Ординатура / Офтальмология / Английские материалы / Mechanisms of the Glaucomas_Shields, Tombran-Tink, Barnstable_2008
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other regions had loss of trabecular cells from the lamellae, and other regions had fusion of adjacent lamellae (see Figs 14–17). In addition, loss of the connecting fibril attachments to the cribriform region and Schlemm’s canal inner wall was noted in many areas (see Fig. 18). This seemed especially noted in those areas around the circumference of eyes that had a change in the architecture of Schlemm’s canal and the inner-wall-cribriform region. Instead of the classic large lumen of Schlemm’s canal, these regions had an expansion of the cribriform cells into the canal, partially filling it with stellate cytoplasmic processes (see Fig. 14). Whether this change is a secondary reaction in regions of higher aqueous flow or is part of the increased resistance to aqueous outflow characteristic of this disease is unknown.
Fig. 14. Pigmentary glaucoma. Lamellae separated with normal aqueous spaces. Anterior portion of Schlemm’s canal filled with stellate cellular processes. Light microscopy. Reprinted with permission from Lippincott Williams & Wilkins from reference (38) (Figure 2A).
Fig. 15. Pigmentary glaucoma. Aqueous spaces open in this area of corneoscleral meshwork. Transmission electron microscopy. Reprinted with permission from Lippincott Williams & Wilkins from reference (38) (Figure 1C).
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Fig. 16. Pigmentary glaucoma. Lamellae closely packed, with obliteration of aqueous spaces. Schlemm’s canal relatively small; large vascular channel present in sclera overlying meshwork region. Light microscopy. Reprinted with permission from Lippincott Williams & Wilkins from reference (38) (Figure 1B).
Fig. 17. Pigmentary glaucoma. Aqueous spaces have collapsed, with fusion of adjacent lamellae. Transmission electron microscopy.
Fig. 18. Pigmentary glaucoma, cribriform region. Separation of connecting fibrils from inner wall is apparent. Transmission electron microscopy. SC, Schlemm’s canal.
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Pigmentary glaucoma patients can have transient elevations of IOP during “pigment showers” that may accompany physical activity (46). Although these pigment showers do not occur in every patient, the free pigment granules broken from the iris during physical activity can presumably fill the intertrabecular spaces and cribriform region and obstruct aqueous outflow. Much of this acute load of pigment must pass directly through the meshwork and inner wall into Schlemm’s canal, as the elevation of IOP characteristically lasts only a few hours. The mechanism of the passing of the pigment granules through the outflow system probably involves egress through the intercellular and intracellular pores of the endothelial cells of Schlemm’s canal. These pores are generally about 1 μm in diameter and can range up to 3 μm (47), both large enough to allow the pigment granules of 0.6 μm size to pass through. In keeping with this, experimental infusions of pigment granules in living monkey eyes caused transient elevations of IOP, but no lasting pressure increase nor any pathologic changes in the trabecular meshwork (43).
CORTICOSTEROID-INDUCED GLAUCOMA
Corticosteroid-induced glaucoma is associated with characteristic findings in the trabecular meshwork. Electron microscopic examination reveals layers of a fibrillar material in the extracellular matrix of the outer corneoscleral and inner cribriform regions (48–50) (see Fig. 19). This material resembles a fingerprint pattern and is reminiscent of the single layers of basement membrane and basal lamina found in the trabecular meshwork. In addition to this fingerprint material, dense patch accumulations of a fine fibrillar material in the cribriform region under the inner wall of Schlemm’s canal are found (50) (see Fig. 20). These patches of material are not large enough nor extensive enough to obstruct aqueous outflow but may cause some loss of portions of the aqueous flow pathways.
Fig. 19. Corticosteroid glaucoma. “Fingerprint” material resembling basement membrane accumulates in outer corneoscleral region. Transmission electron microscopy.
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Fig. 20. Corticosteroid glaucoma. Dense patches of a fine, fibrillar material under inner wall of Schlemm’s canal. Transmission electron microscopy. SC, Schlemm’s canal.
These cortico-steroid-associated changes have not been seen in eyes with acute elevations of IOP, as the meshwork in histologic reports in eyes requiring trabeculectomy after 8 weeks of steroid use is generally normal (51,52). Although histologic studies of steroid glaucoma are rare, the earliest report of these ultrastructural changes was after 5 months of steroid use (48). This presumably means that a “biochemical” change, unseen by electron microscopy, must occur to cause the initial IOP elevations. With time, trabecular cells secrete increased amounts of these fibrillar materials that finally accumulate in the meshwork (50).
SUMMARY
Although histologic studies are the foundation of knowledge about the pathogenesis of glaucoma, they cannot reveal the active, dynamic changes that occur in living tissues. The cause of glaucoma and the exact mechanism causing increased resistance to aqueous outflow remain unknown. If the cause is a derangement of a cellular activity, such as a shape change in response to stretching of the tissues, histologic study cannot reveal this active process. Similarly, cytoskeletal stiffening or relaxation would not easily be seen by microscopy. Because of the fixation and processing required for histologic examination, enzymatic activity and turnover of extracellular matrix cannot be seen with conventional preparations. Despite advances in visualization techniques, such as quick-freeze deep-etch, glycosaminoglycans and other materials are lost during processing (53). It remains unknown whether the apparently empty spaces seen by microscopy are truly empty, containing only aqueous, or are instead filled with an extracellular matrix. Although much insight into the pathophysiology of glaucoma has been gained from histologic study, a true understanding of the problem requires the combination of study of living cells and tissues, assessment of changes of IOP with histo-
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logic findings, and molecular and biochemical methods to probe the living cellular processes of the trabecular meshwork. We are only at the surface of this complex disease.
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Trabecular Mechanisms of Intraocular Pressure Elevation
Pseudoexfoliation Syndrome
Ursula Schlötzer-Schrehardt, phd, and Gottfried O. H. Naumann, md
CONTENTS
Introduction
Pathobiology of PEX Syndrome
Open-Angle Glaucoma Associated with PEX Syndrome Management of Glaucomas Associated with PEX Syndrome Summary and Perspectives
References
INTRODUCTION
Pseudoexfoliation (PEX) syndrome is a common age-related generalized disorder of the extracellular matrix, which is characterized by an excessive production and progressive accumulation of an abnormal fibrillar material throughout the anterior segment of the eye (1,2). This disorder may affect up to 30% of people over age 60 in a worldwide distribution and is frequently associated with severe chronic secondary open-angle glaucoma. It is clinically diagnosed by observation of dandruff-like white flakes on ocular structures that line the aqueous-bathed surfaces of the anterior segment, particularly the anterior lens surface and the pupillary border of the iris (see Fig. 1A–C). The terms PEX or exfoliation syndrome have been widely used for this entity although the process does not represent a true exfoliation of the lens capsule, as in infrared (“glass-blower’s”) cataract. In addition to glaucoma development, the characteristic tissue alterations represent a broad spectrum of intraocular abnormalities including weakness of lens zonulas with phacodonesis, lens subluxation and complicated cataract surgery, melanin dispersion, insufficient mydriasis, posterior synechiae, blood–aqueous barrier defects, anterior chamber hypoxia, and corneal endothelial decompensation (3).
From: Ophthalmology Research: Mechanisms of the Glaucomas
Edited by: J. Tombran-Tink, C. J. Barnstable, and M. B. Shields © Humana Press, Totowa, NJ
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Fig. 1. Clinical signs of pseudoexfoliation (PEX) syndrome. (A) Classic target-shaped pattern on the lens. (B) Different pattern of lenticular PEX material deposition with absence of central disc and curled edges of the peripheral zone. (C) PEX deposits on the pupillary border. (D) Flecks of PEX material in the chamber angle (courtesy: G.K. Krieglstein, Köln). (E) Pigment loss from the peripupillary iris pigment epithelium. (F) Uneven trabecular meshwork pigmentation (adapted with permission (55)).
Recent years have seen a greater understanding of this disorder (4) although its precise etiology and pathogenesis still remain unclear. It has been realized that PEX syndrome is a condition of worldwide significance, not limited to certain geographical areas. Refinement of diagnostic criteria has improved the recognition of early stages, and elaboration of the effects of the PEX process on the various ocular tissues involved helped to explain the mechanisms of the ocular abnormalities and to develop preventive strategies. Apart from the long-known intraocular manifestations, PEX syndrome has also been shown to be a systemic process (5,6), which appears to be associated with increased cardiovascular and cerebrovascular morbidity (4).
PEX syndrome was described by Lindberg over 100 years ago (7) and recognized as a frequent cause of glaucoma by Vogt almost 90 years ago (8). It is currently the most common single identifiable cause of open-angle glaucoma (9), which is seen in 20–60% of patients with PEX syndrome in different series (10). In some populations
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(e.g., Baltic, Mediterranean, and Arabian), the frequency of PEX-associated open-angle glaucoma may reach a higher percentage of the population than primary open-angle glaucoma (POAG). For instance, PEX syndrome accounts for 77% of all open-angle glaucomas in the eastern region of the Arabian peninsula (11). Despite its clinical significance, the PEX-associated glaucoma still is amazingly underestimated, often not clearly differentiated from POAG, leading to unexpected problems in clinical management and surgery. This chapter outlines the current concepts of pathogenetic mechanisms and clinical management of this common and important type of glaucoma.
PATHOBIOLOGY OF PEX SYNDROME
Etiology
The role of genetic and environmental factors in the pathogenesis of PEX syndrome is not known although a genetic predisposition is very likely. Lines of evidence that support a genetic basis for PEX include regional clustering, familial aggregation, transmission in two-generation families, higher concordance rates in monozygous twins, loss of heterozygosity, and HLA studies (12,13). Preliminary linkage analyses identified three putative gene loci: 2p16, 2q35–36, and 3q13–24. PEX syndrome appears to be inherited as an autosomal dominant trait with late onset and incomplete penetrance.
A number of nongenetic environmental factors have also been hypothesized to be involved in the pathogenesis of PEX syndrome. These include exposure to ultraviolet light, dietary factors, autoimmunity, infectious agents, and trauma (2). Altogether, it appears that PEX syndrome represents a complex, multifactorial, late onset disease involving both genetic and nongenetic mechanisms.
Molecular Pathobiology
The specific pathogenesis of PEX syndrome and the exact chemical composition of PEX material are still not known. However, the pathologic process is characterized by the chronic accumulation of an abnormal fibrillar matrix product, which is either the result of an excessive production or an insufficient breakdown or both and which is regarded as pathognomonic for the disease based on its unique light microscopic and ultrastructural criteria (see Fig. 2A–D) (1,2). Previous immunohistochemical studies have shown PEX material to represent a complex glycoprotein/proteoglycan structure bearing epitopes of the basement membrane and elastic fiber system. The characteristic fibrils, which are composed of microfibrillar subunits resembling elastic microfibrils (see Fig. 2E), contain predominantly epitopes of elastic fibers, such as elastin, tropoelastin, amyloid P, vitronectin, and components of elastic microfibrils, such as fibrillin-1, microfibril-associated glycoprotein-1 (MAGP-1), and the latent TGF- -binding proteins (LTBP-1 and LTPB-2) (see Fig. 2F). These immunohistochemical and recent molecular biologic data, confirming an overexpression of fibrillin- 1 and LTBP-1/2 mRNA in most cell types involved (14,15), give strong support to the elastic microfibril theory of pathogenesis, which explains PEX syndrome as a type of elastosis affecting elastic microfibrils (16). Recently, a direct analytical approach that used liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) has been accomplished and showed PEX material to consist of the