Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008

Fig. 2. Mapstone’s conception of forces on the iris. The iris is shown in gray. The sphincter pulls in toward the pupil generating a force FS, the combined passive and active contributions from the dilator pull outward and slightly posterior generating a net force FD, and the pressures in the posterior PPC and anterior PAC chambers push on the surfaces of the iris. The net effect of the sphincter and dilator forces is the “pupil blocking force” FPB, which pulls the iris very close to the lens and creates a strong resistance to flow through the pupil.

•The sphincter pulls the iris toward the lens, overcoming resistance of the dilator and creating a “pupil blocking force.”

•The pupil-blocking force causes the gap between the iris and lens to be very small, generating high resistance and thereby a large pressure difference between the posterior and anterior chambers.

•The pressure difference causes anterior bowing of the iris. This effect has been analyzed without consideration of the other effects (53,54).

It is important to recognize that because of the vectorial nature (directionality) of the forces acting in the above cascade, each force will affect the iris in a different way. This is confirmed by a recent study that showed that the changes in peripheral iris contour following iridotomy (primarily affecting posterior–anterior pressure gradient) were different from those observed following increased room lighting (primarily affecting sphincter force) (55).

Although much work has been done since the late 1960s, Mapstone’s insights remain the fundamental basis for understanding iris mechanics. For example, the Mapstone analysis provides an explanation for the effectiveness of peripheral iridotomy for pupillary block angle closure, i.e., if the aqueous humor can bypass the iris–lens gap, then the large pressure difference between the chambers is not generated. The elimination of this pressure difference leads to a flattening of the iris, an increase in iris– lens contact (56), and, most importantly, opening of the angle. On the contrary, the non-pupil-block angle closures (Chapter 20) are generally not corrected by iridotomy.

Iris bombé presents an extreme and thus highly illustrative case of Mapstone’s concepts in action, where iris adherence to the lens prevents anterior flow of the aqueous humor through the pupil. The posterior chamber fills with aqueous humor and develops a very high pressure, causing dramatic anterior bowing of the iris.

Application of Mapstone’s Ideas to Dynamic Systems

Mapstone considered only steady conditions, but the eye is in reality a highly dynamic mechanical environment. Blinking occurs every few seconds, and accommodation and pupil dilation/miosis occur with comparable frequency. These phenomena all change the shape of the anterior segment, forcing the aqueous humor to move

between the chambers. Because of the importance of these dynamic activities in determining the iris contour, we address each in turn.

Blinking indents the cornea (57) and may also affect the shape of the globe. The exact mechanism by which blinking affects aqueous-humor-iris mechanics is not well understood, but it has been observed in patients with pigment dispersion syndrome that prevention of blinking causes anterior drift of the iris (58,59). The precise nature of the forces involved in blinking remain unknown, but it is clear that blinking can play a significant role in ocular biomechanics.

Accommodation is probably the best-studied dynamic biomechanical event in the anterior segment, and it provides an important example of the ideas of Mapstone as applied to dynamic systems. As the lens moves forward, it creates an inversion of the normal pressure situation, with the anterior segment temporarily rising to a higher pressure than the posterior chamber (60). The force balance of Fig. 2 still holds, but the pressure difference pushes posteriorly instead of anteriorly, so that the iris bows back, especially in the case of patients with pigmentary glaucoma, who are predisposed to a flat or concave iris (61–63).

The elevated anterior chamber pressure might be expected to drive aqueous humor into the posterior chamber and quickly restore the normal configuration, but that does not occur because of the valve-like behavior of the iris. Because flow resistance through the iris–lens gap increases dramatically as the gap narrows, the anterior chamber pressure, by pushing the iris toward the lens, effectively prevents any flow from anterior to posterior [so-called reverse pupillary block (64)]. The iris valve effect was demonstrated compellingly by Pavlin et al. (65) by injecting microbubbles into the anterior and posterior chambers of eye bank eyes and observing them under ultrasound biomicroscopy (see Fig. 3). Microbubbles injected into the posterior chamber were seen to enter the anterior chamber, but microbubbles injected into the anterior chamber did not enter the posterior chamber. The right panel of Fig. 3 also shows the posterior bowing that arises from the pressurization of the anterior chamber.

Because aqueous humor is continuously secreted into the posterior chamber and continuously exits the anterior chamber, the reverse pupillary block is eventually

Fig. 3. Left panel shows a high-frequency ultrasound image acquired after injection of contrast agent (reflective microbubbles) into the anterior chamber of a human eye bank eye. The posterior chamber remains free of contrast agent (arrow). Right panel shows the situation after further injection of contrast agent into the anterior chamber. Posterior iris bowing and increased iris–lens contact (arrow) are evident. No contrast agent enters the posterior chamber (PC). From Pavlin et al. (65).

eliminated; computer simulations of the process predict a 3- to 5-min recovery time (60). Karickhoff (64) argued that peripheral iridotomy in patients with pigment dispersion syndrome and pigmentary glaucoma would bypass the reverse pupillary block, a result confirmed clinically (66,67).

Dilation has long been implicated in angle closure, with the prevailing opinion being that a patient is at greatest risk for angle closure when at mid-dilation. It is well established that the angle is more likely to close in the dark (68,69), which is the basis for the dark room provocative test (70,71), in which the patient is placed in the dark and the change in iris contour is observed. Although this effect is well known, it is difficult to reconcile with the classic Mapstone force balance because dilation would tend to imply a smaller pupil-blocking force and thus less pressure difference between the posterior and anterior chamber (72). It must be concluded that another biomechanical factor is at work, possibly dynamic effects from the motion of the iris or changes in the mechanical properties of the iris at different pupil diameters.

BIOMECHANICS OF THE OPTIC NERVE HEAD IN GLAUCOMA

The IOP generates a pressure load on the inner surface of the eye, which is primarily resisted by a hoop stress [a stress tangent to the wall of the eye (73)] borne mainly by the collagenous sclera (74). Conversely, the nerve fiber layer, retina, and choroid do not carry much load because of their relatively high compliance and are therefore spared the brunt of IOP-related stress (74). The lamina cribrosa spanning the scleral canal possesses approximately one-third of the connective tissue mass of the surrounding sclera (75). As a result, the optic nerve head (ONH) is the weak spot in the otherwise strong corneo-scleral envelope. Engineering theory and several computational studies have shown that a hole the size and shape of the scleral canal in an eye-sized pressure vessel concentrates stresses in the vessel wall surrounding the hole (73,76–80). The net effect is an elevation of IOP-induced stress and strain at the ONH, which is generally accepted as the principle site of damage to the retinal ganglion cell axons in glaucoma.

There has been some controversy surrounding the role of IOP in the development and progression of glaucoma. This arises from the clinical observation that significant numbers of patients with relatively low IOPs develop glaucoma (81), whereas other individuals with elevated IOP show no signs of the disease (see Fig. 4). The individual susceptibility of a particular patient’s ONH to IOP insult is likely a function of the biomechanical response of the constituent tissues. Individual ONH biomechanics, and hence individual susceptibility to IOP, is governed by the geometry (size, shape of the scleral canal, scleral thickness, regional laminar density and trabecular orientation) and the material properties (stiffness) of the lamina and sclera (74,75,77–80,82). Both the geometry and material properties contribute to the overall structural stiffness of the ONH and peripapillary sclera.

Biomechanics of Retinal Ganglion Cell Dysfunction in Glaucoma

The strain induced from IOP in the ONH tissues can begin a cascade of events that lead to axonal distress and eventual death, and this cascade likely involves mechanisms that are not commonly associated with the mechanical theory of glaucomatous damage (83). The direct mechanical effects of IOP-related strain are scleral canal

Fig. 4. Individual susceptibility to intraocular pressure (IOP)-related glaucomatous damage can be partially explained by optic nerve head (ONH) biomechanics and the cascade of mechanical, ischemic, and cellular damage that results from exceeding an individual’s safe IOP, even if that IOP is in the normal range.

expansion (84), posterior laminar deformation (84), and likely include yield and eventual failure of individual laminar trabeculae, and direct compression, stretch, and shear of the contained axons. These effects are manifest at all levels of IOP but only become pathologic beyond a safe IOP that is likely to vary according to individual susceptibility (83).

The biomechanical effects of elevated IOP can also manifest themselves in other ways, including ischemia. The posterior ciliary arteries form a ring around the ONH within the peripapillary sclera known as the circle of Zinn-Haller. If the peripapillary sclera is subjected to an increase in IOP-related strain, even at low IOP, changes in the conformation of the Zinn-Haller vasculature could diminish blood flow to the ONH (85,86). The laminar blood supply is principally composed of a network of capillaries that are contained within the individual laminar trabeculae, which are fed primarily by the posterior ciliary arteries and to a lesser extent by the central retinal artery (87). If the laminar trabeculae are subjected to high IOP-induced strain, the lumen of the contained capillaries is likely to become smaller, diminishing the flow of nutrients and oxygen to the surrounding axons (88–90). At the microstructural level, failure of individual, capillary-containing laminar trabeculae can lead to nerve fiber layer hemorrhages, which are not uncommon in glaucoma patients. These ischemic insults can be driven by individual ONH biomechanics (as well as other factors) and are a component of individual susceptibility to IOP. Hence, patients who have relatively weak ONH blood flow are likely to be more susceptible to IOP-induced glaucomatous damage (i.e., axons damaged at a lower IOP) at mechanical strain magnitudes that would not otherwise be pathologic. Similarly, patients with very robust ocular blood flow could endure elevated IOP if their connective tissues were similarly robust.

Astrocytes and lamina cribrosa cells can sense mechanical strain in the laminar microstructure through cytoskeletal mechanotransduction (91–93). Levels of strain that may not induce yield in the laminar ECM may still be high enough to induce a response from these cells. The response could be as simple as the release of factors designed to make the cell’s environment more homeostatic, but that might be cytotoxic to the adjacent axon. Biomechanically induced ischemia also may play a role in ONH cellular responses, wherein local decreases in blood flow could cause cells in the surrounding laminar trabeculae to release factors such as MMPs to increase diffusion of nutrients and oxygen from the underlying capillary endothelium (92). Although

increasing nutrient diffusion to the activated cells, these factors also break down the collagen and elastin ECM that provides the load-bearing capacity of the lamina, which can induce laminar hypercompliance (84,94).

There is a continuum of cellular activity that is associated with the onset and progression of glaucomatous damage. Studies have shown that astrocytes, glia, microglia, and lamina cribrosa cells become activated in response to glaucomatous damage in vivo and applied strain in vitro. This cellular activity changes the material properties (stiffness) of the connective tissues of the posterior pole and changes the geometry in measurable ways. Specifically, the peripapillary sclera stiffens (95) and the posterior scleral shell thins (96) in monkey eyes with early experimental glaucoma compared with normal controls. Roberts and coworkers (75) have shown that the laminar architecture is radically changed at the earliest detectable stage of glaucoma in the primate, with the laminar connective tissue volume increasing by an average of 87% compared with contralateral normal controls. Finite element (FE) models of those same eyes showed that even though the lamina cribrosa was much more substantial in the glaucomatous eyes, it was considerably less stiff than the lamina in contralateral normal controls (75,82). These studies were undertaken at the earliest detectable stage of glaucomatous damage in the monkey and are somewhat counterintuitive because previous human studies of more advanced stages of the disease have shown that the glaucomatous lamina is thinner and less substantial than age-matched normal eyes (97). That trend may hold in the monkey model as well, as the biomechanical damage and remodeling processes are highly dynamic, and the lamina may well consolidate into a more organized, stiffer structure in later stages of experimental glaucoma.

Technical Challenges in Studying ONH Biomechanics

The dearth of data on the role of ONH biomechanics in glaucoma is due in large part to the technical challenges involved in the measurement of ONH tissue mechanical properties (stiffness) and the complexity of the ONH geometry. Further complications include biologic variability in the load-bearing structure, which includes geometry (scleral thickness, neural canal shape and size, laminar pore size and beam thickness, etc.), and tissue stiffness, which may change with age, pathology, ECM composition, and connective tissue remodeling.

There are no available imaging techniques that have the penetration depth and the spatial resolution necessary to measure IOP-induced deformation of the peripapillary sclera and lamina cribrosa in vivo. As a result, all studies to date have focused on the histomorphometric analysis of laminar deformation in post-mortem tissues. In human donor eyes and the primate model of glaucoma, multiple studies have reported on the posterior deformation of the ONH connective tissues in the various stages of glaucoma. There are also several studies in the primate model of glaucoma that use the Heidelberg Retinal Tomograph (confocal scanning laser tomograph) to track ONH surface compliance (94,98,99). These studies, although not able to measure underlying laminar deformation, have shown that there is significant fixed posterior deformation and hypercompliance of the ONH surface (vitreo–retinal interface) at the earliest stages of glaucomatous damage in the monkey. Subsequent histomorphometric measure of laminar position in these same animals has confirmed that fixed posterior deformation

and hypercompliance of the underlying lamina coincides with those same phenomena measured at the ONH surface. Although optical coherence tomography (OCT) and other imaging techniques will likely gain sufficient depth and resolution to image the deformations of the scleral canal and anterior laminar surface within the next few years, there is no technology on the horizon that will measure strain (local deformation).

In the absence of a direct measurement technique, several researchers have employed computational modeling to study the biomechanics of the posterior pole and lamina cribrosa. Modeling can estimate the biomechanical behavior of the ONH and therefore provide insight into those features of anatomy or material properties that contribute to glaucomatous susceptibility. Several studies have attempted to model the posterior pole or lamina analytically using a purely mathematical approach in idealized geometries (100–102). Analytical solutions are attractive because they allow variables to be changed independently and their effects on the analytical solution to be solved directly. The realism of the models is very limited however, as the need to maintain sufficient mathematical simplicity constrains the geometric and material property descriptions employed. The most sophisticated of these studies suggest that the structural stiffness of the sclera (combined geometry and material properties) is the most important determinant of ONH biomechanics (102).

When modeling the ONH with anatomic fidelity, the principle method employed is FE modeling, which breaks complex geometries into small, simply shaped elements, computes the stress and strain within each element, then superposes the results into the mechanical response of the entire structure. The three components necessary as input for ONH modeling are the 3D geometry of the tissue structure to be modeled, the material properties of the different tissues in the model, and appropriate loading and boundary conditions. The ONH geometry can be constructed either by serial histologic methods (103,104) or by 3D imaging (105,106), and material properties are generally determined through direct mechanical testing (107–110). Unfortunately, imaging of the lamina in vivo is not yet possible, and no technology exists for experimental biomechanical testing of laminar trabeculae. As a result, ONH FE models are typically constructed from eyes that are perfusion or immersion fixed at a selected IOP, then undergo 3D reconstruction ex vivo. Material properties of the sclera, retina, and nerve tissue have been determined experimentally, and the properties of the lamina are estimated. These efforts occur in both human donor eyes and the experimental monkey model of glaucoma.

There are two basic approaches to biomechanical modeling of the ONH: parametric and individual-specific. Parametric modeling involves computing stress and strain in average, idealized geometries that do not conform to any individual’s particular anatomy. Within these models, parameters such as peripapillary scleral thickness and laminar stiffness can be varied independently to gauge their influence on ONH biomechanics as a whole. This is a similar computational approach to analytical modeling, but the geometries are much more fidelic and the results more intuitive. Although parametric models are by nature simplistic in their geometries and there are limited cases that can be modeled, these investigations yield interesting insight into the contributions of individual anatomical elements and tissue material properties to overall ONH biomechanics.

Sigal and coworkers (74,80) have constructed an idealized parametric FE model of the human eye (see Fig. 5A and B), within which various geometric and tissue stiffness parameters can be varied to determine which of those parameters are most important in determining the response of the ONH to IOP. This work is useful in several ways. First, their results suggest that there are several factors that dominate the ONH’s biomechanical response to IOP, many of which are not clinically intuitive. More specifically, the five factors identified as the most important determinants of ONH biomechanics are, in rank order: the stiffness of the sclera, the size of the eye, IOP, the stiffness of the lamina cribrosa, and the thickness of the sclera. As the authors acknowledge, these results should be viewed with some caution because of the simplifying assumptions necessary to construct the model, such as the model’s inability to consider regional laminar density or stiffness, the simplicity of the laminar and scleral geometries, and its limitation to scleral canals of circular shape. All these remaining factors likely work with the considered parameters in complex ways to contribute to an individual ONH’s susceptibility to IOP-related glaucomatous damage, and more work is needed to elucidate these mechanisms. Nonetheless, this body of work has used computational biomechanical modeling of the posterior pole to identify important biomechanical factors that can be studied more carefully by experimental and advanced modeling methods.

To address the limitations of parametric FE models, individual-specific models can also be created from the reconstructed geometries of particular eyes. Typically, the complex geometries of the sclera and lamina are acquired using a serial histologic sectioning technique, wherein serial sections are imaged, then stacked to create 3D geometries from which FE models are then constructed. Roberts and coworkers (75) have demonstrated that the lamina cribrosa has a solid volume fraction and predominant

Fig. 5. (A) Parametric finite element modeling within simplified geometries allows for independent variation of parameters (shown) to assess their effects on optic nerve head (ONH) biomechanics; B) Maximum principal strain in the ONH for two runs of a parametric model with the laminar modulus (stiffness) varied from 0.1 MPa (B, top) to 0.9 MPa (B, bottom). C) Anterior view of the maximum principal strain within the laminar region of an individualspecific, 3D finite element (FE) model of a normal monkey posterior pole showing the variation in strains because of underlying laminar architecture; D) Individual-specific microstructural FE model of the lamina cribrosa from the superior mid-periphery of the parent continuum model

(C) showing the distribution of maximum principal strain within the laminar trabeculae. A and B courtesy of I.A. Sigal.

trabecular orientation that varies regionally throughout the ONH and that regional variability must be represented in FE models to fully capture its biomechanical behavior (see Fig. 5C). Also, 3D models are necessary to capture the biomechanics of anisotropic scleral material properties (varying collagen fibril orientation) and scleral canals that are non-circular and have varying optic nerve insertion angles (e.g., optic nerve inserting from the nasal side resulting in a thinner peripapillary sclera in that quadrant). These studies are limited to investigations into individual ONH biomechanics and are in their infancy in both human and monkey eyes, but should yield further insight into the biomechanics of IOP-related glaucomatous damage.

Each of the aforementioned modeling techniques provides insight into the macroscale behavior of the lamina cribrosa and surrounding sclera, but does not predict that behavior at the level of individual laminar trabeculae. Information at the trabecular level is needed to determine strains that the cells in the lamina are experiencing, under both normal and pathologic conditions. Downs and coworkers (82) have developed a substructuring technique in which the laminar microstructure contained within parent, macroscale, continuum finite elements (FE) is isolated and modeled using the parent continuum elements’ displacements as loading condition for the included laminar trabeculae. Initial results for these models have indicated that resultant strains in the laminar trabeculae range from 1 to 15% in normal eyes, whereas average regional strains are approximately 4% (see Fig. 5D). Although there are little data available to validate these micro-FE models, they are useful in predicting the patterns of stress and strain in the laminar microstructure and define the ranges of strain that cells in the lamina are experiencing.

In summary, biomechanics can influence the ONH’s response to IOP at the mechanical, ischemic, and cellular levels, and could provide a framework through which individual susceptibility to glaucomatous damage can be studied and eventually understood (83). It is very important to note that IOP-related stress in the ONH is substantial even at normal levels of IOP and individual combinations of laminar and peripapillary scleral geometries and connective tissue stiffness likely lead to a continuum of ONH biomechanical responses to IOP: in some patients that combination could lead to a particularly robust structure that is resistant to glaucomatous damage at high IOP, and there are those in whom even normal levels of IOP cause strains in the ONH that could be sufficient to begin the cascade of events leading to axonal death. The robustness of the ONH vasculature and the sensitivity of an individual’s cells to mechanical strain could also play a role in individual susceptibility, and these factors are driven, in part, by biomechanics.

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