The Robust Lamina Cribrosa Vasculature: Perfusion and Oxygenation Under Elevated Intraocular Pressure.

Purpose: Elevated intraocular pressure (IOP) is thought to cause lamina cribrosa (LC) blood vessel distortions and potentially collapse, adversely affecting LC hemodynamics, reducing oxygenation, and triggering, or contributing to, glaucomatous neuropathy. We assessed the robustness of LC perfusion and oxygenation to vessel collapses. Methods: From histology, we reconstructed three-dimensional eye-specific LC vessel networks of two healthy monkey eyes. We used numerical simulations to estimate LC perfusion and from this the oxygenation. We then evaluated the effects of collapsing a fraction of LC vessels (0%-36%). The collapsed vessels were selected through three scenarios: stochastic (collapse randomly), systematic (collapse strictly by the magnitude of local experimentally determined IOP-induced compression), and mixed (a combination of stochastic and systematic). Results: LC blood flow decreased linearly as vessels collapsed-faster for stochastic and mixed scenarios and slower for the systematic one. LC regions suffering severe hypoxia (oxygen <8 mm Hg) increased proportionally to the collapsed vessels in the systematic scenario. For the stochastic and mixed scenarios, severe hypoxia did not occur until 15% of vessels collapsed. Some LC regions had higher perfusion and oxygenation as vessels collapsed elsewhere. Some severely hypoxic regions maintained normal blood flow. Results were equivalent for both networks and patterns of experimental IOP-induced compression. Conclusions: LC blood flow was sensitive to distributed vessel collapses (stochastic and mixed) and moderately vulnerable to clustered collapses (systematic). Conversely, LC oxygenation was robust to distributed vessel collapses and sensitive to clustered collapses. Locally normal flow does not imply adequate oxygenation. The actual nature of IOP-induced vessel collapse remains unknown.

[Minoxidil-induced ophthalmic hypertension (case report)]. / Indutsirovannaya minoksidilom oftal'mogipertenziya (klinicheskoe nablyudenie).

This article presents a case of a 31-year-old male patient who presented to the outpatient department of the Krasnov Research Institute of Eye Diseases with complaints of diplopia and increased intraocular pressure (IOP) up to 30 mm Hg. The patient had been using minoxidil topically for androgenic alopecia for 8 years. On examination, mild swelling of the bulbar conjunctiva in the upper fornix was revealed; optical coherence tomography showed thinning of the ganglion cell layer, most likely due to moderate myopia. The patient responded well to discontinuation of minoxidil and topical therapy with prostaglandin analogues. After 4 months, an attempt was made to replace topical hypotensive therapy with carbonic anhydrase inhibitors, but the previous hypotensive regimen had to be resumed due to an increase in IOP. During 10 months of observation, no signs of progression were detected according to optical coherence tomography and static perimetry.

[Topical application of hypotensive drugs for the prevention of intraocular pressure elevation after intravitreal injections of anti-VEGF drugs]. / Mestnoe primenenie gipotenzivnykh preparatov s tsel'yu profilaktiki povysheniya urovnya vnutriglaznogo davleniya posle intravitreal'nykh in"ektsii anti-VEGF-preparatov.

The management protocol for patients with neovascular age-related macular degeneration (nAMD) involves multiple intravitreal injections (IVI) of anti-VEGF drugs. The ability to reduce the peak intraocular pressure (IOP) rise is greatly important in clinical practice. PURPOSE: This study evaluates the effect of topical hypotensive drugs on the short-term IOP rise after IVI of anti-VEGF drugs in patients with nAMD. MATERIAL AND METHODS: The prospective study included 80 patients with newly diagnosed nAMD. Before the start of treatment, the patients were divided into 4 groups of 20 people each: 1st - controls, who received no prophylactic drugs, in the 2nd, 3rd and 4th groups local instillations of one drop of hypotensive drugs brinzolamide 1%, brinzolamide-timolol, brimonidine-timolol were performed in the conjunctival sac twice: 1 day before the injection (at 20:00) and on the day of the injection 2 hours before the manipulation (at 08:00), respectively. IOP was measured in each patient using ICare Pro non-contact tonometer before injection, as well as 1 min, 30 and 60 min after injection. RESULTS: Prophylactic use of hypotensive drugs was associated with a significant decrease in IOP immediately after IVI compared to the same parameter in the 1st group (p<0.001), the maximum decrease in IOP values was observed when using a fixed combination of brimonidine-timolol by 12.1 mm Hg compared to the controls (p<0.001), the combination of brinzolamide-timolol reduced IOP by 8.5 mm Hg (p<0.001), brinzolamide 1% led to the smallest decrease in IOP - by 5.1 mm Hg (p<0.001). CONCLUSION: Study patients that received instillations of brimonidine-timolol combination of one drop into the conjunctival sac 1 day before the injection and on the day of the injection showed the maximum decrease in IOP compared to patients of the other groups.

A digoxin derivative that potently reduces intraocular pressure: efficacy and mechanism of action in different animal models.

Glaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side effects or become progressively ineffective, highlighting the need for novel compounds. We have synthesized a family of perhydro-1,4-oxazepine derivatives of digoxin, the selective inhibitor of Na,K-ATPase. The cyclobutyl derivative (DcB) displays strong selectivity for the human α2 isoform and potently reduces IOP in rabbits. These observations appeared consistent with a hypothesis that in ciliary epithelium DcB inhibits the α2 isoform of Na,K-ATPase, which is expressed strongly in nonpigmented cells, reducing aqueous humor (AH) inflow. This paper extends assessment of efficacy and mechanism of action of DcB using an ocular hypertensive nonhuman primate model (OHT-NHP) (Macaca fascicularis). In OHT-NHP, DcB potently lowers IOP, in both acute (24 h) and extended (7-10 days) settings, accompanied by increased aqueous humor flow rate (AFR). By contrast, ocular normotensive animals (ONT-NHP) are poorly responsive to DcB, if at all. The mechanism of action of DcB has been analyzed using isolated porcine ciliary epithelium and perfused enucleated eyes to study AH inflow and AH outflow facility, respectively. 1) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. 2) DcB significantly increases AH outflow facility via the trabecular meshwork (TM). Taken together, the data indicate that the original hypothesis on the mechanism of action must be revised. In the OHT-NHP, and presumably other species, DcB lowers IOP by increasing AH outflow facility rather than by decreasing AH inflow.NEW & NOTEWORTHY When applied topically, a cyclobutyl derivative of digoxin (DcB) potently reduces intraocular pressure in an ocular hypertensive nonhuman primate model (Macaca fascicularis), associated with increased aqueous humor (AH) flow rate (AFR). The mechanism of action of DcB involves increased AH outflow facility as detected in enucleated perfused porcine eyes and, in parallel, increased (AH) inflow as detected in isolated porcine ciliary epithelium. DcB might have potential as a drug for the treatment of open-angle human glaucoma.

Anterior Segment Optical Coherence Tomography for Cases of High Intraocular Pressure Following XEN Implant for Glaucoma.

PRCIS: This study showed that the XEN patency should be verified by OCT imaging in cases of encapsulated blebs. Although fibrosis plays the principal role, humor aqueous flow reduction could affect the "spacer" effect that inhibits the fibroblast attachments. PURPOSE: To evaluate the application of the anterior segment optical coherence tomography (AS-OCT) imaging in studying the relationship between a low flow rate through the XEN63 and the development of a cystic bleb. METHODS: Retrospective case series of 3 eyes presenting a cystic bleb after an XEN63 implantation for uncontrolled intraocular pressure (IOP). Demographic and clinical data were obtained from medical records. The imaging findings, complications, and managements following the surgery were evaluated. RESULTS: Three patients, with an average age of 67.3 years, initially showed a patent stent lumen and a functional bleb after surgery. The IOP of all eyes increased on average at 28.3 days from the surgery, with a mean value of 39.66 mm Hg. The slit lamp examination showed a cystic bleb. The AS-OCT imaging confirmed the previous finding and revealed either a partial or total occlusion of the stent internal ostium. A Nd:YAG laser, in proximity to the ostium, was performed to resolve the obstruction. Although the AS-OCT imaging showed the device patency and the IOP immediately decreased, the latter became elevated again. Consequently, in all the cases, a further needling procedure was needed to achieve an adequate IOP reduction. Six months after the two-step procedure, the IOP averaged 13.33 mm Hg, the XEN63 lumens appeared cleared, and the blebs showed a functional morphology. No adverse events were observed. CONCLUSION: The development of a cystic bleb may result from an altered balance between the flow rate through the XEN63 and the fibrosis development in the postoperative healing process. A proper follow-up based on slit lamp biomicroscopy, IOP measurement, and AS-OCT imaging is advisable to estimate and manage a cystic bleb following XEN63 implantation.

Evaluation of Retinal Layers in Individuals With Pseudoexfoliation Syndrome and Ocular Hypertension.

PRCIS: This study investigated the retinal segmental thicknesses in individuals with pseudoexfoliation syndrome and ocular hypertension. Maximum thinning was found at 6 mm inferior to the inner plexiform layer. This layer is very important for the early diagnosis of glaucoma. PURPOSE: To analyze the thickness of the peripapillary retinal nerve fiber layer and 8 macular layers using optical coherence tomography in eyes with ocular hypertension (OHT) and pseudoexfoliation syndrome (PXS) and healthy eyes and to evaluate between-group differences. MATERIALS AND METHODS: In a prospective study, the macular segmentation of retinal layers in 120 eyes of 120 participants was performed automatically using current Heidelberg Spectralis optical coherence tomography software, which provides measurements for 8 retinal layers. Thickness maps divided into nine subfields (ie, 1, 3, and 6 mm) were extracted from the software for each retinal layer and compared between groups. RESULTS: The thinnest macular layers appeared in the ocular hypertensive PXS, normotensive PXS, and OHT groups in that order. In the inner retinal layers (macular retinal nerve fiber layer, ganglion cell layer, and inner plexiform layer), statistically significant differences emerged between the PXS and control groups in all quadrants of the 3 and 6 mm areas. No significant difference between the OHT group and control group appeared except in the 6 mm temporal quadrant of the inner plexiform layer (IPL). Receiving operating characteristic analysis revealed quadrants with high area-under-the-curve values at 3 and 6 mm in macular segments in all 3 groups compared with the control group. CONCLUSION: In macular segment analysis, the inner retinal layers showed the most thinning in patients with ocular hypertensive PXS. According to receiving operating characteristic curve analysis, examinations performed 6 mm inferior to the IPL, as the quadrant with the highest area under the curve in all 3 groups, are critical for the early diagnosis of glaucoma.

Effect of ATP-sensitive Potassium Channel Openers on Intraocular Pressure in Ocular Hypertensive Animal Models.

Purpose: To evaluate the effect of ATP-sensitive potassium channel openers cromakalim prodrug 1 (CKLP1) and diazoxide on IOP in three independent mouse models of ocular hypertension. Methods: Baseline IOP was measured in TGFß2 overexpression, steroid-induced, and iris dispersion (DBA/2J) ocular hypertension mouse models, followed by once daily eyedrop administration with CKLP1 (5 mM) or diazoxide (5 mM). The IOP was measured in conscious animals with a handheld rebound tonometer. Aqueous humor dynamics were assessed by a constant perfusion method. Effect of treatment on ocular tissues was evaluated by transmission electron microscopy. Results: CKLP1 decreased the IOP by 20% in TGFß2 overexpressing mice (n = 6; P < 0.0001), 24% in steroid-induced ocular hypertensive mice (n = 8; P < 0.0001), and 43% in DBA/2J mice (n = 15; P < 0.0001). Diazoxide decreased the IOP by 32% in mice with steroid-induced ocular hypertension (n = 13; P < 0.0001) and by 41% in DBA/2J mice (n = 4; P = 0.005). An analysis of the aqueous humor dynamics revealed that CKLP1 decreased the episcleral venous pressure by 29% in TGFß2 overexpressing mice (n = 13; P < 0.0001) and by 72% in DBA/2J mice (n = 4 control, 3 treated; P = 0.0002). Diazoxide lowered episcleral venous pressure by 35% in steroid-induced ocular hypertensive mice (n = 3; P = 0.03). Tissue histology and cell morphology appeared normal when compared with controls. Accumulation of extracellular matrix was reduced in CKLP1- and diazoxide-treated eyes in the steroid-induced ocular hypertension model. Conclusions: ATP-sensitive potassium channel openers CKLP1 and diazoxide effectively decreased the IOP in ocular hypertensive animal models by decreasing the episcleral venous pressure, supporting a potential therapeutic application of these agents in ocular hypertension and glaucoma.

Consensus Recommendation for Mouse Models of Ocular Hypertension to Study Aqueous Humor Outflow and Its Mechanisms.

Due to their similarities in anatomy, physiology, and pharmacology to humans, mice are a valuable model system to study the generation and mechanisms modulating conventional outflow resistance and thus intraocular pressure. In addition, mouse models are critical for understanding the complex nature of conventional outflow homeostasis and dysfunction that results in ocular hypertension. In this review, we describe a set of minimum acceptable standards for developing, characterizing, and utilizing mouse models of open-angle ocular hypertension. We expect that this set of standard practices will increase scientific rigor when using mouse models and will better enable researchers to replicate and build upon previous findings.

Honeycomb Epithelial Edema Associated With Rho Kinase Inhibition: A Case Series and Review of the Literature.

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.

The Effect of Achieving Target Intraocular Pressure on Visual Field Worsening.

PURPOSE: To estimate the effect of achieving target intraocular pressure (IOP) values on visual field (VF) worsening in a treated clinical population. DESIGN: Retrospective analysis of longitudinal data. PARTICIPANTS: A total of 2852 eyes of 1688 patients with glaucoma-related diagnoses treated in a tertiary care practice. All included eyes had at least 5 reliable VF tests and 5 IOP measures on separate visits along with at least 1 target IOP defined by a clinician on the first or second visit. METHODS: The primary dependent variable was the slope of the mean deviation (MD) over time (decibels [dB]/year). The primary independent variable was mean target difference (measured IOP - target IOP). We created simple linear regression models and mixed-effects linear models to study the relationship between MD slope and mean target difference for individual eyes. In the mixed-effects models, we included an interaction term to account for disease severity (mild/suspect, moderate, or advanced) and a spline term to account for the differing effects of achieving target IOP (target difference ≤0) and failing to achieve target IOP (target difference >0). MAIN OUTCOME MEASURES: Rate of change in MD slope (changes in dB/year) per 1 mmHg change in target difference at different stages of glaucoma severity. RESULTS: Across all eyes, a simple linear regression model demonstrated that a 1 mmHg increase in target difference had a -0.018 dB/year (confidence interval [CI], -0.026 to -0.011; P < 0.05) effect on MD slope. The mixed-effects model shows that eyes with moderate disease that fail to achieve their target IOP experience the largest effects, with a 1 mmHg increase in target difference resulting in a -0.119 dB/year (CI, -0.168 to -0.070; P < 0.05) worse MD slope. The effects of missing target IOP on VF worsening were more pronounced than the effect of absolute level of IOP on VF worsening, where a 1 mmHg increase in IOP had a -0.004 dB/year (CI, -0.011 to 0.003; P > 0.05) effect on the MD slope. CONCLUSIONS: In treated patients, failing to achieve target IOP was associated with more rapid VF worsening. Eyes with moderate glaucoma experienced the greatest VF worsening from failing to achieve target IOP.

Blood Pressure and Glaucomatous Progression in a Large Clinical Population.

PURPOSE: To investigate the effect of systemic arterial blood pressure (BP) on rates of progressive structural damage over time in glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 7501 eyes of 3976 subjects with glaucoma or suspected of glaucoma followed over time from the Duke Glaucoma Registry. METHODS: Linear mixed models were used to investigate the effects of BP on the rates of retinal nerve fiber layer (RNFL) loss from spectral-domain OCT (SD-OCT) over time. Models were adjusted for intraocular pressure (IOP), gender, race, diagnosis, central corneal thickness (CCT), follow-up time, and baseline disease severity. MAIN OUTCOME MEASURE: Effect of mean arterial pressure (MAP), systolic arterial pressure (SAP), and diastolic arterial pressure (DAP) on rates of RNFL loss over time. RESULTS: A total of 157 291 BP visits, 45 408 IOP visits, and 30 238 SD-OCT visits were included. Mean rate of RNFL change was -0.70 µm/year (95% confidence interval, -0.72 to -0.67 µm/year). In univariable models, MAP, SAP, and DAP during follow-up were not significantly associated with rates of RNFL loss. However, when adjusted for mean IOP during follow-up, each 10 mmHg reduction in mean MAP (-0.06 µm/year; P = 0.007) and mean DAP (-0.08 µm/year; P < 0.001) but not SAP (-0.01 µm/year; P = 0.355) was associated with significantly faster rates of RNFL thickness change over time. The effect of the arterial pressure metrics remained significant after additional adjustment for baseline age, diagnosis, sex, race, follow-up time, disease severity, and corneal thickness. CONCLUSIONS: When adjusted for IOP, lower MAP and DAP during follow-up were significantly associated with faster rates of RNFL loss, suggesting that levels of systemic BP may be a significant factor in glaucoma progression.

Intravitreally Injected Methylene Blue Protects Retina against Acute Ocular Hypertension in Rats.

PURPOSE: To assess the neuroprotective effects of methylene blue (MB) in a rat model of acute ocular hypertension (AOH) and explore its possible mechanisms. METHODS: Our AOH rat model was obtained with anterior chamber perfusion for 60 min. After that, 100 µM MB was injected into the vitreous cavity immediately after injury. Electroretinogram, fundus photography, optical coherence tomography (OCT) and retina morphology examination were utilized to quantify retinal damage before surgery, as well as 7, 14 and 28 days after. The average number of surviving retinal ganglion cells (RGCs) was counted after fluorescent retrograde labelling with 4% DiI. And TUNEL assay was used to investigate retinal cell apoptosis at 24 hours after AOH. Nrf2 and BACE1 in the retina were determined by RT-qPCR analysis. RESULTS: AOH did produce a severe degeneration effect on the whole retinal layer. Intravitreally injected MB maintained certain retinal thickness after AOH, reduced the destruction of electroretinograms, and enhanced RGCs survival. The average number of TUNEL-labelled cells statistically reduced in the MB-treated retina tissue compared with retina treated with normal saline. The relative mRNA level of Nrf2 was also much higher in the MB-treated retinas after AOH, and the expression of BACE1 had a decline in the AOH + MB group. CONCLUSIONS: MB can protect the retina from AOH injury and the possible mechanism might involve the inhibition of BACE1 expression and the activation of Nrf2 antioxidant pathway.

Impact of Early Intraocular Pressure Elevation on Postoperative Outcomes After Descemet Membrane Endothelial Keratoplasty in Non-glaucoma Patients.

PURPOSE: The purpose of this study was to investigate the impact of transient elevations in postoperative intraocular pressure (IOP) on the clinical outcome of Descemet membrane endothelial keratoplasty (DMEK) surgery in non-glaucoma patients. METHODS: Retrospective analysis from a prospective database of eyes without preexisting glaucoma that underwent DMEK with 90% anterior chamber and 20% sulfur hexafluoride endotamponade. Group A included eyes without postoperative IOP increase (IOP <30 mm Hg and a relative increase from preoperative value <10 mm Hg). Group B included eyes with IOP elevation (postoperative IOP ≥30 mm Hg or a relative increase from preoperative value ≥10 mm Hg) handled according to a standardized protocol. The impact of elevated IOP within 3 days after DMEK surgery was evaluated regarding best-corrected visual acuity (BCVA), central corneal thickness (CCT), and endothelial cell count (ECC) at 1, 3, and 6 months. RESULTS: One hundred seventy-six eyes from 164 patients were included. An IOP increase after DMEK occurred in 20 eyes (11.3%; 19 patients, group B), and the mean peak IOP was 48 ± 12 mm Hg (range 32-69 mm Hg). There were no significant postoperative differences in BCVA, CCT, and ECC on comparing both groups. The BCVA increased significantly (P < 0.001, respectively), whereas CCT (P < 0.001, respectively) and ECC (P < 0.001, respectively) decreased significantly from preoperative values. The rebubbling rate tended to be higher in group B without statistical significance (6.4% vs. 10%, P = 0.648). CONCLUSIONS: Temporary IOP elevation after DMEK may not affect functional and morphological outcomes in non-glaucoma patients. However, careful postoperative IOP monitoring and appropriate management are crucial to avoid irreversible ocular damage.

Elevated intraocular pressure in children with acute lymphoblastic leukaemia: A prospective study.

Most childhood acute lymphoblastic leukaemia (ALL) protocols include high-dose steroid therapy. However, the known potential of high-dose steroids to significantly elevate intraocular pressure (IOP) and lead to glaucomatous optic neuropathy has not been intensively investigated in children with ALL. Moreover, as children with ALL do not routinely undergo IOP measurements, the need for IOP monitoring and therapy is unknown. We prospectively measured IOP in 90 children with newly diagnosed ALL attending a tertiary paediatric haematology/oncology centre, at diagnosis and at the middle and end of induction therapy. Ocular hypertension (IOP > 21 mm Hg) at any time point was documented in 64 children (71%), and the prevalence increased during induction. Thirty-six children (40%) had elevated IOP at ALL diagnosis before therapy initiation, and stratification to non-standard ALL was a risk factor. IOP reduction therapy was administered to 13 children (14%); none required surgery. Values normalised in all cases. On multivariate logistic regression analysis, dexamethasone therapy was a significant risk factor for ocular hypertension. High body mass index was an additional risk factor in children with elevated IOP at ALL diagnosis. Routine evaluation of IOP during steroid therapy is very important in children with ALL to ensure early intervention which may prevent permanent ocular damage.

Corneal biomechanics and glaucoma beyond the bidirectional impact of intraocular pressure and corneal deformation response / Biomecânica corneana e glaucoma além do impacto bididirecional da pressão intraocular e da resposta da deformação corneana

ABSTRACT The purpose of this study was to highlight the impact of biomechanical corneal response in available in vivo tonometry methods for glaucoma management. Systematic review of non-contact air-puff tonometers that analyzes the corneal deformation response, with special focus on the investigation of the correlation of derived parameters with intraocular pressure measurements. The two actual and commercially available in vivo corneal tonometers provide promising information about biomechanical characteristics of the cornea and its relation to glaucoma, allowing the development of new protocols to evaluate, diagnose, and manage this disease.

RESUMO O objetivo deste estudo é destacar o impacto da resposta biomecânica corneana em métodos de tonometria in vivo disponíveis para o manejo do glaucoma. Trata-se de revisão sistemática de tonômetros de ar que analisa a resposta à deformação corneana, com foco especial na investigação da correlação dos parâmetros derivados com as medições da pressão intraocular. Os dois tonômetros mais recentes e comercialmente disponíveis fornecem informações promissoras sobre as características biomecânicas da córnea e sua relação com o glaucoma, permitindo o desenvolvimento de novos protocolos para avaliar, diagnosticar e controlar a doença.

Analysis of Microvasculature in Nonhuman Primate Macula With Acute Elevated Intraocular Pressure Using Optical Coherence Tomography Angiography.

Purpose: To investigate responses of macular capillary vessel area density (VAD) of superficial and deep retinal vascular plexuses to elevations in intraocular pressure (IOP) in cynomolgus macaque monkeys using optical coherence tomography angiography (OCTA). Methods: In five general anesthetized male cynomolgus monkeys, the IOP was increased incrementally by 10 mmHg from baseline (10 mmHg) to 70 mmHg and then decreased back to 10 mmHg (recovery state). Structural OCT (30° × 30°) and OCTA (20° × 15°) centered on the macula were obtained at each IOP and 3, 15, and 30 minutes after recovery. En face images of the superficial vascular complex (SVC) and deep vascular complex (DVC) were extracted, and VAD (%) compared with that at baseline was calculated. Results: The VADs in the SVC and DVC at baseline and at 30 mmHg IOP were 34.96%, 34.15%, 35.38%, and 30.12%, respectively. The VAD plateaued until 30 mmHg; however, the VAD was affected more in the DVC than in the SVC (P = 0.008) at 30 mmHg. It showed a significant reduction at 40 mmHg (16.52% SVC, P = 0.006; 18.59% DVC, P = 0.012). In the recovery state, the SVC showed full retention of baseline VAD, but the DVC maintained VAD approximately 70% of that at baseline. Structural OCT showed hyperreflectivity in the nuclear layer, retinal swelling, and an undifferentiated ellipsoid zone from 50 mmHg. Conclusions: Despite physiological autoregulation, perifoveal microcirculation was affected at high IOP ≥ 40 mmHg, especially in the DVC, which explains the pathological mechanism of macular vulnerability in ischemic diseases.

Interplay between intraocular and intracranial pressure effects on the optic nerve head in vivo.

Intracranial pressure (ICP) has been proposed to play an important role in the sensitivity to intraocular pressure (IOP) and susceptibility to glaucoma. However, the in vivo effects of simultaneous, controlled, acute variations in ICP and IOP have not been directly measured. We quantified the deformations of the anterior lamina cribrosa (ALC) and scleral canal at Bruch's membrane opening (BMO) under acute elevation of IOP and/or ICP. Four eyes of three adult monkeys were imaged in vivo with OCT under four pressure conditions: IOP and ICP either at baseline or elevated. The BMO and ALC were reconstructed from manual delineations. From these, we determined canal area at the BMO (BMO area), BMO aspect ratio and planarity, and ALC median depth relative to the BMO plane. To better account for the pressure effects on the imaging, we also measured ALC visibility as a percent of the BMO area. Further, ALC depths were analyzed only in regions where the ALC was visible in all pressure conditions. Bootstrap sampling was used to obtain mean estimates and confidence intervals, which were then used to test for significant effects of IOP and ICP, independently and in interaction. Response to pressure manipulation was highly individualized between eyes, with significant changes detected in a majority of the parameters. Significant interactions between ICP and IOP occurred in all measures, except ALC visibility. On average, ICP elevation expanded BMO area by 0.17 mm2 at baseline IOP, and contracted BMO area by 0.02 mm2 at high IOP. ICP elevation decreased ALC depth by 10 µm at baseline IOP, but increased depth by 7 µm at high IOP. ALC visibility decreased as ICP increased, both at baseline (-10%) and high IOP (-17%). IOP elevation expanded BMO area by 0.04 mm2 at baseline ICP, and contracted BMO area by 0.09 mm2 at high ICP. On average, IOP elevation caused the ALC to displace 3.3 µm anteriorly at baseline ICP, and 22 µm posteriorly at high ICP. ALC visibility improved as IOP increased, both at baseline (5%) and high ICP (8%). In summary, changing IOP or ICP significantly deformed both the scleral canal and the lamina of the monkey ONH, regardless of the other pressure level. There were significant interactions between the effects of IOP and those of ICP on LC depth, BMO area, aspect ratio and planarity. On most eyes, elevating both pressures by the same amount did not cancel out the effects. Altogether our results show that ICP affects sensitivity to IOP, and thus that it can potentially also affect susceptibility to glaucoma.

Chronic social defeat stress causes retinal vascular dysfunction.

PURPOSE: The roles of vascular dysfunction and chronic stress have been extensively discussed in the pathophysiology of glaucoma. Our aim was to test whether chronic stress causes retinal vascular dysfunction and therewith induces retinal ganglion cells (RGCs) loss. METHODS: Twelve mice underwent chronic social defeat (CSD) stress, while 12 mice received control treatment only. Intraocular pressure (IOP) was measured with a rebound tonometer. Blood plasma corticosterone concentration and adrenal gland weight were used to assess stress levels. Brn-3a staining in retinas and PPD staining in optic nerve cross sections were conducted to assess the survival of RGCs and axons respectively. The ET-1 and α-SMA levels were determined in retina. Retinal vascular autoregulation, functional response to various vasoactive agents and vascular mechanics were measured using video microscopy. RESULTS: No significant difference in IOP levels was observed during and after CSD between CSD mice and controls. CSD stress caused hypercortisolemia 2 days post-CSD. However, increased corticosterone levels went back to normal 8 months after CSD. CSD-exposed mice developed adrenal hyperplasia 3 days post-CSD, which was normalized by 8 months. RGC and axon survival were similar between CSD mice and controls. However, CSD stress caused irreversible, impaired autoregulation and vascular dysfunction of retinal arterioles in CSD mice. In addition, impaired maximal dilator capacity of retinal arterioles was observed 8 months post-CSD rather than 3 days post-CSD. Remarkably, ET-1 levels were increased 3 days post-CSD while α-SMA levels were decreased 8 months post-CSD. CONCLUSIONS: We found that CSD stress does not cause IOP elevation, nor loss of RGCs and their axons. However, it strikingly causes irreversible impaired autoregulation and endothelial function in murine retinal arterioles. In addition, CSD changed vascular mechanics on a long-term basis. Increased ET-1 levels and loss of pericytes in retina vessels may involve in this process.