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

immunohistochemical data (16a). Together, these findings support the notion that PEX material represents an elastotic material arising from abnormal aggregation of elastic microfibril components interacting with multiple ligands.

As suggested by ultrastructural studies, the characteristic PEX fibrils appear to be multifocally produced by various intraocular cell types including the preequatorial lens epithelium, nonpigmented ciliary epithelium, trabecular endothelium, corneal endothelium, vascular endothelial cells, and virtually all cell types of the iris. All sources are believed to result from active fibrillogenesis (see Fig. 2G and H), which is accompanied by a destruction of the cells’ normal basement membrane (1).

Differential gene expression analyses of PEX and control tissues, using suppression subtractive hybridization and cDNA-array hybridization, identified a number of differentially expressed genes in PEX tissues, which were mainly involved in extracellular matrix metabolism and in cellular stress (15). One set of genes consistently upregulated in anterior segment tissues from PEX patients comprised the elastic microfibril components fibrillin-1, LTBP-1, and LTBP-2, the cross-linking enzyme transglutaminase (TGase)-2, tissue inhibitor of matrix metalloproteinase (TIMP)-2, the transforming growth factor (TGF- 1), several heat shock proteins (Hsp 27, Hsp 40, and Hsp 60), proinflammatory cytokines (IL-1 , IL-1 , and IL-2), and the adenosine receptor (AdoR)-A3. Genes reproducibly downregulated in PEX tissues included TIMP-1, the chaperone clusterin, the glutathione-S-transferases mGST-1 and GST-T1, glutaredoxin, components of the ubiquitin-proteasome pathway (ubiquitin conjugating enzymes E2A and E2B), and several DNA repair proteins (ERCC1, hMLH1, and GADD 153).

Together, these findings provide evidence that the underlying pathophysiology of PEX syndrome is associated with an excessive production of elastic microfibril components, enzymatic cross-linking processes, overexpression of the fibrotic growth factor TGF- 1, a proteolytic imbalance between matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), low-grade inflammatory processes, increased cellular and oxidative stress, and an impaired cellular stress response, as reflected by the downregulation of antioxidative enzymes, ubiquitinconjugating enzymes, clusterin, and DNA repair proteins.

Pathogenetic Factors

Most of the experimental work has been done by analyzing the aqueous humor composition of PEX patients, because aqueous humor can be easily obtained at intraocular surgery and because all ocular tissues involved are bathed by the aqueous humor and should therefore be influenced by the factors contained therein. The studies showed increased concentrations of growth factors (bFGF, HGF, CTGF, and TGF- 1) (14,17,18), an imbalance of MMPs and TIMPs (19–21), an increase in oxidative stress markers (8-isoprostaglandin-F2 ) with a concomitant decrease in antioxidative protective factors (ascorbic acid) (22), and an increase of the vasoactive peptide endothelin-1 (23).

The growth factor TGF- 1, which is a major modulator of matrix formation in many fibrotic diseases, is considered a key mediator in the fibrotic PEX process. It

is significantly increased in the aqueous humor of PEX patients, both in its latent and active form, is upregulated and actively produced by anterior segment tissues, promotes PEX material formation in vitro, and is known to regulate most of the genes found to be differentially expressed in PEX eyes, for example, fibrillin-1, LTBP-1 and -2, TGase-2, and clusterin. Binding of TGF- 1 to PEX material through the TGF- - binding proteins LTBP-1 and -2 may represent a mechanism of regulation of growth factor activity in PEX eyes (14).

Aqueous humor from PEX patients also had higher levels of MMP-2 and MMP-3 as well as TIMP-1 and TIMP-2 as compared to controls (21). However, levels of endogenously active MMP-2, which is the major MMP in human aqueous humor, were significantly decreased as was the ratio of MMP-2 to TIMP-2. These findings suggest that an excess of TIMP-2 over MMP-2 and a reduced MMP-2 activity in the aqueous humor of PEX eyes may promote the abnormal matrix accumulation due to impaired matrix turnover. TIMPs also bind to PEX material creating so-called the cold spots for proteolysis.

There is increasing evidence that cellular stress conditions, such as oxidative stress and ischemia/hypoxia, constitute major mechanisms involved in the pathobiology of PEX syndrome. Significantly reduced levels of ascorbic acid, the most effective free radical scavenger in the eye, and concomitantly increased levels of 8-Isoprostaglandin- F2 , a marker of oxidative stress (22), suggest a faulty antioxidative defense system and increased oxidative stress in the anterior chamber of PEX eyes. In agreement with these findings, decreased glutathione levels and increased levels of malondialdehyde, a lipid peroxidation product, were detected in lens epithelial cells from PEX patients (24). An analysis of the serum concentrations of oxidative stress markers, such as myeloperoxidase and malondialdehyde, as well as antioxidative factors, such as vitamins A, C, E, catalase, and total antioxidant status in patients with PEX syndrome, revealed significantly lower vitamin C concentrations and significantly higher malondialdehyde concentrations (25). In addition, the activity of superoxide dismutase was significantly decreased and products of protein oxidation were significantly increased in serum samples of PEX patients compared to control patients (26).

PEX syndrome is also associated with ocular ischemia, particularly iris hypoperfusion and anterior chamber hypoxia (27), and with a reduced ocular and retrobulbar microand macrovascular blood flow in patients with and without glaucoma (28–30). Moreover, higher rates of central retinal vein occlusions have been reported in PEX glaucoma patients (31,32). Endothelin-1, which is known as the most potent vasoconstrictor in the body, is significantly increased in the aqueous humor of normotensive PEX patients compared with that of age-matched controls (23). On the other hand, aqueous levels of nitric oxide, which is a potent physiological vasodilator, were decreased in a small number of PEX patients (33). This imbalance between vasoconstrictors and vasodilators may play a role in the obliterative vasculopathy of the iris causing local ischemia early in the disease process. Elevated homocysteine levels in the aqueous humor of patients with PEX syndrome (34) may further contribute to ischemic alterations, such as endothelial dysfunction, oxidative stress, enhancement of platelet aggregation, reduction of nitric oxide bioavailability, and abnormal perivascular matrix metabolism.

Fig. 3. Summary of pathogenetic concept of pseudoexfoliation (PEX) syndrome (adapted with permission (55)).

Pathogenetic Concept

The current concept for the mechanism of PEX syndrome is a specific type of a stress-induced elastic microfibrillopathy, with the excessive production of elastic microfibrils and their aggregation into typical PEX fibrils, produced by a variety of potentially elastogenic cells (4,15). Growth factors, particularly TGF- 1, increased cellular oxidative stress, an impaired cellular protection system, and the stable aggregation of misfolded stressed proteins appear to be involved in this process. Because of an imbalance between MMPs and TIMPs and extensive cross-linking processes involved in fiber formation, the pathologic material is not properly degraded but progressively accumulated within the tissues over time (see Fig. 3).

OPEN-ANGLE GLAUCOMA ASSOCIATED WITH PEX SYNDROME

Chronic Open-Angle Glaucoma

Epidemiology

PEX syndrome occurs in all geographic regions worldwide with reported prevalence rates varying between 5 and 40% of the general population over age 60 (2,35). Among glaucoma patients, the frequency of PEX syndrome is typically high, ranging from 10 to 30% in the USA and from 50 to 60% in Northern Europe and the Mediterranean area. At our department in Germany, about 40% of all glaucoma patients undergoing filtering surgery have PEX syndrome.

Elevated intraocular pressure (IOP) with or without glaucomatous damage occurs in 15–50% of PEX patients or about 6–10 times the rate in eyes without PEX syndrome. The probability that PEX eyes will develop glaucoma has been reported to vary from 5 to 35% within 5 years and from 15 to 40% within 10 years. The progression from

unilateral to bilateral glaucoma was found in 48% of patients with bilateral PEX syndrome within 15 years (2). In a 10-year prospective study of patients with clinically unilateral PEX syndrome, the conversion rate to glaucoma was 32% in the involved eyes (i.e., 3.2% per year) and 38% in the fellow eyes, suggesting that glaucoma may develop before there are any clinical signs of PEX material (36). The relative risk of conversion to glaucoma was found to be dependent on initial IOP, degree of pupillary dilation, and difference in IOP between the two eyes. Development of glaucomatous damage in normotensive fellow eyes of patients with unilateral PEX glaucoma has also been reported (37).

Clinical Features

Compared to POAG, PEX glaucoma has a more aggressive clinical course and a worse prognosis. It is typically associated with higher mean IOP levels, greater diurnal pressure fluctuations, marked pressure spikes, higher frequency and severity of optic nerve damage, more rapid visual field loss, poorer response to medications, and a greater necessity for surgical intervention (38,39). PEX glaucoma further differs from POAG by a more frequent asymmetry of manifestation, more pronounced chamber angle pigmentation, and acute pressure rises after mydriasis. In contrast to patients with POAG, patients with PEX glaucoma are not abnormal steroid responders, that is, only one-third respond to topical steroids with a significant pressure rise. There is a greater rate of conversion from ocular hypertension in PEX patients than in those without PEX, and damage progresses more rapidly with PEX glaucoma than with POAG. In the early manifest glaucoma trial, the presence of PEX was the most important independent risk factor for progression (40).

The percentage area of optic disc pallor was shown to be significantly greater in PEX eyes than in control eyes (41), and the mean disc area has been reported to be significantly smaller in eyes with PEX, with or without glaucoma, than in POAG eyes and normal control eyes (42). There were no significant differences in neuroretinal rim area, area of peripapillary atrophy, rim/disc ratio, cup area and cup volume between PEX eyes and control, or POAG eyes (43). However, cupping and neuroretinal rim defects tended to be more diffuse in eyes with PEX glaucoma compared to those with POAG (44). A relatively small optic disc in eyes with PEX glaucoma is diagnostically important, because early glaucomatous damage may be more difficult to recognize.

Mechanisms of Open-Angle Glaucoma

A study of aqueous humor dynamics in patients with unilateral PEX glaucoma showed a higher resistance to trabecular outflow and a slight reduction in aqueous flow in the affected eyes (45). Patients with PEX syndrome, with and without ocular hypertension, have also been reported to have a significant decrease in uveoscleral outflow compared to age-matched controls (ARVO Meeting 2006, Abstract #2943).

Chronic pressure elevation in PEX eyes is caused by the increased outflow resistance in the trabecular meshwork (45,46), most probably as a result of blockage of the outflow channels by PEX material. Aggregates of PEX material have been found by electron microscopy in the intertrabecular spaces, within the trabecular beams, and in the periphery of Schlemm’s canal. Most deposits are found in the juxtacanalicular tissue

Fig. 5. Light microscopic semithin sections showing involvement of the trabecular meshwork and Schlemm’s canal in pseudoexfoliation (PEX) syndrome (toluidine blue, magnification ×250, AC anterior chamber, and SC Schlemm’s canal). (A) Accumulation of small deposits of PEX material (arrows) in the juxtacanalicular meshwork. (B) Accumulation of large masses of PEX material (arrows) in the juxtacanalicular tissue. (C) Disorganization of Schlemm’s canal area by PEX material accumulation (arrows) in the juxtacanalicular tissue. (D) Pretrabecular deposits of PEX material overgrown by migrating corneal endothelial cells (adapted with permission (55)).

invaginations of the endothelial cells of Schlemms canal, suggesting local production by these endothelial cells (see Fig. 6A and B). In advanced cases, masses of PEX material accumulate along the whole periphery of Schlemm’s canal, often associated with degenerative changes of the canal with narrowing, fragmentation, and obstruction (see Figs 5C and 6C and D). Therapeutic efforts to improve outflow need to address the changes in this area to obtain lasting IOP reduction. Collapse of aqueous veins because of perivascular accumulation of PEX material can also occasionally be observed.

The amount of PEX material within the juxtacanalicular region and the mean crosssectional area of Schlemm’s canal correlated with the presence of glaucoma in one study (48) and also with the IOP level and the axon count in the optic nerve in another (49). These findings indicate a direct causative relationship between the buildup of PEX material in the trabecular meshwork and the IOP level and the presence and severity of glaucomatous optic nerve damage.

PEX glaucoma can be clearly differentiated from POAG at a histopathological level. Trabecular meshwork cellularity, which is decreased in POAG (50), does not differ from age-matched normal eyes in PEX glaucoma. Axon loss in the optic nerve of eyes with POAG but not with PEX glaucoma was reported to be associated with increased fibrosis of the connective tissue septa and with decreased capillary density, suggesting that other pathogenetic factors for glaucomatous optic neuropathy in addition to the IOP may be involved in POAG (51).

Fig. 6. Transmission electron micrographs showing involvement of the trabecular meshwork in pseudoexfoliation (PEX) syndrome. (A) Accumulation of PEX material (arrows) in the subendothelial juxtacanalicular tissue along the inner wall of Schlemm’s canal (SC). (B) Apparent production of PEX fibrils (arrow) by the inner wall endothelium (EN) of SC. (C) Thickening of the juxtacanalicular tissue and narrowing of SC lumen by massive accumulation of PEX material. (D) Focal collapse of SC with contact of inner and outer walls due to accumulating PEX masses (Fig. 6A and B adapted with permission (55); Fig. 6C and D adapted with permission from Schlötzer-Schrehardt U, Naumann GOH (1997) Pseudoexfoliations-Syndrome: Morphologie und Komplikationen. In: Naumann GOH (Ed), Pathologie des Auges. Springer, Berlin).

In addition to obstruction of the trabecular meshwork by PEX material, other sources of outflow obstruction may include melanin granules from a degenerate or damaged iris pigment epithelium (see Fig. 1E) (52) and increased aqueous protein concentrations (53–55). PEX aggregates in the trabecular meshwork may serve as a nidus for nonspecific accumulation of serum proteins, such as albumin, derived from a defective blood–aqueous barrier (54). Increased trabecular meshwork pigmentation is a prominent and early clinical sign of PEX syndrome (see Fig. 1F) along with occasional flecks of PEX material in the anterior chamber angle (see Fig. 1D). Pigment is also characteristically seen on or anterior to Schwalbe’s line, which is called Sampaolesi’s line. Unlike the gonioscopic picture of the pigment dispersion syndrome, the distribution of the pigment on the meshwork of PEX syndrome tends to be less dense and rather uneven or patchy. The degree of chamber angle pigmentation does not correlate with the degree of glaucomatous disc damage in most studies of PEX syndrome (56), raising a question as to the role of pigment dispersion in the chronic pressure elevation. By electron microscopy, pigment granules are invariably present within trabecular endothelial cells, preferentially in the innermost uveal portions of the meshwork in contrast to the deeper involvement seen in the pigment dispersion syndrome (48,57). It, therefore, has been suggested that pigment dispersion and accumulation do not appear

to play a significant role in chronic pressure elevation in PEX eyes but may lead to acute and transient pressure rises.

Another reported observation in some eyes with PEX is the migration and proliferation of corneal endothelial cells beyond Schwalbe’s line resulting in a pretrabecular layer of endothelial cells that produce extracellular material including PEX fibrils (see Fig. 5D) (54). This may be a consequence of anterior chamber hypoxia in PEX eyes, stimulating corneal endothelial cell proliferation (58). Such observations may partially explain why there is a variable response to medical therapy in patients with PEX.

Although PEX glaucoma is characteristically a high-pressure disease with a predominant mechanical component of optic nerve damage, pressure-independent risk factors, such as an impaired ocular and retrobulbar perfusion (28–30) and abnormalities of elastic tissue of the lamina cribrosa (59), may further increase the individual risk for glaucomatous damage. In a prospective study of patients with clinically unilateral involvement, in whom IOP was equal throughout the follow-up period, disc changes took place only in the involved eye, suggesting that the PEX process may be an IOP-independent risk factor for optic nerve damage (43).

Patients with PEX syndrome are also at increased risk for developing marked, transient IOP rises following diagnostic pupillary dilation due to dispersion of pigment granules and PEX material into the anterior chamber. The pressure elevation, which can rise to 30 mmHg above baseline, typically peaks within 2–3 h post-dilation and returns to normal levels after 10–24 h (60). Such pressure peaks can mimic the clinical picture of acute angle-closure glaucoma including pain, a red eye, diffuse corneal edema, and pressure rises over 50 mmHg despite an open angle (1,61).

In rare cases, the spontaneous luxation of the lens into the vitreous or of lens fragments in complicated cataract surgery may lead to phacolytic glaucoma (62).

Angle-Closure Glaucoma

Although the glaucoma in PEX syndrome typically has an open-angle mechanism, an association with angle-closure glaucoma is not rare (63,64). Ritch (65) found signs of PEX in 28% of consecutive patients with angle-closure glaucoma. Because some eyes with PEX syndrome have narrowed anterior chamber angles and smaller anterior chamber volumes (46,64,66), the addition of weak lens zonules and minimal anterior subluxation of the lens may predispose to angle-closure by a pupillary block mechanism. The decrease in anterior chamber depth between the supine and prone position was shown to be greater in eyes with unilateral PEX than in fellow eyes (67). Another feature of PEX eyes that may predispose to pupillary block angle-closure glaucoma is the formation of posterior synechiae, which may result from rigidity and decreased motility of the iris and an impaired blood–aqueous barrier function with increased aqueous protein concentrations (1,2). Miotics may aggravate both pupillary block and forward movement of the lens–iris diaphragm. In rare cases with marked zonular laxity, anterior displacement of the lens and ciliary muscle contraction may cause ciliary block angle-closure glaucoma (“malignant glaucoma”) (68).

Angle-closure glaucoma following central retinal vein occlusion with neovascular glaucoma may also occur in PEX eyes, in which retinal vein occlusion appears to be more common than in non-PEX eyes (31,32).

MANAGEMENT OF GLAUCOMAS ASSOCIATED

WITH PEX SYNDROME

Role of IOP

In the past, little emphasis was put on distinguishing PEX glaucoma from POAG, because the treatment modalities of both were felt to be identical. However, such a distinction has direct clinical importance, because IOP in PEX glaucoma is generally more difficult to control with medical therapy than in POAG. This may be related to the higher mean IOP levels, greater diurnal fluctuations in IOP, and marked pressure spikes in PEX glaucoma (38,39,69). A significant correlation between the IOP level at the time of diagnosis and the mean visual field defect (70) as well as between diurnal IOP fluctuations and retinal nerve fiber layer thickness (71) has been reported in patients with PEX glaucoma, but is less clear with POAG. These findings suggest that glaucomatous nerve damage in PEX patients may be more directly related to IOP than in POAG patients, where the mechanism of the optic neuropathy may be more complex. Correspondingly, reduction and stabilization of mean IOP levels and IOP fluctuations have been shown to improve visual field prognosis more in PEX glaucoma than in POAG (72).

In one study, reduction of IOP below a target of 17 mmHg was found to prevent or slow progressive glaucomatous damage in PEX glaucoma patients (73). Because peak levels of IOP often occur in the early morning, outside office hours, and because of the IOP fluctuation in PEX, single IOP measurements are not sufficient for assessing mean IOP levels in these patients (39,69,71). Measurements of IOP must also take into account that the central corneal thickness is significantly lower in PEX eyes, with or without glaucoma, as compared to control eyes (74).

As previously noted, patients with PEX also are at increased risk of marked, transient increases in IOP after diagnostic pupillary dilation because of dispersion of melanin granules and PEX material into the anterior chamber. Unrecognized pressure spikes may exacerbate glaucomatous damage, and it may be advisable to recheck IOP after dilation.

PEX may also be an independent risk factor for conversion to glaucoma in patients with ocular hypertension. In one study, the glaucoma conversion rate among ocular hypertensives was twice as high in patients with PEX as those without PEX, implying that patients with PEX and ocular hypertension may have a lower threshold for medical treatment (75).

Medical Therapy

While the approach to the medical management of PEX glaucoma is similar to that for POAG, more aggressive treatment is usually required. In many PEX glaucoma cases, it is more difficult to reach the target IOP with monotherapy, and combination therapy is often required, along with diurnal pressure monitoring and examinations