Glaucomatous cupping of the lamina cribrosa: a review of the evidence for active progressive remodeling as a mechanism

Abstract

The purpose of this review is to examine the literature in an attempt to elucidate a biomechanical basis for glaucomatous cupping. In particular, this work focuses on the role of biomechanics in driving connective tissue remodeling in the progression of laminar morphology from a normal state to that of an excavated glaucomatous state. While there are multiple contributing factors to the pathogenesis of glaucoma, we focus on laminar extracellular matrix (ECM) remodeling in glaucoma and the feedback mechanisms and signals that may guide progressive laminar cupping. We review the literature on the potential mechanisms of glaucomatous changes in the laminar ECM at the anatomic, structural, cellular and subcellular levels in the context of the biomechanical paradigm of glaucomatous onset and progression. Several conclusions can be drawn from this review. First, extensive remodeling of the lamina cribrosa ECM occurs in primary open angle glaucoma. Second, there is surprisingly little evidence to support acute mechanical damage to the lamina as the principal mechanism of cupping. Third, ONH astrocytes and lamina cribrosa cells can sense their mechanical environment and respond to mechanical stimuli by remodeling the ECM. Fourth, there is evidence suggesting that chronic remodeling of the lamina results in a progressive posterior migration of the laminar insertion into the canal wall, which eventually results in the posterior lamina inserting into the pia mater. Finally, modeling studies suggest that laminar remodeling may be a biomechanical feedback mechanism through which cells modify their environment in an attempt to return to a homeostatic mechanical environment. It is plausible that biomechanics-driven connective tissue remodeling is a mechanism in the progression of laminar morphology from a normal state to that of a cupped, excavated glaucomatous state.

Figure 1

Scanning electron micrographs of trypsin-digested optic nerve heads from normal (left) and advanced glaucoma (right) human eyes. The lamina cribrosa is cupped and excavated beneath the scleral canal rim in the glaucomatous eye. The connective tissue cups of both eyes are delineated in the lower panels. Note the thick pia mater, the laminar insertion into the pia (arrow), and the difficulty in distinguishing between the lamina and the retrolaminar septa in the glaucomatous eye. Scl, sclera. Images courtesy of Harry A. Quigley, MD.

Figure 2

The biomechanical paradigm of glaucomatous pathophysiology. IOP acts mechanically on the tissues of the eye, producing deformations, strain and stress within the tissues. These deformations depend on the particular tissue geometry and material properties of an individual eye. IOP-induced stress and strain could acutely alter blood flow in the laminar region, and/or delivery of nutrients (secondarily) through chronic alterations in connective tissue. IOP-related stress and strain could also induce alterations in the connective tissues directly (collagen or elastin fiber yield or failure), or indirectly. Indirect effects could include cell-mediated ECM remodeling or non-cell mediated alterations in laminar collagen (Ruberti and Hallab, 2005). These changes in the ONH connective tissues alter their geometries and mechanical responses to loading, which feeds back directly into the mechanical effects of IOP on the ONH. Adapted from Figure 1 in (Sigal, Roberts et al., 2010).

Figure 3

From a mechanical perspective it is useful to recognize two components of IOP-induced deformation of the lamina cribrosa (top row). One component is the effect of IOP on the anterior laminar surface, which deforms the lamina posteriorly (top middle). Another component is the effect of IOP on the sclera, which causes an expansion of the canal (top right). The deformations are transmitted to the lamina through its insertion into the canal wall, resulting in a lamina that pulls “taut” displacing anteriorly. As IOP increases, both components act simultaneously. The magnitudes of the components of deformation depend on both the material stiffnesses of the lamina and sclera (Sigal, Flanagan et al., 2005; Roberts, Liang et al., 2010; Roberts, Sigal et al., In-Press (May 2010)). Interestingly, models (Roberts, Hart et al., 2007; Sigal, Flanagan et al., 2007; Sigal, Flanagan et al., 2009; Sigal, Yang et al., In revision) and recent experimental evidence in both monkeys (Yang, Downs et al., 2009) and humans (Agoumi, Artes et al., 2009) suggests that often the two components of laminar deformation combine to produce a very small (under 10 um) net anterior-posterior laminar displacement (bottom). The bottom panel shows a schematic representation of the lamina cribrosa and peripapillary sclera of contralateral eyes of a monkey, fixed at low (10 mmHg, solid colors) or high (45 mmHg, dotted lines) IOP (adapted from (Yang, Downs et al., 2009)). It is important to note that even under a very small net anterior-posterior laminar displacement, the IOP-related strains and stresses within the lamina and peripapillary sclera may be substantial.

Figure 4

3D reconstructions of the laminar connective tissues of a monkey, with one eye having early experimental glaucoma. Shown are en face views of the laminar reconstructions, as well as views of the central vertical (left) and horizontal (below) sections. Note the thicker and deeper (cupped) lamina in the early glaucoma eye (Roberts, Grau et al., 2009). Both eyes are shown in OD configuration. S, superior; I, inferior; N, Nasal; T, temporal.

Figure 5

Example of lamina cribrosa partially inserting into the pia mater (from (Sigal, Flanagan et al., 2010)). Shown is a superior-inferior section of an ostensibly healthy (i.e. not glaucomatous) eye from a 79-year-old male donor fixed at 5 mmHg. The bottom panel is a zoomed view of the rectangle marked in the top panel. The bottom right panel shows outlines of the regions delineated as lamina cribrosa (green), sclera (blue) and pia mater (red). It has been traditionally thought that the lamina inserted solely into the sclera, but a laminar insertion into the pia has now been reported in humans (Sigal, Flanagan et al., 2010) and monkeys (Yang, Williams et al., 2010).

Figure 6

Generic, axisymmetric finite element model of the ONH with five tissue regions: sclera, lamina cribrosa, pre- and post-laminar neural tissues and the pia mater (top). The model was used to predict the IOP-related strains at normal (12.5 mmHg, middle) and elevated (25 mmHg, bottom) IOP. Note the regions of high strain in the post-laminar neural tissues near the laminar insertion into the sclera, and in the pre-laminar neural tissues near the scleral canal opening.

Figure 7

Diagram illustrating our proposed progression of an ONH from a normal morphology, through early IOP-induced laminar remodeling, to end stage glaucomatous cupping and excavation. The top left pane shows a normal, healthy ONH (the lamina cribrosa is blue, pre-and retrolaminar tissues are yellow, and the sclera and pia mater are brown). Following chronic exposure to stress and/or strain that are beyond the physiologic tolerance of the resident cells, the lamina is remodeled to a thickened and cupped shape, and the laminar insertion begins to move posteriorly into the pia (top right; normal lamina in blue and remodeled lamina in red). As glaucomatous damage progresses with continued exposure to a biomechanically driven insult, the prelaminar neural tissues begin to thin (bottom left). Eventually, most of the RGC axons are lost and the lamina scars and thins to a classic cupped, excavated glaucomatous morphology (bottom right).