Elsevier

Experimental Eye Research

Volume 89, Issue 5, November 2009, Pages 618-628
Experimental Eye Research

Histomorphometric measurements in human and dog optic nerve and an estimation of optic nerve pressure gradients in human

https://doi.org/10.1016/j.exer.2009.06.002Get rights and content

Abstract

Intraocular pressure and cerebrospinal fluid (CSF) pressure are important determinants of the trans-laminar pressure gradient which is believed to be important in the pathogenesis of glaucomatous optic nerve degeneration. Computational models and finite element calculations of optic nerve head biomechanics have been previously used to predict pressures and stresses in the human optic nerve. The purpose of this report is to morphometrically compare the optic nerve laminar and pia mater structure between humans and dogs, and to use previously reported tissue pressure measurements in the dog optic nerve to estimate individual-specific human optic nerve pressures and pressure gradients. High resolution light microscopy was used to acquire quantitative histological measurements from sagittal sections taken from the middle of the optic nerve in 34 human cadaveric eyes and 10 dog eyes. Parameters measured included the pre-laminar and lamina cribrosa thickness, distance from posterior boundary of lamina cribrosa to inner limiting membrane (ILM), shortest distance between anterior lamina cribrosa surface and subarachnoid space, shortest distance between ILM and inner surface of pia mater in contact with the subarachnoid space and optic nerve diameter. Pia mater thickness in the proximal 4 mm of post-laminar nerve was also determined. There was no significant difference in lamina cribrosa thickness between dog and human eyes (P = 0.356). The distance between the intraocular and subarachnoid space was greater in dogs (P < 0.001). Pia mater thickness was greatest at the termination of subarachnoid space in both species. In humans, pia mater thickness decreased over the proximal 500 μm to reach a constant value of approximately 60 μm. In dogs this decrease occurred over 1000 μm to reach a constant diameter of approximately 30 μm. Using previous measurements of optic nerve pressures and pressure gradients in dogs we estimate that at an IOP of 15 mmHg and a CSF pressure of 0 mmHg the mean pressure difference across the human pia mater will be 4.8 ± 2.2 mmHg. If we assume that the pressure difference between the intraocular space and post-laminar tissue falls across the entire thickness of the human lamina cribrosa then an estimate of the trans-laminar pressure gradient is 2.0 ± 0.8 mmHg/100 μm. If we assume that this pressure difference only occurs across the dense collagenous plates of the posterior lamina cribrosa then a trans-laminar pressure gradient high estimate of 3.3 ± 1.4 mmHg/100 μm is calculated. Changes in tissue pressure gradients in the optic nerve may be an important factor in the pathogenesis of glaucomatous optic neuropathy.

Introduction

The optic nerve head is situated in a unique physiological environment where retinal ganglion cell axons experience a change in tissue pressure and a significant pressure gradient as they exit the eye in their course towards the brain (Morgan et al., 1995, Morgan et al., 1998). The lamina cribrosa partitions the optic disk and plays an important role in accommodating the pressure gradient between the eye and cerebrospinal fluid (CSF) pressure compartment (Sigal et al., 2007, Anderson, 1969a). Neural tissue pressure anterior to the lamina cribrosa is determined by intraocular pressure (IOP) while post-laminar neural tissue pressure is largely determined by CSF pressure in the subarachnoid space (Morgan et al., 1995, Morgan et al., 1998). Long term changes in the physiological pressure gradient acting across the lamina cribrosa due to alterations in IOP or CSF pressure can result in axonal injury leading to the irreversible loss of retinal ganglion cells (Tso and Hayreh, 1977, Quigley and Green, 1979). Elevated IOP results in an increase in the trans-laminar pressure gradient and is major risk factor for the development of glaucomatous optic nerve damage (Sommer et al., 1991). More recent work demonstrates that low CSF pressure is also associated with glaucoma, emphasising the importance of considering the gradient across the optic nerve when considering glaucoma aetiology (Berdahl et al., 2008a, Berdahl et al., 2008b).

The size of a pressure gradient is dependent on the total pressure on either side of the boundary, the boundary tissue characteristics and its thickness. Although there have been several studies that have examined the relationship between lamina cribrosa structure and the trans-laminar pressure gradient (Jonas et al., 2003, Jonas et al., 2004), there is still a paucity of knowledge regarding the structure, dimensions and physiological environment of the post-laminar human optic nerve. Because post-laminar tissue pressure is a major determinant of the trans-laminar pressure gradient a detailed understanding regarding the structure and function of this region may be important in clarifying the process underlying optic nerve axonal damage following IOP and CSF pressure changes.

The physiological and cellular environment of the post-laminar optic nerve is different to that of the pre-laminar region with retinal ganglion cell axons acquiring a myelin and meningeal sheath as they pass through the lamina cribrosa. The pia mater, which is the innermost layer of the optic nerve meninges is comprised mostly of connective tissue that is lined by mesothelial cells on the CSF surface and a glial network on the neural surface (Anderson, 1969b). Although the structure of the pia mater has been previously reported in the form of detailed histological studies (Anderson, 1969b), the functional role of this structure remains uncertain. Recent work using finite element modelling has predicted large stresses within proximal pia mater following IOP elevation, suggesting that pia mater structural characteristics may be important for bearing optic nerve forces (Sigal et al., 2007). We have previously performed in vivo tissue pressure measurements of the dog optic nerve and have shown that the pia mater supports a pressure difference between the subarachnoid space and post-laminar neural tissue (Morgan et al., 1998). In this previous report we were able to demonstrate that the pressure difference between the subarachnoid space and post-laminar tissue space remains relatively constant when CSF pressure fluctuated below 1.3 mmHg, and increased equally with CSF pressure when the latter was above 1.3 mmHg (Morgan et al., 1998). This suggests that optic nerve pia mater plays a damping role by minimising post-laminar tissue pressure decrease as CSF pressure falls and by doing so may diminish the increase in the pressure gradient acting across the lamina cribrosa. In this regard the pia mater may be important in providing some indirect protection to RGC axons at the lamina cribrosa.

The detailed histomorphometric studies of the human optic nerve that have been performed by Jonas and colleagues have greatly enhanced our understanding of lamina cribrosa and optic nerve head structure (Jonas et al., 1990, Jonas et al., 2003, Jonas et al., 2004). These studies have also provided insight into the anatomical relationship between the intraocular space and CSF space and have provided critical knowledge regarding the patho-physiological mechanisms underlying pressure-induced optic nerve damage. Theoretical studies concerning optic nerve biomechanics have often modelled the post-laminar optic nerve as a cylinder (Sigal et al., 2005a, Sigal et al., 2005b, Sigal et al., 2007). In addition to laminar thickness, input factors that have been used to approximate optic nerve stresses in these theoretical studies have also included pia mater thickness and optic nerve diameter (Sigal et al., 2005a).

This report is a detailed morphometric study of the human and dog optic nerve head that includes the optic nerve region immediately posterior to the lamina cribrosa. The purpose of the study is to compare the morphometric structure of key regions of the human optic nerve with that in the dog, an animal model in which tissue pressures and pressure gradients have been determined by direct measurement. After establishing similarities and differences between dog and human optic nerves we extrapolate optic nerve pressure gradient data from dog eyes to predict likely tissue pressures and pressure gradients in the human optic nerve. In making our extrapolations and calculations we account for inter-individual differences in human optic nerve head geometry by using individual-specific laminar, pia mater and optic nerve measurements to determine individual-specific estimates of optic nerve pressure gradients. The predicted tissue pressure gradients in the human optic nerve presented in this report may be an important pathogenic factor in glaucomatous optic nerve degeneration.

Section snippets

Materials and methods

All experiments were conducted and all laboratory animals were treated in accordance with the ARVO statement for the Use of Animals in Ophthalmic and Vision Research. All human tissue was handled according to the tenets of the Declaration of Helsinki. The study was approved by the University of Western Australia Animal Ethics and Human Ethics Committees.

Human donor and dog details

The mean age of human donors was 43.0 ± 3.1 years (age range 15–64 years). We examined 17 right eyes and 17 left eyes from a total of 17 male and 3 female donors. The average postmortem time before human eyes were enucleated was 11.6 ± 0.8 h. Dog eyes were obtained from a cohort of animals that consisted of Bull Terriers, Blue Heelers, Kelpie and Alsation. The mean weight of dogs was 20 kg (range 15–22 kg).

Human histomorphometric measurements

The mean values for human histomorphometric measurements are presented in Table 2. The

Discussion

The major findings in this study are: (1) there is no significant difference in lamina cribrosa thickness between dogs and humans. (2) The shortest distance between intraocular space and subarachnoid space is greater in dogs than in humans. (3) The diameter of the human optic nerve 1 mm behind the lamina cribrosa is greater than dogs. (4) Pia mater thickness is greatest at the termination of the optic nerve subarachnoid space in both species and gradually declines in thickness along the

Acknowledgements

The authors thank staff from the Lions Eye Bank of Western Australia, Lions Eye Institute for provision of human donor eyes and staff from DonateWest the Western Australian agency for organ and tissue donation who facilitated the recruitment of donors into the study by referral and completion of consent processes. Grant support was provided by the National Health and Medical Research Council of Australia and the Australian Research Council Centre of Excellence in Vision Science.

References (34)

  • J.P. Berdahl et al.

    Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma

    Ophthalmology

    (2008)
  • D.E. Brooks et al.

    Histomorphometry of the optic nerves of normal dogs and dogs with hereditary glaucoma

    Exp. Eye Res.

    (1995)
  • I.A. Sigal et al.

    Predicted extension, compression and shearing of optic nerve head tissues

    Exp. Eye Res.

    (2007)
  • D.H. Abramson et al.

    Optic nerve tissue shrinkage during pathologic processing after enucleation for retinoblastoma

    Arch. Ophthalmol.

    (2003)
  • D.R. Anderson

    Ultrastructure of human and monkey lamina cribrosa and optic nerve head

    Arch. Ophthalmol.

    (1969)
  • D.R. Anderson

    Ultrastructure of meningeal sheaths. Normal human and monkey optic nerves

    Arch. Ophthalmol.

    (1969)
  • D.R. Anderson

    Ultrastructure of the optic nerve head

    Arch. Ophthalmol.

    (1970)
  • D.R. Anderson et al.

    Ultrastructure of intraorbital portion of human and monkey optic nerve

    Arch. Ophthalmol.

    (1969)
  • J.P. Berdahl et al.

    Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study

    Invest. Ophthalmol. Vis. Sci.

    (2008)
  • D.E. Brooks et al.

    Morphologic changes in the lamina cribrosa of beagles with primary open-angle glaucoma

    Am. J. Vet. Res.

    (1989)
  • C.F. Burgoyne et al.

    Three-dimensional reconstruction of normal and early glaucoma monkey optic nerve head connective tissues

    Invest. Ophthalmol. Vis. Sci.

    (2004)
  • C. Dean et al.

    An anatomic atlas of the medulla oblongata of the adult goat

    J. Appl. Physiol.

    (1999)
  • J.C. Downs et al.

    Three-dimensional histomorphometry of the normal and early glaucomatous monkey optic nerve head: neural canal and subarachnoid space architecture

    Invest. Ophthalmol. Vis. Sci.

    (2007)
  • Y. Glovinsky et al.

    Retinal ganglion cell loss is size dependent in experimental glaucoma

    Invest. Ophthalmol. Vis. Sci.

    (1991)
  • S.J. Goldberg et al.

    Summation of extraocular motor unit tensions in the lateral rectus muscle of the cat

    Muscle. Nerve

    (1997)
  • J.B. Jonas et al.

    Anatomic relationship between lamina cribrosa, intraocular space, and cerebrospinal fluid space

    Invest. Ophthalmol. Vis. Sci.

    (2003)
  • J.B. Jonas et al.

    Lamina cribrosa thickness and spatial relationships between intraocular space and cerebrospinal fluid space in highly myopic eyes

    Invest. Ophthalmol. Vis. Sci.

    (2004)
  • Cited by (53)

    • A review of potential novel glaucoma therapeutic options independent of intraocular pressure

      2022, Survey of Ophthalmology
      Citation Excerpt :

      Abnormally high trans-lamina cribrosa pressure difference (high IOP or low CSF pressure) will lead to glaucomatous cupping. This means that glaucomatous optic neuropathy may occur with low CSF pressure even if the IOP is normal.15 An interesting retrospective observational study described the history, clinical findings, and possible etiologies of ophthalmic findings discovered in 7 astronauts after long-duration space flight of 6 months.

    • Optic nerve head anatomy in myopia and glaucoma, including parapapillary zones alpha, beta, gamma and delta: Histology and clinical features

      2021, Progress in Retinal and Eye Research
      Citation Excerpt :

      It then also allows an estimation of the central retinal vein pressure. The physiology and pathophysiology of the central retinal vein pulsations and its pressure has not fully been explored yet (Balaratnasingam et al., 2007, 2009; Heimann et al., 2020; Matthé et al., 2019; Morgan et al., 2004, 2005, 2008, 2009; Stodtmeister et al., 2018). It was hypothesized that the positional change of the vessel trunk and central vasculature represented the change of the inner retinal structures and outer bear-loading structures, especially the lamina cribrosa and peripapillary sclera.

    View all citing articles on Scopus
    View full text