Histomorphometric studies have suggested that the thickness of the lamina cribrosa may play a role in the pathogenesis of glaucomatous optic nerve damage.
15 16 17 18 The lamina cribrosa at the bottom of the optic cup is a barrier between the intraocular space on its inner side and the retrobulbar cerebrospinal fluid space surrounding the optic nerve on its outer side. Since the lamina cribrosa forms the border between the intraocular space with a higher pressure and the retrobulbar space with a lower pressure, a pressure gradient—intraocular pressure minus pressure in the retrobulbar cerebrospinal fluid space—exists across the lamina cribrosa. This trans–lamina-cribrosa pressure gradient is of importance in ocular diseases in which the pressure on one or on both sides of the lamina cribrosa is abnormally high and/or abnormally low
10 11 22 An abnormal pressure gradient influences the physiology of the optic nerve fibers with their orthograde and retrograde axoplasmic flow.
23 24 25 26 The trans–lamina-cribrosa pressure gradient depends on the difference in pressure and the thickness of the lamina cribrosa. Because the lamina cribrosa is not indefinitely thin, the pressure reduction does not occur in an indefinitely thin layer of the lamina cribrosa, but the pressure may decrease gradually or in steps along the whole thickness of the lamina cribrosa. A recent investigation has suggested that in non–highly myopic eyes with advanced glaucomatous optic nerve damage, the lamina cribrosa is markedly thinner than in normal eyes.
15 It has been inferred that the thinning and condensation of the lamina cribrosa in advanced glaucoma may be the histopathologic correlate of clinical studies in which an advanced stage of glaucomatous optic neuropathy, independent of the level of intraocular pressure, was shown to be a risk factor for further progression of glaucoma.
27 28 29 30 It has been speculated that the same pressure difference between the intraocular space and the retrobulbar space across a thinner lamina cribrosa may lead to a steepening of the trans–lamina-cribrosa pressure gradient, similar to the effect of an elevated intraocular pressure with an increased trans–lamina-cribrosa pressure difference on a lamina cribrosa of normal thickness. As a corollary, another histomorphometric investigation has suggested that highly myopic nonglaucomatous eyes have a significantly thinner lamina cribrosa than nonglaucomatous non–highly myopic eyes.
18 The thinner lamina cribrosa in highly myopic eyes may explain the presumably increased susceptibility to glaucoma of highly myopic eyes compared with non–highly myopic eyes.
31 32 33 34 35
In view of the possible importance of the thickness of the lamina cribrosa at the bottom of the optic nerve head in the pathogenesis of glaucomatous optic nerve damage, considering that the dimensions of the cornea, such as horizontal and vertical diameter and anterior corneal curvature, correlate with the diameters and area of the optic nerve head, and since a thin central cornea has been described as a predictive factor for further progression of chronic open-angle glaucoma, the purpose of the present study was to evaluate whether the central corneal thickness correlates with the thickness of the lamina cribrosa. The findings showed that in nonglaucomatous human globes, the thicknesses of the central cornea and the lamina cribrosa do not correlate significantly
(Figs. 2 3) , which suggests that an assumed relationship between central corneal thickness and susceptibility to glaucoma may not be explained by a corresponding anatomy between corneal thickness and thickness of the lamina cribrosa. This finding holds true in non–highly myopic eyes and in highly myopic eyes, since for both study subgroups, central corneal thickness was unrelated to thickness of the lamina cribrosa. The data of the present study indirectly correspond with results of the Early Manifest Glaucoma Trial (EMGT), in which the corneal thickness was unrelated to the development of visual field defects in the study population.
36 The data of the present investigations also correspond with another study in this issue of
IOVS in which central corneal thickness did not have a major impact on the rate of the progression of chronic open-angle glaucoma.
37
In addition to the lamina cribrosa thickness, thickness of the peripapillary sclera and the shortest distance between the intraocular space and the cerebrospinal fluid space did not correlate significantly with central corneal thickness
(Figs. 4 5) . Even if it can be assumed that a short distance between the intraocular space and the cerebrospinal fluid space steepens the trans–lamina-cribrosa gradient and increases susceptibility to glaucoma, and even if it can be assumed that a thin peripapillary sclera is associated with a weak suspension of the lamina cribrosa, again leading to a higher susceptibility to glaucoma, the data of the present study did not find a correlation between the optic nerve head parameters and central corneal thickness. This result may again suggest that an assumed relationship between central corneal thickness and susceptibility to glaucoma cannot be explained by a corresponding anatomy between corneal thickness and histomorphometry of the optic nerve head.
The finding that corneal thickness and thickness of the lamina cribrosa were not significantly associated with each other may be due to differences in embryonic development. The corneal stroma and corneal endothelium start to be formed by the fourth to sixth weeks of gestation by immigrating cells from the neural crest. The lamina cribrosa begins to develop as the lamina scleralis in the region of the primitive optic nerve head during the eighth week. Invading glial cells of the outer wall of the optic stalk form a sieve-like scaffolding around the pre-existing ganglion cell axons, followed by ingrowing of sclera-derived cells in the fourth month, which forms the mesenchymal part of the lamina cribrosa, including connective tissue fibers penetrating the glial lamina cribrosa and running between glia-covered ganglion cell axons and the centrally located hyaloid vessel. The lamina cribrosa is vascularized by the 13th to 14th weeks, and its mature structure is reached during the 7th month. It should be emphasized that, during formation of the lamina cribrosa, the ganglion cell axons and the hyaloid vessels are the first to be present. They form the contents of the future lamina cribrosa pores, followed by formation of the lamina cribrosa trabecula in two steps: In the first step, glial cells of the outer optic stalk wall create a provisional net that is stabilized and further strengthened in the second step by ingrowing sclera-derived mesenchymal cells. Consequently, the mature lamina cribrosa can be considered a result of the secondary development of vascularized scleral connective tissue penetrating the preformed glial lamina, including the ganglion cell axons and the hyaloid vessels.
38 Because of the loss of approximately two thirds of the originally formed retinal ganglion cell axons in the primitive optic nerve, the primitive lamina cribrosa furthermore undergoes a continuous remodeling during the embryonic stage. These differences between the cornea and lamina cribrosa in their embryonic development may contribute to the result of the present study that central corneal thickness appeared to be unrelated to the thickness of the optic nerve head structures.
There are several weaknesses in this study. First, postmortem tissue swelling and artifact in either the cornea or lamina cribrosa have certainly introduced some bias in the correlation between corneal thickness and measured optic disc parameters. There is little reason to believe that histologic artifacts would be related to corneal thickness, and thus this bias is probably nondifferential. However, any nondifferential bias would be toward the null, which may explain the lack of any significant associations. In addition, histologic sections were not of a consistent orientation, and lamina cribrosa thickness in each eye was characterized from a single histologic section. Considering that the lamina is remarkably variable in its three-dimensional geometry, as shown in Bellezza et al.
12 14 and Burgoyne and Morrison,
13 the lamina cribrosa may be thinnest in different regions in each eye, and anything less than a three-dimensional reconstruction or serial sectioning of each eye may fail to find the thinnest portion of the lamina that in fact correlates. From that point of view, the present investigation may be regarded as a pilot study, with findings that must be confirmed by an investigation with three-dimensional reconstruction of the anatomy of the lamina cribrosa. Another limitation of the study is the relatively small number of eyes included in the investigations. The scattergrams show, however, that there is not even a tendency toward correlation between central corneal thickness and thickness of the lamina cribrosa
(Figs. 2 3 4 5) . This finding may suggest that even had a larger number of eyes been included in the study, the correlation between central corneal thickness and thickness of the lamina cribrosa may not have become relevant.
In conclusion, the present study suggests that in nonglaucomatous human globes, corneal thickness does not correlate significantly with lamina cribrosa thickness, thickness of the peripapillary sclera, or the shortest distance between the intraocular space and the cerebrospinal fluid space. In the interpretation of the measurements, it has to be taken into account, that histologic artifact and sectioning methods led to corneal thickness measurements well over 600 to 800 μm in many eyes, which results in a nondifferential bias toward the null that may also explain the lack of any significant associations. Direct clinical–histomorphometric comparisons of enucleated eyes may answer the question of how much the histomorphometric measurements in the present study were influenced by postmortem- and preparation-induced changes. If the results of the present study are confirmed by other studies, they suggest that an assumed relationship between central corneal thickness and susceptibility to glaucoma may not be explained by a correspondence between central corneal thickness and thickness of the lamina cribrosa and peripapillary sclera.
The authors thank Claude F. Burgoyne (LSU Eye Center, New Orleans, LA) for the initiation of the study and for his support and constructive criticism of the manuscript.