis-Glaucoma-Hyphema (UGH) syndrome is characterized by episodes of anterior chamber inflammation, elevated intraocular pressure and hyphema. It is caused by a mechanical chafing of the iris or ciliary body typically by a malpositioned intraocular lens. We present a rare case of UGH syndrome related to the insertion of a Hydrus Microstent. Because of the increased number of microinvasive glaucoma surgeries being performed and a reduction of UGH syndrome patients related to the insertion of intraocular lenses, it is an important diagnosis to consider in patients with recurrent postoperative inflammation., Competing Interests: Disclosure: A.J.S. has received research funding from Aerie Pharmaceuticals, Inc and Qlaris Bio, Inc., and has been a consultant for Allergan, Inc., Injectsense, Inc., PolyActiva, Pty, and Qlaris Bio, Inc. The remaining author declares no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To review the current published literature for high-quality studies on the use of selective laser trabeculoplasty (SLT) for the treatment of glaucoma. This is an update of the Ophthalmic Technology Assessment titled, "Laser Trabeculoplasty for Open-Angle Glaucoma," published in November 2011., Methods: Literature searches in the PubMed database in March 2020, September 2021, August 2022, and March 2023 yielded 110 articles. The abstracts of these articles were examined to include those written since November 2011 and to exclude reviews and non-English articles. The panel reviewed 47 articles in full text, and 30 were found to fit the inclusion criteria. The panel methodologist assigned a level I rating to 19 studies and a level II rating to 11 studies., Results: Data in the level I studies support the long-term effectiveness of SLT as primary treatment or as a supplemental therapy to glaucoma medications for patients with open-angle glaucoma. Several level I studies also found that SLT and argon laser trabeculoplasty (ALT) are equivalent in terms of safety and long-term efficacy. Level I evidence indicates that perioperative corticosteroid and nonsteroidal anti-inflammatory drug eye drops do not hinder the intraocular pressure (IOP)-lowering effect of SLT treatment. The impact of these eye drops on lowering IOP differed in various studies. No level I or II studies exist that determine the ideal power settings for SLT., Conclusions: Based on level I evidence, SLT is an effective long-term option for the treatment of open-angle glaucoma and is equivalent to ALT. It can be used as either a primary intervention, a replacement for medication, or an additional therapy with glaucoma medications., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To investigate the in vivo effect of scleral buckle surgery on ocular biomechanics and aqueous humor dynamics., Design: Prospective observational cross-sectional study., Participants: Nine patients with unilateral 360 degree encircling scleral buckles without vitrectomy for rhegmatogenous retinal detachments, between 3 and 39 months postoperative., Methods: All measurements were performed in both eyes of all participants. Intraocular pressure (IOP) was measured in the seated and supine positions using pneumatonometry. Outflow facility was measured using 2-minute weighted pneumatonography. Ocular rigidity coefficient was determined from the Friedenwald equations based on the difference in IOP with and without a weighted tonometer tip. The percentage change in IOP upon transitioning from seated to supine was calculated. Measurements for buckled and nonbuckled eyes were compared using paired Student t test of means., Main Outcome Measures: Sitting and supine IOP and percentage difference between the 2 positions; outflow facility; ocular rigidity coefficient., Results: Seated IOP was similar between buckled and nonbuckled eyes (16.1 ± 2.5 vs. 16.7 ± 2.7 mmHg; P = 0.5) whereas supine IOP was lower in buckled eyes compared with nonbuckled eyes (18.7 ± 2.6 vs. 21.3 ± 2.5 mmHg; P = 0.008). The percentage increase in IOP upon change in body position from seated to supine was greater in nonbuckled eyes (17.4 ± 9.4% vs. 27.6 ± 9.5%; P = 0.005). Ocular rigidity coefficient was lower in buckled (9.9 × 10 -3 ± 1.4 × 10 -3 μL -1 ) vs. nonbuckled eyes (14.4 × 10 -3 ± 3.1 × 10 -3 μL -1 ; P = 0.006). Outflow facility was not significantly different in buckled and nonbuckled eyes., Conclusions: Scleral buckling decreases ocular rigidity but does not affect outflow facility. This change in ocular biomechanics likely results in the attenuated IOP change from seated to supine position. Decreased ocular rigidity may also reduce IOP fluctuations and potentially reduce the risk for glaucoma progression., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2023 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Objective: The purpose of this study was to evaluate our novel ultrasound vibro-elastography (UVE) technique for assessing patients with papilledema by non-invasively measuring shear wave speed (SWS), elasticity and viscosity properties of the optic nerve and sclera., Methods: Shear wave speeds were measured at three frequencies-100, 150 and 200 Hz-on the optic nerve and sclera tissues for assessing patients with papilledema resulting from idiopathic intracranial hypertension (IIH). The method was evaluated in six papilledema patients and six controls on two separate locations for each participant (i.e., optic nerve and posterior sclera). SWSs of the optic nerve and sclera were analyzed by using a 2-D speed map technique within a circular region of interest (ROI) (i.e., the diameter of the ROI was 1.5 mm × 3.0 mm at the optic nerve and sclera, respectively). Elasticity and viscosity were then analyzed using the wave speed dispersion over the three frequencies., Results: We measured values of SWS at both locations, optic nerve and sclera, of the right eye and left eye at three different frequencies in IIH patients and controls. The SWS (mean ± standard deviation [m/s]) of the right eye was significantly higher at the sclera in IIH patients compared with controls (i.e., patients vs. controls: 5.91 ± 0.54 vs. 3.86 ± 0.56, p < 0.0001 at 100 Hz), but there was no significant difference at the optic nerve (i.e., patients vs. controls: 3.62 ± 0.39 vs. 3.36 ± 0.35, p = 0.1100 at 100Hz). We observed increased elasticity (kPa) in IIH patients, indicating there are significant differences in elasticity between patients and controls at the optic nerve and sclera (i.e., right eye [patients vs. controls]: 14.42 ± 6.59 vs. 6.5 ± 5.71, p = 0.0065 [optic nerve]; 33.04 ± 10.62 vs. 9.16 ± 7.15, p < 0.0001 [sclera]). Viscosity was also (Pa·s) higher in the sclera and optic nerve of the left eye (i.e., left eye [patient vs. control]: 8.89 ± 4.37 vs. 7.27 ± 5.01, p = 0.3790 (optic nerve); 16.05 ± 10.79 vs. 8.49 ± 6.09, p < 0.0194 [sclera])., Conclusion: This research illustrates the feasibility of using our UVE system to evaluate stiffness of different tissues in the eye non-invasively. It suggests that the viscoelasticity of the posterior sclera is higher than that of the optic nerve. We found that the posterior sclera is stiffer than the optic nerve in patients with papilledema resulting from IIH, making UVE a potential non-invasive technique for assessing papilledema., Competing Interests: Conflict of interest The authors declare no competing interests., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Prcis: When comparing patients on systemic immunosuppressive therapy to those without, there was no difference in intraocular pressure (IOP) early after SLT; however, at 1 year following SLT, IOP was higher in the immunosuppression group compared with controls., Purpose: To determine whether patients taking systemic immunosuppressive medications have a different IOP-lowering response to selective laser trabeculoplasty (SLT) compared with a control group of patients., Methods: All patients who underwent SLT at Mayo Clinic 2017-2021 were identified. Patients on systemic immunosuppressive medications at the time of SLT were compared with control patients not receiving systemic immunosuppressive medications. The primary endpoints of this study were the percentage IOP reduction at 1 to 2, 3 to 6, and 12 months. Additional analyses included the percentage of patients who did not require additional therapy at each time point., Results: There were 108 eyes of 72 patients that underwent SLT in the immunosuppressed group and 1997 eyes of 1417 patients in the control group. There was no significant difference in age-adjusted change in IOP between groups at the first postoperative visit 1 to 2 months following SLT (-18.8±20.7% vs. -16.0±16.5%, P =0.256) or 3-6 months following SLT (-15.2±21.6% vs. -18.3±23.2%, P =0.062). However, at 12 months following SLT, the IOP reduction in the immunosuppressive therapy group was significantly less compared with the control group (-15.1±21.2% vs. -20.3±22.9%, P =0.045). There was no difference between groups in the number of additional treatments during the study intervals., Conclusion: Patients in the systemic immunosuppressive therapy group showed equivalent early IOP-lowering after SLT compared with a control group, but the treatment response was diminished at 1 year. Further studies investigating IOP regulation after SLT in immunosuppressed patients are needed., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To review the current published literature on the utility of corneal hysteresis (CH) to assist the clinician in the diagnosis of glaucoma or in the assessment of risk for disease progression in existing glaucoma patients., Methods: Searches of the peer-reviewed literature in the PubMed database were performed through July 2022. The abstracts of 423 identified articles were examined to exclude reviews and non-English articles. After inclusion and exclusion criteria were applied, 19 articles were selected, and the panel methodologist rated them for level of evidence. Eight articles were rated level I, and 5 articles were rated level II. The 6 articles rated level III were excluded., Results: Corneal hysteresis is lower in patients with primary open-angle glaucoma, primary angle-closure glaucoma, pseudoexfoliative glaucoma, and pseudoexfoliation syndrome compared with normal subjects. Interpretation of low CH in patients with high intraocular pressure (IOP) or on topical hypotensive medications is complicated by the influence of these parameters on CH measurements. However, CH is also lower in treatment-naïve, normal-tension glaucoma patients compared with normal subjects who have a similar IOP. In addition, lower CH is associated with an increased risk of progression of glaucoma based on visual fields or structural markers in open-angle glaucoma patients, including those with apparently well-controlled IOP., Conclusions: Corneal hysteresis is lower in glaucoma patients compared with normal subjects, and lower CH is associated with an increased risk of disease progression. However, a causal relationship remains to be demonstrated. Nevertheless, measurement of CH complements current structural and functional assessments in determining disease risk in glaucoma suspects and patients., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2022. Published by Elsevier Inc.)

Purpose: To improve understanding of intraocular pressure (IOP) and its variance, this project identifies systemic and ocular characteristics of healthy eyes of adult volunteers including IOP variation, ocular biometrics, and aqueous humor dynamics (AHDs). These data serve as baseline controls for further studies from the Eye Dynamics and Engineering Network (EDEN) Consortium., Design: Multicenter open-label clinical trial in healthy adults randomized to 1 week treatment with 2 approved glaucoma drugs in a crossover design., Participants: Among 135 healthy participants, 122 participants (aged 55.2 ± 8.8 years; 92 females, 30 males) completed the protocol., Methods: Participants from the University of Michigan, Mayo Clinic, and University of Nebraska Medical Center underwent measurements of ocular biometrics, AHD, and IOP using 4 tonometers. Intraocular pressure data during 3 study visits without glaucoma medications were used in the analysis. The PhenX Toolkit survey acquired standardized data on medical history, surgical history, medications, smoking and alcohol exposures, and physical measures., Main Outcome Measures: The variability of IOP measurements within eyes was assessed as visit-to-visit IOP variation, within-visit IOP variation, and within-visit positional IOP variation. The concordance (or correlation) between eyes was also assessed., Results: Average positional change of > 4.7 mmHg was detected with a range of 0.5-11.0 mmHg. Pearson correlation of IOP between eyes within a visit was 0.87 (95% confidence interval [CI], 0.82-0.91) for Goldmann applanation tonometry, 0.91 (95% CI, 0.88-0.94) for Icare rebound tonometry, and 0.91 (95% CI, 0.88-0.94) for pneumatonometry. There was a 4% to 12% asymmetric fluctuation of 3 mmHg or more between eyes between visits using rebound tonometry, 9% with Goldmann applanation tonometry, and 3% to 4% by pneumotonometry. The coefficient of variation between visits for the same eye ranged from 11.2% to 12.9% for pneumatonometry, from 13.6% to 17.4% for rebound tonometry, and 15.8% to 16.2% for Goldmann applanation tonometry., Conclusions: The current study from the EDEN Consortium describes measurement methods and data analyses with emphasis on IOP variability. Future papers will focus on changes in ocular biometrics and AHD with timolol or latanoprost treatment., Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references., (Copyright © 2022 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To examine the risk, prevalence, and progression of glaucoma development in age-related macular degeneration (AMD) eyes receiving intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections compared to controls., Design: Retrospective clinical cohort study., Methods: Retrospective review of eyes receiving intravitreal anti-VEGF injections from January 1, 2004, to December 31, 2013, for exudative AMD. Age- and sex-matched control groups of eyes included eyes with nonexudative AMD (NEAMD) and no AMD. Eyes with a diagnosis of glaucoma or glaucoma suspect were reviewed for injection details, type and date of glaucoma diagnosis, glaucoma treatments, standard automated perimetry (SAP), and spectral domain optical coherence tomography (SD-OCT). Qualitative progression was determined by indication of glaucoma progression in provider notes. Quantitative progression was assessed based on change in mean deviation (MD) on SAP, retinal nerve fiber layer thickness on SD-OCT, and intraocular pressure (IOP)., Results: There were 707 eyes of 504 patients treated with anti-VEGF injections and 1008 eyes in the NEAMD and no-AMD cohorts. There was no difference in glaucoma or suspect prevalence at initial presentation between eyes treated with injections and NEAMD (6.9% vs 9.7%, P = .22) or no-AMD controls (vs 8.5%, P = .55). There was no difference in cumulative 5-year probability of new glaucoma diagnosis after anti-VEGF injections compared to NEAMD (1.9% vs 1.0%, P = .69) or no-AMD controls (vs 1.6%, P = .88). There was no difference in qualitative progression of glaucoma in the injection cohort vs NEAMD (P = .19) or no-AMD controls (P = .61). The rate of MD change in injection eyes was similar to NEAMD eyes (P = .74) but greater than no-AMD eyes (P = .02). Eyes receiving injections required more topical glaucoma medications compared with NEAMD (P = .03) and more glaucoma laser treatments compared with no-AMD controls (P = .009). Eyes receiving injections did not require more frequent incisional glaucoma surgery compared with NEAMD (21.0% vs 15.0%, P = .95) or no-AMD controls (vs 10.0%, P = .10)., Conclusion: Eyes treated with intravitreal anti-VEGF injections for exudative AMD did not have increased risk of developing glaucoma compared with controls. Of those with a glaucoma diagnosis, exudative AMD eyes receiving injections required a greater number of topical glaucoma medications compared with NEAMD eyes and had a greater rate of MD loss than no-AMD controls., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Glaucoma is a progressive optic neuropathy and the leading cause of irreversible vision loss. By 2040, the number of individuals with glaucoma is expected to nearly double. The only known modifiable risk factor for glaucoma is intraocular pressure. Topical medications are often used as first-line therapies. Although there are numerous available treatments, there continues to be a need for the development of new medical therapies due to variable response, intolerable side-effect profiles in some patients, and elevated intraocular pressure refractory to other treatments., Areas Covered: This review will cover glaucoma medications currently undergoing phase II and III of drug development., Expert Opinion: There are numerous drugs currently in development that have demonstrated significant and clinically relevant reduction of intraocular pressure. Differentiating factors include improved tolerability, novel mechanisms of action, multiple mechanisms of action, or superior IOP reduction. However, the availability of generic prostaglandin analogs may limit adoption of these novel compounds as first-line agents, except for certain subgroups of glaucoma patients. Use as adjuvant or second-line therapy appears more likely for the majority of glaucoma patients.

Trabeculectomy surgery remains the gold standard incisional glaucoma surgical procedure in many practices, particularly for patients requiring intraocular pressure (IOP) in the low teens or below. However, trabeculectomy surgery is associated with complications including leakage, over filtration, or fibrosis of the surgical bleb. Morphology of the surgical bleb is an important predictor of surgical success defined as long-term IOP reduction with minimal to no complications. There have been many, often subtle, variations in the surgical technique in hopes of improving long-term IOP reduction. However, fewer changes have been implemented specifically to modify bleb morphology. In our surgical practice, we began performing a thorough dissection and advancement of Tenon's layer with incorporation into the conjunctival closure in a 2-layered manner. This technique allowed flow of aqueous to a delineated potential space between sclera and Tenon's layer. Our clinical observations were improved bleb morphology characterized by diffuse, low-lying blebs with nonischemic overlying conjunctiva compared with those performed with a more traditional trabeculectomy technique. Since we incorporated this change into our practice at a defined time, we have a small number of patients in our practice that had a more traditional trabeculectomy technique in the fellow eye. Therefore, in our surgical practice, a small number of patients had trabeculectomy in 1 eye before implementation of this new technique, and then had trabeculectomy in the fellow eye after this technique was adopted, providing opportunity for comparison of bleb morphology with and without Tenon advancement. In series we present two representative, index cases and describe our surgical technique., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: The Rho kinase inhibitor netarsudil is a recently approved therapeutic option for the management of increased intraocular pressure in the United States. Although phase 3 clinical trials noted corneal changes related to the medication-namely, nonvisually-significant corneal verticillata-descriptions of a unique form of cystic epithelial edema began to surface as netarsudil (and its sister drug ripasudil, approved in Japan) gained widespread use. This series adds 3 new cases and reviews the current literature on this unique side effect., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To characterize the effects of timolol and latanoprost on calculated ocular perfusion pressure (OPP) in a multicenter, prospective, crossover-design study. Methods: Nonglaucomatous volunteers were evaluated at baseline, after 1 week of timolol 0.5% dosed twice daily, and after 1 week of latanoprost 0.005% dosed nightly (randomized treatment order; 6-week washout period). Pneumatonometric intraocular pressure (IOP) and brachial blood pressure (BP) were evaluated at each visit. Using 3 commonly used equations, OPP was calculated based on IOP and BP. The OPPs at each visit were compared by using linear mixed-effects models. Results: This analysis includes 121 participants (242 eyes; 75% female, 87% White, mean age 55 years). Mean OPP (standard deviation) calculated with mean arterial pressure was 46.8 (8.1) mmHg at baseline, 48.5 (7.9) mmHg with timolol ( P  = 0.005), and 49.6 mmHg (8.2) with latanoprost ( P  < 0.001). When compared with baseline, OPP calculated with diastolic BP was significantly increased with both timolol (1.3 mmHg) and latanoprost (3.1 mmHg). The OPP calculated with systolic BP was increased with latanoprost (2.8 mmHg) but decreased with timolol (-1.3 mmHg). Timolol reduced systolic BP by 3.2 mmHg. Compared with timolol, latanoprost conferred greater increases in OPP calculated with both systolic and diastolic BP compared with baseline; however, the difference in treatment effects on OPP calculated with mean arterial pressure was not significantly different ( P  = 0.068). Conclusion: In this crossover study of nonglaucomatous volunteers, latanoprost increased OPP. However, timolol's benefit to OPP may be limited in part because it reduced systolic BP. Clinical Trial Registration number: NCT01677507.

Purpose: Phenylephrine has been shown to affect intraocular pressure (IOP) but the mechanism of action is poorly understood. However, its action as a vasoconstrictor suggests possible effects on episcleral venous pressure (EVP). In this study, we evaluated the effect of phenylephrine on EVP and IOP in healthy subjects., Methods: Forty eyes of 20 subjects were included. Each subject received 3 drops of phenylephrine 2.5% in one eye at 1-minute intervals. The fellow eye served as control. Blood pressure, heart rate, and IOP and EVP of both eyes were measured at baseline, 15 minutes, and 60 minutes after instillation of phenylephrine. IOP was measured by pneumatonometry. EVP was assessed by using a computer-controlled episcleral venomanometer. Changes in IOP, EVP, blood pressure, and heart rate at 15 and 60 minutes were analyzed by paired t-tests., Results: IOP increased 15 minutes after instillation of phenylephrine in both treated (P = 0.001) and control eyes (P = 0.01) and returned to baseline at 60 minutes. The change in IOP at 15 minutes was not significantly different between the 2 groups. EVP in treated eyes was unchanged at 15 minutes (P = 0.8) but decreased significantly at 60 minutes (P < 0.001). In control eyes, there was no change in EVP at any time (P > 0.6). There were no significant changes from baseline in systolic and diastolic blood pressure and heart rate after instillation of phenylephrine., Conclusions: IOP elevation associated with topical phenylephrine is not caused by an increase in EVP in healthy subjects. Instead, EVP decreases with phenylephrine, but the mechanism remains to be determined.

Precis: Ocular biomechanics were compared between treated glaucoma patients and healthy subjects matched for age, intraocular pressure (IOP), and axial length. There was no difference in corneal wave propagation speed, but ocular rigidity was lower in glaucomatous eyes., Purpose: Ocular biomechanical properties are important in understanding glaucoma pathogenesis but the affected tissues are unclear. In this study, we compared corneal wave speed (a measure of corneal elasticity) and ocular rigidity coefficient between glaucomatous and normal eyes., Materials and Methods: Twenty glaucomatous eyes from 10 patients and 20 normal eyes from 13 controls, matched for age, IOP, and axial length were included. Ocular rigidity was calculated based on the difference in supine IOP by pneumatonometry with and without a 10-g weight. Corneal wave speed was determined by ultrasound surface wave elastography. A small, 0.1-second harmonic vibration at 100 Hz was generated through the closed eyelids. Wave propagation was captured by an ultrasound transducer, and wave speed was determined from the phase change with distance. Comparisons were performed using generalized estimating equation models., Results: There were no significant differences in corneal wave speed between glaucomatous and normal eyes (2.16±0.25 vs. 2.07±0.16 m/s, P=0.17). However, ocular rigidity was significantly lower in glaucomatous eyes (0.0218±0.0033 vs. 0.0252±0.0050/μL, P=0.01). Corneal wave speed was not correlated with age and IOP in either group (P≥0.23) but was correlated with ocular rigidity (R=0.48, P=0.02) and inversely correlated with axial length (R=-0.53, P=0.01) in glaucomatous eyes., Conclusion: Glaucomatous eyes tend to have lower ocular rigidity than healthy eyes with similar age, IOP, and axial length. However, the lack of a difference in corneal wave speed suggests that corneal tissue may not be significantly affected, and scleral changes likely play a more important role in glaucoma., Competing Interests: Disclosure: A.J.S.: Consultant at Aerie Pharmaceuticals Inc., Allergan Inc., Bausch & Lomb Inc., Injectsense Inc., PolyActiva, Pty, and research support at Qlaris Bio Inc. X.Z. is a co-inventor of ultrasound surface wave elastography (Patent number 9044192) but no royalties have been paid. The remaining authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: To review the current published literature on the use of OCT angiography (OCTA) to help detect changes associated with the diagnosis of primary open-angle glaucoma., Methods: Searches of the peer-reviewed literature were conducted in March 2018, June 2018, April 2019, December 2019, and June 2020 in the PubMed and Cochrane Library databases. Abstracts of 459 articles were examined to exclude reviews and non-English articles. After inclusion and exclusion criteria were applied, 75 articles were selected and the panel methodologist rated them for strength of evidence. Three articles were rated level I and 57 articles were rated level II. The 15 level III articles were excluded., Results: OCT angiography can detect decreased capillary vessel density within the peripapillary nerve fiber layer (level II) and macula (level I and II) in patients with suspected glaucoma, preperimetric glaucoma, and perimetric glaucoma. The degree of vessel density loss correlates significantly with glaucoma severity both overall and topographically (level II) as well as longitudinally (level I). For differentiating glaucomatous from healthy eyes, some studies found that peripapillary and macular vessel density measurements by OCTA show a diagnostic ability (area under the receiver operating characteristic curve) that is comparable with structural OCT retinal nerve fiber and ganglion cell thickness measurements, whereas other studies found that structural OCT measurements perform better. Choroidal or deep-layer microvasculature dropout as measured by OCTA is also associated with glaucoma damage (level I and II). Lower peripapillary and macular vessel density and choroidal microvasculature dropout are associated with faster rates of disease progression (level I and II)., Conclusions: Vessel density loss associated with glaucoma can be detected by OCTA. Peripapillary, macular, and choroidal vessel density parameters may complement visual field and structural OCT measurements in the diagnosis of glaucoma., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Precis: Diplopia was present in ~20% of patients with Ahmed FP7 (FP7) or Baerveldt 350 (B350), compared with 5% to 6% in those with Baerveldt 250 (B250) or controls, suggesting risk of diplopia should be included in preoperative counseling., Purpose: The purpose of this study was to examine the prevalence of diplopia and strabismus in patients with B250, B350, or FP7 glaucoma drainage devices (GDD)., Materials and Methods: In this cohort study, glaucoma patients 18 years and above who had received, or would be receiving, a B250, B350, or FP7 GDD, and medically treated controls were consecutively enrolled from August 8, 2017, through July 31, 2019. The Diplopia Questionnaire was administered ≥30 days postoperatively, and upon enrollment to the controls. All diplopic patients underwent orthoptic measurements, which were reviewed by a strabismus specialist. Patients with GDDs in quadrants other than superotemporal, multiple GDDs, or scleral buckles were excluded. Bonferroni correction was applied for pairwise comparisons., Results: Diplopia was reported in 23/129 (17.8%) GDD patients and 5/99 (5.1%) control patients (P=0.003): 8/35 (22.9%) FP7, 2/32 (6.3%) B250, and 13/62 (21.0%) B350, with significant differences between FP7 versus controls (P=0.014) and B350 versus controls (P=0.011). Diplopia was attributable to GDD in 2 FP7 (5.9%, 95% confidence interval: 0.7-19.2), 0 B250, and 4 B350 (6.5%, 95% confidence interval: 1.7-15.2) patients, without significant differences between the GDDs., Conclusions: Patients with the larger (B350) or the higher profile plate (FP7) GDDs were more likely to experience diplopia than controls, and diplopia was attributable to the GDD in ~6% of patients with either a FP7 or a B350 GDD. Since diplopia can affect patients' quality of life, preoperative counseling for GDD surgery, particularly B350 and FP7, should include a discussion of the risk of diplopia., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Intraocular pressure (IOP) reduction is key to controlling primary open angle glaucoma (POAG). Pharmacotherapies for POAG or ocular hypertension (OHT) commonly lower IOP by increasing uveoscleral outflow or decreasing aqueous humor production. Netarsudil (Rhopressa), a Rho kinase inhibitor, reduces IOP by improving trabecular outflow facility, which is reduced in POAG. We investigated the effects of netarsudil on aqueous humor dynamics in patients with POAG or OHT., Design: Double-masked, randomized, vehicle-controlled, Phase 2 trial., Methods: Netarsudil 0.02% was instilled in 1 eye and vehicle into the contralateral eye of 20 patients once daily in the morning for 7 days. The primary endpoint was change in mean diurnal outflow facility on day 8 versus that on day 1 (baseline). Outflow facility was measured by using Schiøtz tonography, IOP by pneumotonometry, and episcleral venous pressure (EVP) by automated venomanometry., Results: Eighteen patients (90%) completed the study. Mean diurnal outflow facility increased 0.039 versus 0.007 µL/min/mm Hg from baseline in the netarsudil- and the vehicle-treated groups, respectively (P < .001 vs. baseline for netarsudil), a treatment difference of 0.03 µL/min/mm Hg (P ≤ .001). Mean diurnal IOP change from baseline at day 8 was -4.52 mm Hg for netarsudil versus -0.98 mm Hg for vehicle, a treatment difference of -3.54 mm Hg (P < .0001). Mean diurnal EVP change from baseline was -0.79 mm Hg in the netarsudil-treated group versus 0.10 mm Hg for vehicle, a treatment difference of -0.89 mm Hg (P < .001). All patients reporting an adverse event reported conjunctival hyperemia of mild or moderate severity., Conclusions: Netarsudil acts on the conventional outflow pathway, both proximal and distal, to significantly reduce IOP in POAG and OHT by improving trabecular outflow facility and decreasing EVP., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Precis: In this population-based study of 509 open-angle glaucoma (OAG) patients over a 36-year period, we identified a decreased rate of developing dementia compared with the rate in the general population., Purpose: The aim was to determine the incidence of dementia and Alzheimer disease (AD) among patients with OAG., Patients and Methods: Retrospective, population-based cohort study. All residents of Olmsted County, Minnesota (≥40 y) who were diagnosed with OAG between January 1, 1965 and December 31, 2000, were eligible for inclusion in this study. A total of 509 patients were included over the 36-year period. The cumulative probability of developing dementia was calculated and compared with the population risk of dementia., Results: Of the 509 patients included, 300 (58.9%) were female, the median age was 67.5 years, and 278 patients (54.6%) had primary OAG. Other subgroups were pseudoexfoliation in 15.1%, treated ocular hypertension in 14.1%, normal tension glaucoma in 10.6%, and pigmentary glaucoma in 5.5% of the patients. Respectively, 118 (23.0%) and 99 (19.4%) patients developed dementia and AD. The 10-year cumulative probability of developing dementia and AD was 12.0% and 9.9%, with a 95% confidence interval of 9.3%-15.3% and 7.5%-13%, respectively. The observed 10-year incidence of dementia and AD were significantly lower than the expected population incidence (19.0% and 19.0%; P<0.001). Older age at diagnosis of glaucoma was a strong predictor for the development of dementia by multivariate analysis (hazard ratio: 3.31, 95% confidence interval: 2.61-4.20, P<0.001)., Conclusion: The risk of developing dementia or AD was decreased in OAG patients compared with the general population. OAG with onset at a later age may present as a different etiopathogenetic entity compared with onset at a younger age, and represent the optic nerve findings of generalized neurodegenerative processes., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Importance: Genetic variants associated with primary open-angle glaucoma (POAG) are known to influence disease risk. However, the clinical effect of associated variants individually or in aggregate is not known. Genetic risk scores (GRS) examine the cumulative genetic load by combining individual genetic variants into a single measure, which is assumed to have a larger effect and increased power to detect relevant disease-related associations., Objective: To investigate if a GRS that comprised 12 POAG genetic risk variants is associated with age at disease diagnosis., Design, Setting, and Participants: A cross-sectional study included individuals with POAG and controls from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) study. A GRS was formulated using 12 variants known to be associated with POAG, and the alleles associated with increasing risk of POAG were aligned in the case-control sets. In case-only analyses, the association of the GRS with age at diagnosis was analyzed as an estimate of disease onset. Results from cohort-specific analyses were combined with meta-analysis. Data collection started in August 2012 for the NEIGHBOR cohort and in July 2008 for the GLAUGEN cohort and were analyzed starting in March 2018., Main Outcomes and Measures: Association of a 12 single-nucleotide polymorphism POAG GRS with age at diagnosis in individuals with POAG using linear regression., Results: The GLAUGEN study included 976 individuals with POAG and 1140 controls. The NEIGHBOR study included 2132 individuals with POAG and 2290 controls. For individuals with POAG, the mean (SD) age at diagnosis was 63.6 (9.8) years in the GLAUGEN cohort and 66.0 (13.7) years in the NEIGHBOR cohort. For controls, the mean (SD) age at enrollment was 65.5 (9.2) years in the GLAUGEN cohort and 68.9 (11.4) years in the NEIGHBOR cohort. All study participants were European white. The GRS was strongly associated with POAG risk in case-control analysis (odds ratio per 1-point increase in score = 1.24; 95% CI, 1.21-1.27; P = 3.4 × 10-66). In case-only analyses, each higher GRS unit was associated with a 0.36-year earlier age at diagnosis (β = -0.36; 95% CI, -0.56 to -0.16; P = 4.0 × 10-4). Individuals in the top 5% of the GRS had a mean (SD) age at diagnosis of 5.2 (12.8) years earlier than those in the bottom 5% GRS (61.4 [12.7] vs 66.6 [12.9] years; P = 5.0 × 10-4)., Conclusions and Relevance: A higher dose of POAG risk alleles was associated with an earlier age at glaucoma diagnosis. On average, individuals with POAG with the highest GRS had 5.2-year earlier age at diagnosis of disease. These results suggest that a GRS that comprised genetic variants associated with POAG could help identify patients with risk of earlier disease onset impacting screening and therapeutic strategies.

Papilledemais optic nerve swelling caused by increased intracranial hypertension, which has the potential to cause significant vision loss. Papilledema from idiopathic intracranial hypertension (IIH) is typically bilateral and symmetric, but can be asymmetric and even unilateral. The purpose of this study was to develop ultrasound vibro-elastography (UVE) for non-invasive measurement of ocular tissue wave speed for patients with papilledema. A total of 9 patients with papilledema from IIH and 9 age-matched healthy control patients were enrolled in this study. A local, gentle, 0.1-s harmonic vibration was applied on the eyelid to generate wave propagation in the ocular tissue. We used 3 excitation frequencies of 100, 150 and 200 Hz to measure the wave speeds. A 6.4-MHz ultrasound probe was used to non-invasively measure wave propagation in the ocular structures. Wave speeds were analyzed in the posterior sclera of the maculae of the eyes. The magnitudes of wave speed at each frequency of the IIH patients' posterior sclera were significantly higher than those of healthy patients. It was found that the magnitudes of wave speed at each frequency were statistically higher in the eyes with papilledema than in the contralateral eyes without papilledema for the patients with unilateral papilledema. UVE provides a non-invasive technique to measure the wave speed of posterior sclera, which may be useful for assessing patients with papilledema., (Copyright © 2019 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Purpose: Hyposecretion of aqueous humor has been postulated to adversely affect the health of the trabecular meshwork and outflow resistance. However, the effect of medications that reduce aqueous humor production on outflow facility in living human eyes is unclear. This study evaluated the effect of timolol, an aqueous humor flow suppressant, on outflow facility in healthy eyes., Design: Prospective, before-and-after study., Methods: In a multicenter study, 113 healthy participants over 40 years of age were included. Intraocular pressure (IOP) was measured with the participant in the sitting position by using a pneumatonometer. The outflow facility was measured with the participant in the supine position by 2-minute pneumatonography. After participants self-administered drops of timolol 0.5% for 1 week, twice daily in each eye, both measurements were repeated., Results: Mean IOP decreased from 15.1 ± 3.0 mm Hg at baseline to 12.4 ± 2.4 mm Hg (P < 0.001) after 1 week of timolol use. Mean outflow facility decreased from 0.23 ± 0.08 μL/min/mm Hg at baseline to 0.18 ± 0.08 μL/min/mm Hg (P < 0.001) after timolol. The change in outflow facility was negatively correlated with baseline outflow facility (r = -0.51; P < 0.001)., Conclusions: Timolol reduces outflow facility in healthy human eyes, and this effect is greater in eyes with higher baseline outflow facility. This phenomenon may be related to reduced aqueous humor flow, but the precise mechanism remains to be determined., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To determine the efficacy and safety of ab interno trabeculectomy with Trabectome in juvenile open-angle glaucoma (JOAG) patients., Design: Prospective cohort study., Methods: Evaluation of the 12-month results of 2 patient groups receiving ab interno trabeculectomy: group 1, eyes with no prior incisional surgery; group 2, eyes that had prior incisional cataract or glaucoma surgery., Results: Group 1, 40 eyes (average age 31 ± 7 years), had a significant reduction in intraocular pressure (IOP) of 10.6 mm Hg at 12 months from a baseline of 27.4 mm Hg (p = 0.01), and the number of glaucoma medications reduced by 0.4 (p = 0.80). Four eyes (10%) within the study period required a secondary glaucoma surgery. Group 2, 20 eyes (average age 27 ± 8 years), had a significant reduction in IOP of 8.8 mm Hg from a baseline of 27.1 mm Hg (p = 0.06), and the number of glaucoma medications reduced by 1.4 (p = 0.36). Five eyes (25%) from this group underwent a secondary glaucoma surgery within 12 months., Conclusion: After 1 year of follow-up, ab interno trabeculectomy appears to be an effective and safe intervention for patients with JOAG; however, a reduction in use of topical medications may not be observed in those receiving ab interno trabeculectomy as a primary procedure., (Copyright © 2018 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the risk of primary open-angle glaucoma (POAG) following vitreoretinal surgery., Design: Retrospective, population-based cohort study., Methods: All residents of Olmsted County, Minnesota, undergoing scleral buckle and/or vitrectomy between 2004 and 2015 were included in the operative cohort. The fellow nonoperative eyes were included in the comparison cohort. The study and comparison cohorts consisted of 344 and 277 eyes, respectively. The main outcome measure was the development of POAG. Secondary glaucomas were excluded. The probability of glaucoma in operative eyes and nonoperative fellow eyes was compared. The observed rate of POAG in the operative eyes was also compared to the rate of POAG in the population of Olmsted County., Results: The mean age was 64.7 years and the median follow-up period was 4.9 years. There were 58, 57, and 229 study eyes in the scleral buckle, scleral buckle with vitrectomy, and vitrectomy only cohorts, respectively. The 10-year cumulative probability of developing glaucoma was significantly greater in the operative group (8.9%, 95% confidence interval [CI] 3.8%-14%) compared to the nonoperative group (1.0%, 95% CI 0-2.4%; P = .02). None of the eyes in the scleral buckle group developed glaucoma. The 10-year probability of POAG was 17.5% (95% CI 0-34.9%) and 10.0% (95% CI 3.0%-17.0%) in the scleral buckle with vitrectomy and vitrectomy alone cohorts, respectively. The rates of POAG in operative eyes undergoing scleral buckle with vitrectomy and vitrectomy alone were significantly greater than the rate of POAG for the Olmsted County general population (1.0%, P < .001)., Conclusions: The risk of POAG is increased after vitrectomy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Netarsudil, an inhibitor of Rho kinase and a norepinephrine transporter, has been shown to lower elevated intraocular pressure (IOP) in controlled studies of patients with open-angle glaucoma and ocular hypertension, and in healthy volunteers. The mechanism of this ocular hypotensive effect in humans is unknown., Methods: The objective of this study was to evaluate the effect of netarsudil 0.02% on aqueous humor dynamics (AHD) parameters. In this double-masked, vehicle-controlled, paired-eye comparison study, 11 healthy volunteers received topical netarsudil ophthalmic solution 0.02% or its vehicle once daily for 7 days (morning dosing). The primary endpoints were the change in AHD parameters, compared between active and vehicle-treated eyes., Results: In netarsudil-treated eyes, diurnal outflow facility increased from 0.27 ± 0.10 μL/min/mmHg to 0.33 ± 0.11 μL/min/mmHg (+22%; P = 0.02) after 7 days of treatment. In placebo-treated eyes, diurnal outflow facility did not significantly change (P = 0.94). The difference between netarsudil and placebo eyes in diurnal change of outflow facility was 0.08 μL/min/mmHg (P < 0.001). Diurnal episcleral venous pressure (EVP) in netarsudil-treated eyes decreased from 7.9 ± 1.2 mmHg to 7.2 ± 1.8 (-10%; P = 0.01). Diurnal EVP was not significantly different between netarsudil- and placebo-treated eyes. There was a trend toward decreasing aqueous humor flow rate (-15%; P = 0.08). No treatment changes were seen in uveoscleral outflow rate., Conclusions: Once-daily dosing of netarsudil ophthalmic solution 0.02% lowered IOP through increasing trabecular outflow facility and reducing EVP. This suggests a combination of mechanisms that affect both the proximal and distal outflow pathways.

Purpose: Sex hormones may be associated with primary open-angle glaucoma (POAG), although the mechanisms are unclear. We previously observed that gene variants involved with estrogen metabolism were collectively associated with POAG in women but not men; here we assessed gene variants related to testosterone metabolism collectively and POAG risk., Methods: We used two datasets: one from the United States (3853 cases and 33,480 controls) and another from Australia (1155 cases and 1992 controls). Both datasets contained densely called genotypes imputed to the 1000 Genomes reference panel. We used pathway- and gene-based approaches with Pathway Analysis by Randomization Incorporating Structure (PARIS) software to assess the overall association between a panel of single nucleotide polymorphisms (SNPs) in testosterone metabolism genes and POAG. In sex-stratified analyses, we evaluated POAG overall and POAG subtypes defined by maximum IOP (high-tension [HTG] or normal tension glaucoma [NTG])., Results: In the US dataset, the SNP panel was not associated with POAG (permuted P = 0.77), although there was an association in the Australian sample (permuted P = 0.018). In both datasets, the SNP panel was associated with POAG in men (permuted P ≤ 0.033) and not women (permuted P ≥ 0.42), but in gene-based analyses, there was no consistency on the main genes responsible for these findings. In both datasets, the testosterone pathway association with HTG was significant (permuted P ≤ 0.011), but again, gene-based analyses showed no consistent driver gene associations., Conclusions: Collectively, testosterone metabolism pathway SNPs were consistently associated with the high-tension subtype of POAG in two datasets.

The objective of this study was to extend an ultrasound surface wave elastography (USWE) technique for noninvasive measurement of ocular tissue elastic properties. In particular, we aim to establish the relationship between the wave speed of cornea and the intraocular pressure (IOP). Normal ranges of IOP are between 12 and 22mmHg. Ex vivo porcine eye balls were used in this research. The porcine eye ball was supported by the gelatin phantom in a testing container. Some water was pour into the container for the ultrasound measurement. A local harmonic vibration was generated on the side of the eye ball. An ultrasound probe was used to measure the wave propagation in the cornea noninvasively. A 25 gauge butterfly needle was inserted into the vitreous humor of the eye ball under the ultrasound imaging guidance. The needle was connected to a syringe. The IOP was obtained by the water height difference between the water level in the syringe and the water level in the testing container. The IOP was adjusted between 5mmHg and 30mmHg with a 5mmHg interval. The wave speed was measured at each IOP for three frequencies of 100, 150 and 200Hz. Finite element method (FEM) was used to simulate the wave propagation in the corneal according to our experimental setup. A linear viscoelastic FEM model was used to compare the experimental data. Both the experiments and the FEM analyses showed that the wave speed of cornea increased with IOP., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Abnormal ocular biomechanical properties may be important for understanding the risk of glaucoma. However, there are no clinical methods for measuring standard material properties in patients. In this feasibility study we demonstrated proof-of-principle for a novel method, ultrasound surface wave elastography (USWE), to determine the in vivo Young's modulus of elasticity of corneas in normal human eyes., Methods: In total, 20 eyes of 10 healthy subjects (mean age, 51.4±7.2; ±SD; range, 43 to 64 y) were studied. A spherical-tipped probe (3-mm diameter) was placed on closed eyelids and generated a gentle harmonic vibration at 100 Hz for 0.1 second. Wave speed propagation in the cornea was measured by USWE, and Young's modulus was calculated from the wave speed. Associations between Young's modulus and intraocular pressure (IOP), age, central corneal thickness, and axial length were explored by the Pearson correlation. Statistical significance was determined by using generalized estimating equation models to account for possible correlation between fellow eyes., Results: Mean IOP was 12.8±2.7 mm Hg. Mean wave speed in the cornea was 1.82±0.10 m/s. Young's modulus of elasticity was 696±113 kPa and was correlated with IOP (r=0.57; P=0.004), but none of the other variables (P>0.1)., Conclusions: USWE is a novel noninvasive technique for measuring ocular biomechanical properties. Corneal Young's modulus in normal eyes is associated with IOP, consistent with measurements in cadaver eyes. Further work is needed to determine elasticity in other ocular tissues, particularly the sclera, and if elasticity is altered in glaucoma patients.

Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14-1.21), P=1.8 × 10 -27 ) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10 -5 ); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.

Purpose: The mechanism of IOP change during a body position change is poorly understood. In this study, we investigated changes in episcleral venous pressure (EVP) between two body positions, sitting and inclined, and compared this with changes in IOP., Methods: This study was a prospective, comparative case series of 43 eyes of 24 healthy volunteers. IOP was measured using a pneumatonometer in the seated position. EVP was then measured in a selected episcleral vein by using an automated, slit-lamp-mounted venomanometer. Thirty minutes later, the subject was placed in an inclined position with the neck extended and the head resting on the chin rest of the slit lamp. After 5 minutes, IOP and EVP in the same vein were remeasured. EVP in the inclined position was compared with EVP in the seated position, and the change in IOP was compared with the change in EVP. Statistical significance was determined using generalized estimating equation models., Results: Mean IOP increased from 11.4 ± 3.0 mm Hg (mean ± SD) in the sitting position to 13.1 ± 3.4 mm Hg in the inclined position (P < 0.001). Mean EVP increased from 6.4 ± 1.4 mm Hg in the sitting position to 7.8 ± 1.7 mm Hg in the inclined position (P < 0.001). The postural rise in IOP was not different from the rise in EVP (P = 0.18)., Conclusions: In the inclined position, IOP and EVP are higher than they are in the sitting position. The posture-induced rise in IOP can be attributed to an increase in EVP.