Histomorphometric measurements in human and dog optic nerve and an estimation of optic nerve pressure gradients in human
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)
- et al.
Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma
Ophthalmology
(2008) - et al.
Histomorphometry of the optic nerves of normal dogs and dogs with hereditary glaucoma
Exp. Eye Res.
(1995) - et al.
Predicted extension, compression and shearing of optic nerve head tissues
Exp. Eye Res.
(2007) - et al.
Optic nerve tissue shrinkage during pathologic processing after enucleation for retinoblastoma
Arch. Ophthalmol.
(2003) Ultrastructure of human and monkey lamina cribrosa and optic nerve head
Arch. Ophthalmol.
(1969)Ultrastructure of meningeal sheaths. Normal human and monkey optic nerves
Arch. Ophthalmol.
(1969)Ultrastructure of the optic nerve head
Arch. Ophthalmol.
(1970)- et al.
Ultrastructure of intraorbital portion of human and monkey optic nerve
Arch. Ophthalmol.
(1969) - et al.
Intracranial pressure in primary open angle glaucoma, normal tension glaucoma, and ocular hypertension: a case-control study
Invest. Ophthalmol. Vis. Sci.
(2008) - et al.
Morphologic changes in the lamina cribrosa of beagles with primary open-angle glaucoma
Am. J. Vet. Res.
(1989)
Three-dimensional reconstruction of normal and early glaucoma monkey optic nerve head connective tissues
Invest. Ophthalmol. Vis. Sci.
An anatomic atlas of the medulla oblongata of the adult goat
J. Appl. Physiol.
Three-dimensional histomorphometry of the normal and early glaucomatous monkey optic nerve head: neural canal and subarachnoid space architecture
Invest. Ophthalmol. Vis. Sci.
Retinal ganglion cell loss is size dependent in experimental glaucoma
Invest. Ophthalmol. Vis. Sci.
Summation of extraocular motor unit tensions in the lateral rectus muscle of the cat
Muscle. Nerve
Anatomic relationship between lamina cribrosa, intraocular space, and cerebrospinal fluid space
Invest. Ophthalmol. Vis. Sci.
Lamina cribrosa thickness and spatial relationships between intraocular space and cerebrospinal fluid space in highly myopic eyes
Invest. Ophthalmol. Vis. Sci.
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