Neuroretinal rim response to transient changes in intraocular pressure in healthy non-human primate eyes

https://doi.org/10.1016/j.exer.2020.107978Get rights and content

Highlights

  • Changes in intraocular pressure result in rapid changes in the neuroretinal rim.

  • The neuroretinal rim continues to change over a period of 2 h with sustained IOP.

  • Residual thinning of the neuroretinal rim persists after 2 h of IOP reduction.

  • There is individual variability in the rate and extent of rim tissue thinning.

Abstract

Optic nerve head (ONH) neuroretinal rim thickness, quantified as minimum rim width (BMO-MRW), is a sensitive measure for assessing early glaucomatous disease. The BMO-MRW is sensitive to transient fluctuations in intraocular pressure (IOP), but the time course over which BMO-MRW decreases and recovers with changes in IOP remains unknown. The goal of this study was to investigate the dynamics of BMO-MRW changes over 2-h periods of mild or moderate IOP elevation, and subsequent recovery, in healthy non-human primate eyes. Eight non-human primates were included in the study. For each animal, in two different sessions separated by at least 2 weeks, the anterior chamber IOP of one eye was maintained at either 25 mmHg or 40 mmHg for 2 h and, subsequently, at 10 mmHg for 2 h. For the duration of anterior chamber cannulation, optical coherence tomography (OCT) radial scans centered on the ONH were acquired every 5 min and used to quantify BMO-MRW. An exponential decay or rise to maximum function was used to determine the extent and rate of structural change. Additionally, Bruch's membrane opening (BMO) area, BMO height/displacement, and BMO-referenced anterior lamina cribrosa surface depth (BMO-ALCSD) were computed from radial scans. A circular scan was used to quantify retinal nerve fiber layer thickness (RNFLT) and circumpapillary choroid thickness. The primary results demonstrated that the BMO-MRW changed over an extended duration, while BMO displacement was rapid and remained stable with sustained IOP. The mean maximum predicted BMO-MRW thinning following 2 h of IOP elevation was significantly related to pressure (34.2 ± 13.8 μm for an IOP of 25 mmHg vs 40.5 ± 12.6 μm for 40 mmHg, p = 0.03). The half-life for BMO-MRW thinning was 21.9 ± 9.2 min for 25 mmHg and 20.9 ± 4.2 min for 40 mmHg, not significantly different between IOP levels (p = 0.76). Subsequently, after 2 h of IOP at 10 mmHg, all animals exhibited partial recovery of BMO-MRW with similar degrees of persistent residual thinning for the two IOP levels (21.5 ± 13.7 vs 21.0 ± 12.3 μm, p = 0.88). Similar to BMO-MRW, choroid thickness exhibited gradual thinning with IOP elevation and residual thinning following IOP reduction. However, there was no significant change in BMO area or BMO-ALCSD in either experimental session. The RNFLT gradually decreased over the duration of IOP elevation, with continued decreases following IOP reduction for the 40 mmHg session, resulting in total changes from baseline of −2.24 ± 0.81 and −2.45 ± 1.21 μm for 25 and 40 mmHg, respectively (p < 0.001). The sum of the results demonstrate that the ONH neural tissue is sensitive to changes in IOP, the effects of which are gradual over an extended time course and different for increased vs. decreased pressure. Understanding the duration over which IOP influences BMO-MRW has important implications for studies investigating the effects of IOP on the ONH. Additionally, individual variability in ONH response to IOP may improve our understanding of the risk and progression of disease.

Introduction

Glaucoma is a group of optic neuropathies characterized by progressive vision loss and structural changes to the optic nerve head (ONH) and retinal ganglion cell- (RGC-) containing layers of the retina. Though the mechanism underlying glaucoma remains elusive, intraocular pressure (IOP) is known to be a major risk factor for disease.

The ONH, a relative weak point in the posterior aspect of the globe, is susceptible to the influence of IOP and has been described as the initial site of damage in glaucoma (Downs, 2015; Howell et al., 2007; Quigley et al., 1983). ONH parameters, quantified using optical coherence tomography (OCT), have been shown to change early in disease. In fact, the ONH minimum rim width (BMO-MRW), a measure of the neuroretinal rim, thins prior to other RGC-containing layers such as the retinal nerve fiber layer (RNFL) (Chauhan et al., 2013; He et al., 2014; Ivers et al., 2015; Patel et al., 2014; Reis et al., 2012). These findings suggest that BMO-MRW may have utility in detecting early stages of disease. It has been proposed that early BMO-MRW changes occur as a result of compression and/or stretching of axon bundles within the ONH (Fortune et al., 2016b), but the temporal relationships between BMO-MRW and IOP have not been well-defined. These relationships are necessary to evaluate the general hypothesis that IOP-associated changes of the neuroretinal rim are related to the health of the eye and are a harbinger for IOP susceptibility in glaucoma.

Non-human primates (NHP) are an excellent model for studying ONH structural changes in response to IOP and experimental glaucoma because their ONH anatomy is very similar to that of humans. Studies in healthy NHP have demonstrated that exposure to short-duration changes in IOP results in substantial changes to the neuroretinal rim (Patel et al., 2018; Strouthidis et al., 2011). In our previous work, using 10 mmHg increments in IOP at 10 min intervals, significant changes in ONH BMO-MRW, Bruch's membrane opening (BMO) position, and choroid thickness were seen. While most of these structural measures returned to baseline when IOP was returned to 10 mmHg, there was significant residual thinning of BMO-MRW with IOP reduction (Patel et al., 2018). However, the short periods of IOP challenge did not allow an assessment of neuroretinal rim tissue dynamics with modulation of IOP. As a result, it is not known whether the full extent of neuroretinal rim thinning/recovery was achieved, or if the rim tissue would continue to thin/recover over a longer period. Establishing the dynamics of neuroretinal rim change with short-term, sustained IOP modulation has important implications for both glaucoma pathophysiology and clinical practice. Therefore, the present investigations were undertaken to determine these effects over 2-h periods of mild and moderate IOP elevation, and subsequent IOP reduction, in healthy NHP eyes.

Section snippets

Subjects

Eight healthy NHP (Macaca mulatta) were included in the study. The subjects included six males and two females, ranging in age from 4.8 to 5.8 years (mean age 5.6 years). For each subject, one eye was used in the study. Experimental procedures and animal care protocols were approved by the Institutional Animal Care and Use Committee at the University of Houston and adhered to the National Institutes of Health guidelines for the care and use of laboratory animals.

Animal preparation

Prior to all experimental

Results

All animals maintained good systemic health during the experiments and throughout the duration of the study, and no adverse ocular events occurred as a result of cannulation. For each animal, experimental sessions were separated in time by at least 2 weeks. There was no significant difference in baseline BMO-MRW (p = 0.22) or baseline RNFL thickness (p = 0.72) between the first and second experimental sessions, suggesting that neither elevating IOP for 2 h nor cannulation results in permanent

Discussion

The present study demonstrated that the neuroretinal rim, quantified as minimum rim width (BMO-MRW), thins gradually over a prolonged time course when IOP is elevated and held at a mild-to-moderate level and approaches an asymptote with approximately 2 h of IOP elevation. In addition, the neuroretinal rim does not return to baseline, but rather approaches an asymptote, with 2 h of relatively low IOP. Our results also show that the pressure-induced neuroretinal rim changes are not related to

Conclusions

In conclusion, this study confirms that the neuroretinal rim is sensitive to mild and moderate elevations in IOP and demonstrates that the neuroretinal rim changes over a prolonged time course with substantial residual thinning following IOP reduction and that there is considerable variability among individuals with regards to the extent of thinning and recovery. Characteristics of BMO-MRW dynamics with IOP modulation may provide important information regarding ONH compliance and risk of

Funding

This work was supported by the National Institutes of Health [R01 EY029229, P30 EY007551] and the University of Houston Mary Murphy Research Endowment.

Declaration of competing interest

None.

Acknowledgements

The authors thank Dr. Faith McAllister for her assistance with optical coherence tomography segmentations.

References (55)

  • A.J. Bellezza et al.

    Anterior scleral canal geometry in pressurised (IOP 10) and non-pressurised (IOP 0) normal monkey eyes

    Br. J. Ophthalmol.

    (2003)
  • M.R. Beotra et al.

    In vivo three-dimensional lamina cribrosa strains in healthy, ocular hypertensive, and glaucoma eyes following acute intraocular pressure elevation

    Invest. Ophthalmol. Vis. Sci.

    (2018)
  • C. Boote et al.

    Scleral structure and biomechanics

    Prog. Retin. Eye Res.

    (2019)
  • H.J. Choi et al.

    Astrocytes in the optic nerve head express putative mechanosensitive channels

    Mol. Vis.

    (2015)
  • B. Coudrillier et al.

    Collagen structure and mechanical properties of the human sclera: analysis for the effects of age

    J. Biomech. Eng.

    (2015)
  • B. Coudrillier et al.

    Glaucoma-related changes in the mechanical properties and collagen micro-architecture of the human sclera

    PloS One

    (2015)
  • B. Coudrillier et al.

    Biomechanics of the human posterior sclera: age- and glaucoma-related changes measured using inflation testing

    Invest. Ophthalmol. Vis. Sci.

    (2012)
  • J.C. Downs et al.

    Peripapillary scleral thickness in perfusion-fixed normal monkey eyes

    Invest. Ophthalmol. Vis. Sci.

    (2002)
  • J.C. Downs et al.

    Viscoelastic material properties of the peripapillary sclera in normal and early-glaucoma monkey eyes

    Invest. Ophthalmol. Vis. Sci.

    (2005)
  • M.A. Fazio et al.

    The relationship between scleral strain change and differential cumulative intraocular pressure exposure in the nonhuman primate chronic ocular hypertension model

    Invest. Ophthalmol. Vis. Sci.

    (2019)
  • M.A. Fazio et al.

    Age-related changes in human peripapillary scleral strain

    Biomech. Model. Mechanobiol.

    (2014)
  • M.A. Fazio et al.

    Displacement of the lamina cribrosa in response to acute intraocular pressure elevation in normal individuals of african and European descent

    Invest. Ophthalmol. Vis. Sci.

    (2016)
  • A.J. Feola et al.

    The impact of choroidal swelling on optic nerve head deformation

    Invest. Ophthalmol. Vis. Sci.

    (2018)
  • B. Fortune et al.

    Comparing optic nerve head rim width, rim area, and peripapillary retinal nerve fiber layer thickness to axon count in experimental glaucoma

    Invest. Ophthalmol. Vis. Sci.

    (2016)
  • B. Fortune et al.

    Optic nerve head (ONH) hypercompliance and blood flow autoregulation dysfunction detected by OCT-angiography (OCTA) in early-stage experimental glaucoma

    Invest Ophthalmol Vis Sci ARVO E-Abstract

    (2019)
  • B. Fortune et al.

    Experimental glaucoma causes optic nerve head neural rim tissue compression: a potentially important mechanism of axon injury

    Invest. Ophthalmol. Vis. Sci.

    (2016)
  • B. Fortune et al.

    The effect of acute intraocular pressure elevation on peripapillary retinal thickness, retinal nerve fiber layer thickness, and retardance

    Invest. Ophthalmol. Vis. Sci.

    (2009)
  • Cited by (0)

    View full text