Sustained Retinal Defocus Increases the Effect of Induced Myopia on the Retinal Astrocyte Template.

The aim of this article is to describe sustained myopic eye growth's effect on astrocyte cellular distribution and its association with inner retinal layer thicknesses. Astrocyte density and distribution, retinal nerve fiber layer (RNFL), ganglion cell layer, and inner plexiform layer (IPL) thicknesses were assessed using immunochemistry and spectral-domain optical coherence tomography on seventeen common marmoset retinas (Callithrix jacchus): six induced with myopia from 2 to 6 months of age (6-month-old myopes), three induced with myopia from 2 to 12 months of age (12-month-old myopes), five age-matched 6-month-old controls, and three age-matched 12-month-old controls. Untreated marmoset eyes grew normally, and both RNFL and IPL thicknesses did not change with age, with astrocyte numbers correlating to RNFL and IPL thicknesses in both control age groups. Myopic marmosets did not follow this trend and, instead, exhibited decreased astrocyte density, increased GFAP+ spatial coverage, and thinner RNFL and IPL, all of which worsened over time. Myopic changes in astrocyte density, GFAP+ spatial coverage and inner retinal layer thicknesses suggest astrocyte template reorganization during myopia development and progression which increased over time. Whether or not these changes are constructive or destructive to the retina still remains to be assessed.

Early Alterations in Inner-Retina Neural and Glial Saturated Responses in Lens-Induced Myopia.

Purpose: Myopic marmosets are known to exhibit significant inner retinal thinning compared to age-matched controls. The purpose of this study was to assess inner retinal activity in marmosets with lens-induced myopia compared to age-matched controls and evaluate its relationship with induced changes in refractive state and eye growth. Methods: Cycloplegic refractive error (Rx), vitreous chamber depth (VCD), and photopic full-field electroretinogram were measured in 14 marmosets treated binocularly with negative contact lenses compared to 9 untreated controls at different stages throughout the experimental period (from 74 to 369 days of age). The implicit times of the a-, b-, d-, and photopic negative response (PhNR) waves, as well as the saturated amplitude (Vmax), semi-saturation constant (K), and slope (n) estimated from intensity-response functions fitted with Naka-Rushton equations were analyzed. Results: Compared to controls, treated marmosets exhibited attenuated b-, d-, and PhNR waves Vmax amplitudes 7 to 14 days into treatment before compensatory changes in refraction and eye growth occurred. At later time points, when treated marmosets had developed axial myopia, the amplitudes and implicit times of the b-, d-, and PhNR waves were similar between groups. In controls, the PhNR wave saturated amplitude increased as the b + d-wave Vmax increased. This trend was absent in treated marmosets. Conclusions: Marmosets induced with negative defocus exhibit early alterations in inner retinal saturated amplitudes compared to controls, prior to the development of compensatory myopia. These early ERG changes are independent of refraction and eye size and may reflect early changes in bipolar, ganglion, amacrine, or glial cell physiology prior to myopia development. Translational Relevance: The early changes in retinal function identified in the negative lens-treated marmosets may serve as clinical biomarkers to help identify children at risk of developing myopia.

Choroidal Morphology and Photoreceptor Activity Are Related and Affected by Myopia Development.

Purpose: The choroid is critical for the regulation of eye growth and is involved in the pathogenesis of myopia-associated ocular complications. This study explores the relationship among choroidal biometry, photoreceptor activity, and myopic growth in marmosets (Callithrix jacchus) with lens-induced myopia. Methods: A total of 34 common marmosets aged 92 to 273 days old were included in this study. Axial myopia was induced in 17 marmosets using negative soft contact lenses and 17 marmosets served as untreated controls. Cycloplegic refraction (RE) and vitreous chamber depth (VCD) were measured using autorefraction and A-scan ultrasonography, respectively. Choroidal scans were obtained using spectral-domain optical coherence tomography and binarized to calculate subfoveal choroidal thickness (ChT), total choroidal area (TCA), luminal area (LA), stromal area (SA), choroidal vascularity index (CVI), and LA/SA. To assess photoreceptor activity, the a-wave of the full-field electroretinogram was measured. Regression models were used to investigate the relationship between outcome measures. Results: Eyes induced with axial myopia (RE = -7.14 ± 4.03 diopters [D], VCD = 6.86 ± 0.39 mm) showed significant reductions (4.92-21.24%) in all choroidal parameters (ChT, TCA, LA, SA, CVI, and LA/SA) compared to controls (RE = -1.25 ± 0.60 D, VCD = 6.58 ± 0.26 mm, all P < 0.05), which changed as a function of refraction and vitreous elongation, and were associated with a decrease in the a-wave amplitude. Further, multiple regression showed that a combination of ChT and CVI could well predict RE and VCD. Conclusions: This study reports the existence of significant alterations in choroidal morphology in non-human primate eyes induced with myopia. The changes in choroidal anatomy were associated with reduced light-adapted a-wave amplitude. These findings may represent early markers for reduced visual performance and chorioretinal complications known to occur in eyes with large degrees of myopia.

Age exacerbates the effect of myopia on retinal capillaries and string vessels.

The retinal vasculature supplies oxygen and nutrition to the cells and is crucial for an adequate retinal function. In myopia, excessive eye growth is associated with various anatomical changes that can lead to myopia-related complications. However, how myopia-induced ocular growth affects the integrity of the aged retinal microvasculature at the cellular level is not well understood. Here, we studied how aging interacts with myopia-induced alteration of the retinal microvasculature in fourteen marmoset retinas (Callithrix jacchus). String vessel and capillary branchpoint were imaged and quantified in all four capillary plexi of the retinal vasculature. As marmosets with lens-induced myopia aged, they developed increasing numbers of string vessels in all four vascular plexi, with increased vessel branchpoints in the parafoveal and peripapillary retina and decreased vessel branchpoints in the peripheral retina. These myopia-induced changes to the retinal microvasculature suggest an adaptive reorganization of the retinal microvascular cellular structure template with aging and during myopia development and progression.

Evidence of vascular involvement in myopia: a review.

The benign public perception of myopia (nearsightedness) as a visual inconvenience masks the severity of its sight-threatening consequences. Myopia is a significant risk factor for posterior pole conditions such as maculopathy, choroidal neovascularization and glaucoma, all of which have a vascular component. These associations strongly suggest that myopic eyes might experience vascular alterations prior to the development of complications. Myopic eyes are out of focus because they are larger in size, which in turn affects their overall structure and function, including those of the vascular beds. By reviewing the vascular changes that characterize myopia, this review aims to provide an understanding of the gross, cellular and molecular alterations identified at the structural and functional levels with the goal to provide an understanding of the latest evidence in the field of experimental and clinical myopia vascular research. From the evidence presented, we hypothesize that the interaction between excessive myopic eye growth and vascular alterations are tipping-points for the development of sight-threatening changes.

Development of a novel protocol to evaluate contact-lens related ocular surface health on marmosets (Callithrix jacchus).

Contact lens wear affects the ocular surface and can cause contact lens-induced dry eye (CLIDE). The purpose of this study was bifold: (1) to develop a novel protocol to assess the ocular surface in a non-human primate (NHP) model, the common marmoset (Callithrix jacchus), and (2) to characterize central corneal thickness (CCT), tear osmolarity, blink rate and tear meniscus height (TMH) longitudinally, in untreated marmosets (controls) compared to animals treated with contact lenses (CL). Longitudinal changes in CCT (N = 10 control; N = 10 treated with contact lenses, CL-treated), osmolarity (N = 4 control; N = 6 CL-treated), blink rate (N = 8 control; N = 10 CL-treated) and TMH (N = 8 control; N = 6 CL-treated) were assessed using high frequency A-scan ultrasound, the I-PEN Vet Tear Osmolarity System, a video recording system (745 frames/minute) and Image J respectively, from 70 days to 224 days (5 months) at approx. 9am, and again after 9hrs of CL wear (methafilcon A, 55% water content; Capricornia, Australia) after every 4 weeks of contact lens wear for a total of 22 weeks of treatment. Repeated measures ANOVA was used to compare eyes over time and student t-test was used to compare treated to control eyes at each time point. At baseline, untreated marmosets had a CCT (mean ± SD) of 0.31 ± 0.01 mm, tear osmolarity 311.67 ± 11.48 mOsms/L, blink rate 1.83 ± 1.79 blinks per minute (bpm) and TMH 0.07 ± 0.02 arbitrary units (au), all of which remained stable over 5 months, except blink rate that increased to 5.32 ± 1.58 bpm (p < 0.01) after 5 months. In CL-treated marmosets, however, CCT progressively increased with CL wear (baseline: 0.30 ± 0.01 mm; 5 months: 0.31 ± 0.02 mm, p < 0.05), while osmolarity decreased after 2 and 3 months of CL wear (baseline: 316.11 ± 13.63; 2 months: 302.63 ± 11.27, p < 0.05; 3 months: 302.92 ± 14.58, p < 0.05). The decrease in osmolarity occurred in parallel to an increase in blink rate (baseline: 0.98 ± 1.18 bpm; 2 months: 3.46 ± 3.04 bpm, p < 0.05; 3 months: 3.73 ± 1.50 bpm, p < 0.001). TMH decreased during the third month of CL wear (baseline: 0.06 ± 0.00 au; 3 months: 0.05 ± 0.01 au, p < 0.05), and increased after 4 months (0.08 ± 0.01 au, p < 0.05). As TMH decreased, tear osmolarity increased in both control (R = -0.66, p < 0.05) and CL-treated marmosets (R = -0.64, p < 0.05). The results suggest that marmosets treated with CL for 5 months experienced an increase in blink rate, CCT and TMH, along with a decrease in osmolarity within the first few months of CL treatment that differed from the unaffected stable ocular surface findings observed untreated animals. We hypothesize that CL wear in marmosets might induce an increased blink rate and TMH, in turn delaying the development of hyperosmolarity. These findings confirm that the marmoset is a good novel animal model for ocular surface research for the assessment of novel contact lens materials aimed to alleviate CLIDE.

The age-related pattern of inner retinal thickening is affected by myopia development and progression.

The longitudinal effect of myopic eye growth on each individual retinal layer has not been described to date on an established non-human primate (NHP) model of myopia. We evaluated the changes experienced by the overall and individual central and mid-peripheral retinal thickness profiles in marmosets (Callithrix jacchus) induced with myopia continuously for 5.5 months compared to controls using spectral-domain optical coherence tomography. Cycloplegic refractive state (Rx), vitreous chamber depth (VCD) and retinal thickness were measured at baseline and after 3 and 5.5 months on thirteen marmosets: eight animals with lens-induced myopia and five untreated controls. The overall and individual retinal layer thickness in the central and mid-peripheral retina were obtained and compared between groups. Regression models were used to explore the extent to which VCD or Rx changes could predict the thickness changes observed. While the retinas of control marmosets thickened significantly over 5.5 months, marmosets with lens-induced myopia experienced less retinal thickening and thinning at times, mostly in the inner neuroretinal layers and the ganglion cell-inner plexiform layer. The regression models suggest that 90% of the growth and refractive changes observed could be predicted by the thickness changes in the near to mid peripheral retina. This study confirms the longitudinal effect that myopia has on the inner retina of a NHP model during the early stages of myopia development. The observed myopia-driven differences in inner retina thickness templates might represent early biomarkers of myopia progression and associated complications.

Retinal Microvascular Dysfunction Occurs Early and Similarly in Mild Alzheimer's Disease and Primary-Open Angle Glaucoma Patients.

Purpose: To assess the similarities and differences in retinal microvascular function between mild Alzheimer's disease (AD) patients, early-stage primary open angle glaucoma (POAG) patients and healthy controls. Methods: Retinal vessel reactivity to flickering light was assessed in 10 AD, 19 POAG and 20 healthy age matched control patients by means of dynamic retinal vessel analysis (DVA, IMEDOS, GmbH, Jena, Germany) according to an established protocol. All patients additionally underwent BP measurements and blood analysis for glucose and lipid metabolism markers. Results: AD and POAG patients demonstrated comparable alterations in retinal artery reactivity, in the form of an increased arterial reaction time (RT) to flicker light on the final flicker cycle (p = 0.009), which was not replicated by healthy controls (p > 0.05). Furthermore, the sequential changes in RT on progressing from flicker one to flicker three were found to differ between healthy controls and the two disease groups (p = 0.001). Conclusion: AD and POAG patients demonstrate comparable signs of vascular dysfunction in their retinal arteries at the early stages of their disease process. This provides support for the concept of a common underlying vascular aetiology in these two neurodegenerative diseases.

Myopia Alters the Structural Organization of the Retinal Vasculature, GFAP-Positive Glia, and Ganglion Cell Layer Thickness.

To describe the effect of myopic eye growth on the structure and distribution of astrocytes, vasculature, and retinal nerve fiber layer thickness, which are critical for inner retinal tissue homeostasis and survival. Astrocyte and capillary distribution, retinal nerve fiber (RNFL), and ganglion cell layer (GCL) thicknesses were assessed using immunochemistry and spectral domain optical coherence tomography on eleven retinas of juvenile common marmosets (Callithrix Jacchus), six of which were induced with lens-induced myopia (refraction, Rx: -7.01 ± 1.8D). Five untreated age-matched juvenile marmoset retinas were used as controls (Rx: -0.74 ± 0.4D). Untreated marmoset eyes grew normally, their RNFL thickened and their astrocyte numbers were associated with RNFL thickness. Marmosets with induced myopia did not show this trend and, on the contrary, had reduced astrocyte numbers, increased GFAP-immunopositive staining, thinner RNFL, lower peripheral capillary branching, and increased numbers of string vessels. The myopic changes in retinal astrocytes, vasculature, and retinal nerve fiber layer thickness suggest a reorganization of the astrocyte and vascular templates during myopia development and progression. Whether these adaptations are beneficial or harmful to the retina remains to be investigated.

Temporal properties of positive and negative defocus on emmetropization.

Studying the temporal integration of visual signals is crucial to understand how time spent on different visual tasks can affect emmetropization and refractive error development. In this study we assessed the effect of interrupting positive and negative lens-imposed defocus with brief periods of unrestricted vision or darkness. A total of forty-six marmosets were treated monocularly with soft contact lenses for 4 weeks from 10 weeks of age (OD: + 5D or - 5D; OS: plano). Two control groups wore + 5D (n = 5) or - 5D (n = 13) lenses continuously for 9 h/day. Two experimental groups had lens-wear interrupted for 30 min twice/day at noon and mid-afternoon by removing lenses and monitoring vision while marmosets sat at the center of a viewing cylinder (normal vision interruption, + 5D: n = 7; - 5D: n = 8) or while they were in the dark (dark interruption, + 5D: n = 7; - 5D: n = 6). The interruption period (30 min/day) represented approx. 10% of the total stimulation time (9 h/day). On-axis refractive error (RE) and vitreous chamber depth (VCD) were measured using an autorefractor and high frequency A-scan ultrasound at baseline and after treatment. Wearing + 5D lenses continuously 9 h/day for 4 weeks induced slowed eye growth and hyperopic shifts in RE in treated relative to contralateral control eyes (relative change, VCD: - 25 ± 11 µm, p > 0.05; RE: + 1.24 ± 0.58 D, p > 0.05), whereas - 5D lens wear resulted in larger and myopic eyes (relative change, VCD: + 109 ± 24 µm, p < 0.001; RE: - 2.03 ± 0.56 D, p < 0.05), significantly different from those in the + 5D lens-treated animals (p < 0.01 for both). Interrupting lens induced defocus with periods of normal vision or darkness for approx. 10% of the treatment time affected the resulting compensation differently for myopic and hyperopic defocus. Interrupting defocus with unrestricted vision reduced - 5D defocus compensation but enhanced + 5D defocus compensation (- 5D, VCD: + 18 ± 33 µm; RE: - 0.93 ± 0.50 D, both p > 0.05; + 5D, VCD: - 86 ± 30 µm; RE: + 1.93 ± 0.50 D, both p < 0.05). Interrupting defocus with darkness also decreased - 5D defocus compensation, but had little effect on + 5D defocus compensation (- 5D, VCD: + 73 ± 34 µm, RE: - 1.13 ± 0.77 D, p > 0.05 for both; + 5D, VCD: - 10 ± 28 µm, RE: + 1.22 ± 0.50 D, p > 0.05 for both). These findings in a non-human primate model of emmetropization are similar to those described in other species and confirm a non-linear model of visual signal integration over time. This suggests a mechanism that is conserved across species and may have clinical implications for myopia management in school-aged children.

A Robust Microbead Occlusion Model of Glaucoma for the Common Marmoset.

Purpose: To establish a robust experimental model of glaucoma in the common marmoset (Callithrix jacchus), a New World primate, using an intracameral microbead injection technique. Methods: Elevated intraocular pressure (IOP) was induced by an injection of polystyrene microbeads. Morphologic changes in the retina and optic nerve of glaucomatous eyes were assessed and electroretinogram (ERG) recordings were performed to evaluate functional changes. Results: Microbead injections induced a sustained IOP elevation for at least 10 weeks in a reproducible manner. At the end of the 10-week experimental period, there was significant loss of retinal ganglion cells (RGCs) in all quadrants and eccentricities, although it was more prominent in the mid-peripheral and peripheral regions. This was consistent with a thinning of the Retinal nerve fiber layer (RNFL) seen in spectral domain optical coherence tomography scans. Surviving RGCs showed marked changes in morphology, including somatic shrinkage and dendritic atrophy. Retinas also showed significant gliosis. The amplitude of the ERG photopic negative response, with subsequent a- and b-wave changes, was reduced in glaucomatous eyes. The optic nerve of glaucomatous eyes showed expanded cupping, disorganization of the astrocytic matrix, axonal loss, and gliosis. Conclusions: We developed a robust and reproducible model of glaucoma in the marmoset. The model exhibits both structural and functional alterations of retina and optic nerve characteristic of glaucoma in humans and animal models. Translational Relevance: The glaucoma model in the marmoset described here forms a robust method to study the disease etiology, progression, and potential therapies in a nonhuman primate, allowing for more effective translation of animal data to humans.

Optical mechanisms regulating emmetropisation and refractive errors: evidence from animal models.

Our current understanding of emmetropisation and myopia development has evolved from decades of work in various animal models, including chicks, non-human primates, tree shrews, guinea pigs, and mice. Extensive research on optical, biochemical, and environmental mechanisms contributing to refractive error development in animal models has provided insights into eye growth in humans. Importantly, animal models have taught us that eye growth is locally controlled within the eye, and can be influenced by the visual environment. This review will focus on information gained from animal studies regarding the role of optical mechanisms in guiding eye growth, and how these investigations have inspired studies in humans. We will first discuss how researchers came to understand that emmetropisation is guided by visual feedback, and how this can be manipulated by form-deprivation and lens-induced defocus to induce refractive errors in animal models. We will then discuss various aspects of accommodation that have been implicated in refractive error development, including accommodative microfluctuations and accommodative lag. Next, the impact of higher order aberrations and peripheral defocus will be discussed. Lastly, recent evidence suggesting that the spectral and temporal properties of light influence eye growth, and how this might be leveraged to treat myopia in children, will be presented. Taken together, these findings from animal models have significantly advanced our knowledge about the optical mechanisms contributing to eye growth in humans, and will continue to contribute to the development of novel and effective treatment options for slowing myopia progression in children.

Short Interruptions of Imposed Hyperopic Defocus Earlier in Treatment are More Effective at Preventing Myopia Development.

The purpose of this study was to evaluate the effect of interrupting negative lens wear for short periods early or late during the development of lens-induced myopia in marmosets. Sixteen marmosets were reared with a -5D contact lens on their right eye (plano on contralateral eye) for 8 weeks. Eight marmosets had lenses removed for 30 mins twice/day during the first four weeks (early interruption) and eight during the last four weeks (late interruption). Data were compared to treated controls that wore lenses continuously (N = 12) and untreated controls (N = 10). Interocular differences (IOD) in vitreous chamber (VC) depth and central and peripheral mean spherical refractive error (MSE) were measured at baseline and after four (T4) and eight (T8) weeks of treatment. Visual experience during the interruptions was monitored by measuring refraction while marmosets were seated at the center of a 1 m radius viewing cylinder. At T4 the eyes that were interrupted early were not different from untreated controls (p = 0.10) and at T8 had grown less and were less myopic than those interrupted later (IOD change from baseline, VC: +0.07 ± 0.04 mm vs +0.20 ± 0.03 mm, p < 0.05; MSE: -1.59 ± 0.26D vs -2.63 ± 0.60D, p = 0.13). Eyes interrupted later were not different from treated controls (MSE, p = 0.99; VC, p = 0.60) and grew at the same rate as during the first four weeks of uninterrupted lens wear (T4 - T0: 3.67 ± 1.1 µm/day, T8 - T4: 3.56 ± 1.3 µm/day p = 0.96). Peripheral refraction was a predictive factor for the amount of myopia developed only when the interruption was not effective. In summary, interrupting hyperopic defocus with short periods of myopic defocus before compensation occurs prevents axial myopia from developing. After myopia develops, interruption is less effective.

Gene expression in response to optical defocus of opposite signs reveals bidirectional mechanism of visually guided eye growth.

Myopia (nearsightedness) is the most common eye disorder, which is rapidly becoming one of the leading causes of vision loss in several parts of the world because of a recent sharp increase in prevalence. Nearwork, which produces hyperopic optical defocus on the retina, has been implicated as one of the environmental risk factors causing myopia in humans. Experimental studies have shown that hyperopic defocus imposed by negative power lenses placed in front of the eye accelerates eye growth and causes myopia, whereas myopic defocus imposed by positive lenses slows eye growth and produces a compensatory hyperopic shift in refractive state. The balance between these two optical signals is thought to regulate refractive eye development; however, the ability of the retina to recognize the sign of optical defocus and the composition of molecular signaling pathways guiding emmetropization are the subjects of intense investigation and debate. We found that the retina can readily distinguish between imposed myopic and hyperopic defocus, and identified key signaling pathways underlying retinal response to the defocus of different signs. Comparison of retinal transcriptomes in common marmosets exposed to either myopic or hyperopic defocus for 10 days or 5 weeks revealed that the primate retina responds to defocus of different signs by activation or suppression of largely distinct pathways. We also found that 29 genes differentially expressed in the marmoset retina in response to imposed defocus are localized within human myopia quantitative trait loci (QTLs), suggesting functional overlap between genes differentially expressed in the marmoset retina upon exposure to optical defocus and genes causing myopia in humans. These findings identify retinal pathways involved in the development of myopia, as well as potential new strategies for its treatment.

The Effect of Anesthesia on Blood Pressure Measured Noninvasively by Using the Tail-Cuff Method in Marmosets (Callithrix jacchus).

In this study, we evaluated the validity of measuring blood pressure (BP) noninvasively in marmosets by using the tail-cuff method. The number of measurements needed for a valid reading was calculated by plotting the average SD of 5 consecutive readings in 10 naïve marmosets; the SD for both systolic and diastolic BP readings plateaued after 4 readings. To evaluate how anesthesia (alphaxalone, 15 mg/kg IM) affected BP in marmosets, we measured 4 animals every minute for 60 min after injection. The average length of anesthesia was 47.3 ± 13.2 min. The variability in the systolic and diastolic BP was the smallest at 10 to 30 min after injection (systolic SD, 6.29 mm Hg; diastolic SD, 5.27 mm Hg) and almost doubled at 30 to 60 min after injection (systolic SD, 13.5 mm Hg; diastolic SD, 12.3 mm Hg). The within- and between-session repeatability and reproducibility were calculated by measuring 12 marmosets twice at the same time of day (±1 h) 1 wk apart. The coefficients of repeatability and reproducibility were 1.98% and 14.5% for systolic BP and 3.37% and 16.2% for diastolic BP, respectively. Our results indicate that using the volumetric tail-cuff method to measure BP noninvasively in anesthetized marmosets is safe and feasible. The measures are least variable within 10 to 30 min after the injection of anesthetic, and variability increases slightly between sessions.

Axial eye growth and refractive error development can be modified by exposing the peripheral retina to relative myopic or hyperopic defocus.

PURPOSE: Bifocal contact lenses were used to impose hyperopic and myopic defocus on the peripheral retina of marmosets. Eye growth and refractive state were compared with untreated animals and those treated with single-vision or multizone contact lenses from earlier studies. METHODS: Thirty juvenile marmosets wore one of three experimental annular bifocal contact lens designs on their right eyes and a plano contact lens on the left eye as a control for 10 weeks from 70 days of age (10 marmosets/group). The experimental designs had plano center zones (1.5 or 3 mm) and +5 diopters [D] or -5 D in the periphery (referred to as +5 D/1.5 mm, +5 D/3 mm and -5 D/3 mm). We measured the central and peripheral mean spherical refractive error (MSE), vitreous chamber depth (VC), pupil diameter (PD), calculated eye growth, and myopia progression rates prior to and during treatment. The results were compared with age-matched untreated (N=25), single-vision positive (N=19), negative (N=16), and +5/-5 D multizone lens-reared marmosets (N=10). RESULTS: At the end of treatment, animals in the -5 D/3 mm group had larger (P<0.01) and more myopic eyes (P<0.05) than animals in the +5 D/1.5 mm group. There was a dose-dependent relationship between the peripheral treatment zone area and the treatment-induced changes in eye growth and refractive state. Pretreatment ocular growth rates and baseline peripheral refraction accounted for 40% of the induced refraction and axial growth rate changes. CONCLUSIONS: Eye growth and refractive state can be manipulated by altering peripheral retinal defocus. Imposing peripheral hyperopic defocus produces axial myopia, whereas peripheral myopic defocus produces axial hyperopia. The effects are smaller than using single-vision contact lenses that impose full-field defocus, but support the use of bifocal or multifocal contact lenses as an effective treatment for myopia control.

Primary open-angle glaucoma vs normal-tension glaucoma: the vascular perspective.

OBJECTIVE: To compare and contrast the presence of ocular and systemic vascular function in patients with newly diagnosed and previously untreated primary open-angle glaucoma (POAG) vs those with normal-tension glaucoma (NTG) and comparable early-stage, functional loss. METHODS: The systemic vascular function of 19 patients with POAG, 19 patients with NTG, and 20 healthy individuals serving as controls was assessed using 24-hour ambulatory blood pressure monitoring, peripheral pulse-wave analysis, and carotid intima-media thickness. Retinal vascular reactivity to flicker light was assessed using dynamic retinal vessel analysis (Imedos, GmbH). RESULTS: Compared with controls, patients with POAG and those with NTG exhibited similarly increased nocturnal systemic blood pressure variability (P = .01), peripheral arterial stiffness (P = .02), carotid intima-media thickness (P = .04), and reduced ocular perfusion pressure (P < .001). Furthermore, on dynamic retinal vessel analysis, both glaucoma groups exhibited steeper retinal arterial constriction slopes after cessation of flicker (P = .007) and a similarly increased fluctuation in arterial and venous baseline diameter (P = .008 and P = .009, respectively) compared with controls. CONCLUSIONS: Patients with POAG or NTG exhibit similar alterations in ocular and systemic circulation in the early stages of their disease process. This finding highlights the importance of considering vascular risk factors in both conditions and raises questions about the current separation of the two conditions into distinct clinical entities.

Coexistence of macro- and micro-vascular abnormalities in newly diagnosed normal tension glaucoma patients.

PURPOSE: To investigate the coexistence of ocular microvascular and systemic macrovascular abnormalities in early stage, newly diagnosed and previously untreated normal tension glaucoma patients (NTG). METHODS: Retinal vascular reactivity to flickering light was assessed in 19 NTG and 28 age-matched controls by means of dynamic retinal vessel analysis (IMEDOS GmbH, Jena, Germany). Using a newly developed computational model, the entire dynamic vascular response profile to flicker light was imaged and used for analysis. In addition, assessments of carotid intima-media thickness (IMT) and pulse wave analysis (PWA) were conducted on all participants, along with blood pressure (BP) measurements and blood analyses for lipid metabolism markers. RESULTS: Patients with NTG demonstrated an increased right and left carotid IMT (p = 0.015, p = 0.045) and an elevated PWA augmentation index (p = 0.017) in comparison with healthy controls, along with an enhanced retinal arterial constriction response (p = 0.028), a steeper retinal arterial constriction slope (p = 0.031) and a reduced retinal venous dilation response (p = 0.026) following flicker light stimulation. CONCLUSIONS: Early stage, newly diagnosed, NTG patients showed signs of subclinical vascular abnormalities at both macro- and micro-vascular levels, highlighting the need to consider multi-level circulation-related pathologies in the development and progression of this type of glaucoma.

The effect of simultaneous negative and positive defocus on eye growth and development of refractive state in marmosets.

PURPOSE: We evaluated the effect of imposing negative and positive defocus simultaneously on the eye growth and refractive state of the common marmoset, a New World primate that compensates for either negative and positive defocus when they are imposed individually. METHODS: Ten marmosets were reared with multizone contact lenses of alternating powers (-5 diopters [D]/+5 D), 50:50 ratio for average pupil of 2.80 mm over the right eye (experimental) and plano over the fellow eye (control) from 10 to 12 weeks. The effects on refraction (mean spherical equivalent [MSE]) and vitreous chamber depth (VC) were measured and compared to untreated, and -5 D and +5 D single vision contact lens-reared marmosets. RESULTS: Over the course of the treatment, pupil diameters ranged from 2.26 to 2.76 mm, leading to 1.5 times greater exposure to negative than positive power zones. Despite this, at different intervals during treatment, treated eyes were on average relatively more hyperopic and smaller than controls (experimental-control [exp-con] mean MSE ± SE +1.44 ± 0.45 D, mean VC ± SE -0.05 ± 0.02 mm) and the effects were similar to those in marmosets raised on +5 D single vision contact lenses (exp-con mean MSE ± SE +1.62 ± 0.44 D. mean VC ± SE -0.06 ± 0.03 mm). Six weeks into treatment, the interocular growth rates in multizone animals were already lower than in -5 D-treated animals (multizone -1.0 ± 0.1 µm/day, -5 D +2.1 ± 0.9 µm/day) and did not change significantly throughout treatment. CONCLUSIONS: Imposing hyperopic and myopic defocus simultaneously using concentric contact lenses resulted in relatively smaller and less myopic eyes, despite treated eyes being exposed to a greater percentage of negative defocus. Exposing the retina to combined dioptric powers with multifocal lenses that include positive defocus might be an effective treatment to control myopia development or progression.