XFM – Glaucoma information
With this page, again I have to let you know that I am not a doctor. I am putting here only what has been sent to me for information purposes only. During my research, I was lucky enough to contact this man
Robert Ritch, MD
Professor of Clinical Ophthalmology
Chief, Glaucoma Service Surgeon Director
The New York Eye and Ear Infirmary
310 East 14th Street, New York, NY 10003
Medical Director and Chairman, Scientific Advisory Board
The Glaucoma Foundation http://www.glaucoma.net http://www.nyee.edu
He sent for me the following information about my condition. If you have read the other pages of this story first, you will know why I was interested to get this background. If you have the same interest, then you are probably a patient or have someone close to you who is a sufferer of this problem. If that is the case, read on….. if that is not the case, and you are a casual web surfer looking for general interest stuff, I am sure you will not get far with this thing. It is pretty dry reading, but quite invaluable if this problem has touched your life too.
Why is Glaucoma Associated with Exfoliation Syndrome?
Robert Ritch, MD1
Ursula Schlötzer-Schrehardt, PhD2
Anastasios G.P. Konstas, MD, PhD3
From the Departments of Ophthalmology, 1The New York Eye and Ear Infirmary, New York, NY, USA, 2University Erlangen-Nürnberg, Erlangen, Germany, and 3AHEPA Hospital, Thessaloniki, Greece.
Supported in part by the Joseph and Barbara Cohen Research Fund of the New York Glaucoma Research Institute, New York City, the Deutsche Forschungsgemeinschaft (SFB 539) and KESY, Greece.
Running title: Ritch / Exfoliation syndrome
Corresponding author: Robert Ritch, M.D., Professor and Chief, Glaucoma Service, the New York Eye and Ear Infirmary, 310 East 14th Street, New York, New York 10003.
Tel: 212-673-5140 Fax: 212-420-8743 ritchmd@earthlink.net
ABSTRACT
Exfoliation syndrome (XFS) is an age related, generalized disorder of the extracellular matrix characterized by production and progressive accumulation of a fibrillar material in tissues throughout the anterior segment and also in connective tissue portions of various visceral organs. Mature exfoliation fibrils are composed of 8-10 nm microfibrils resembling elastic microfibrils. The exact chemical composition of exfoliation material remains unknown. It appears to consist of a complex glycoprotein/proteoglycan structure composed of a protein core surrounded by abundant glycoconjugates. The protein components include both non-collagenous basement membrane components and epitopes of the elastic fiber system, particularly components of elastic microfibrils.
Overall, XFS is the most common identifiable cause of glaucoma, accounting for the majority of cases in some countries, and causing both open-angle glaucoma and angle-closure glaucoma. Iridolenticular friction leads to loss of exfoliation material from the anterior lens surface and disruption of the iris pigment epithelium, resulting in pigment deposition in the trabecular meshwork, which also produces exfoliation material locally. The primary cause of chronic pressure elevation appears to be the active involvement of trabecular cells and Schlemm’s canal cells in particular, in the generalized pathologic matrix process with subsequent degenerative changes of Schlemm’s canal and adjacent tissues.
Narrow angles and angle-closure are common in XFS. Pupillary block may be caused by a combination of posterior synechiae, increased iris thickness or rigidity, or anterior lens movement secondary to zonular weakness or dialysis. Enlargement of the lens due to cataract formation and relative pupillary constriction are additional factors.
OUTLINE
I. Introduction
II. Pathophysiology of Exfoliation Syndrome
A. Ultrastructure and composition of exfoliation material
B. Cellular dysfunction in exfoliation syndrome
1. Histopathology of ocular tissues involved in XFS
a. Lens
b. Iris
c. Ciliary body and zonules
d. Trabecular meshwork
e. Cornea
C. Pathogenetic factors in exfoliation syndrome
1. Growth factors
2. Proteolytic enzymes and their inhibitors
3. Free radicals
D. Pathogenetic concept of exfoliation syndrome
III. Clinical Findings in Exfoliation Syndrome
A. Symptoms
B. Lens
C. Iris
D. Pupil
E. Cornea
F. Ciliary body and zonules
G. Anterior chamber angle
H. Vitreous and retina
I. Optic disc
J. Extraocular findings
K. Systemic associations
IV. Pathogenesis of Glaucoma in Exfoliation Syndrome
A. Chronic open-angle glaucoma
1. Natural history and prognosis
2. Asymmetry of involvement
3. Open-angle glaucoma in eyes with XFS
4. Angle-closure glaucoma in eyes with XFS
I. Introduction
Exfoliation syndrome (XFS) is an age related, generalized disorder of the extracellular matrix characterized by production and progressive accumulation of a fibrillar material, not only in ocular tissues, but in skin and connective tissue portions of various visceral organs. Its ocular manifestations affect all of the structures of the anterior segment as well as conjunctiva and orbital tissues. Overall, it is the most common identifiable cause of glaucoma, accounting for the majority of cases in some countries.(Ritch, 1994b) Despite its wide prevalence and clinical importance, the pathogenesis of XFS and the exact composition of the exfoliation material (XFM) remain unknown. New and developing conceptual approaches have increased the importance of accurate diagnosis of what is a potentially curable disorder.
Exfoliation syndrome was first described in 1917 by Lindberg,(Lindberg, 1917; Lindberg, 1989) who noted bluish-gray flecks at the pupillary margin of the iris in 50% of patients with chronic open-angle glaucoma. Angle-closure glaucoma (ACG) has only recently also been found to be common. The epidemiology of XFS in patients with and without has been extensively reviewed and is beyond the scope of this paper.(Forsius, 1988; Ringvold, 1999; Ritch and Schlötzer-Schrehardt, 2001; Tarkkanen, 1962) We will examine the pathophysiologic and clinical features of the disease and describe the etiology of the development of glaucoma as it is presently understood.
II. Pathophysiology of Exfoliation Syndrome
Exfoliation syndrome is a generalized abnormal process of the extracellular matrix characterized by the multifocal excessive production of a typical extracellular fibrillar material, which is not degraded but progressively accumulates in various intra- and extraocular tissues.(Schlötzer-Schrehardt et al., 1992b; Streeten et al., 1992) The etiology of this systemic matrix process remains unknown.
A. Ultrastructure and composition of exfoliation material
The characteristic fibrillar extracellular material still represents the gold standard for diagnosis (Figure 1). Transmission electron microscopy shows the deposits to consist of randomly arranged, electron-dense, fuzzy fibrils with a diameter of 18-25 nm (type A-fibrils) (Figure 1A) or 30-45 nm (type B-fibrils) (Figure 1B) and a banding periodicity of about 50 nm.(Streeten and Dark, 1994) The mature exfoliation fibrils are composed of 8-10 nm microfibrils resembling elastic microfibrils (Figure 1C). The microfibrillar subunits seem to form a core by lateral aggregation and are surrounded and masked by an electron-dense, amorphous matrix, which is suggested to represent glycosaminoglycans on the surface of the exfoliation fibrils.(Davanger, 1977) In spite of minor site-dependent differences of exfoliation fibrils, the ultrastructure of the fibrils is highly characteristic and it is clearly distinguishable from any other known form of extracellular matrix.
Despite extensive research, the exact chemical composition of XFM remains unknown. Indirect histochemical and immunohistochemical evidence suggests a complex glycoprotein/proteoglycan structure composed of a protein core surrounded by abundant glycoconjugates indicating excessive glycosylation processes.(Amari et al., 1994; Hietanen et al., 1994; Kubota et al., 1997; Qi et al., 1997; Uusitalo et al., 1993) Immunohistochemical studies provided evidence for the presence of glycosaminoglycans and proteoglycans such as heparan sulfate proteoglycan, chondroitin sulfate proteoglycan, dermatan sulfate proteoglycan, keratan sulfate proteoglycan, and hyaluronan.(Fitzsimmons et al., 1997; Gartaganis et al., 2001; Schlötzer-Schrehardt et al., 1992a; Tawara et al., 1996; Winkler et al., 2001)
The protein components of XFM include both non-collagenous basement membrane components, such as laminin, nidogen, and fibronectin,(Konstas et al., 1990; Schlötzer-Schrehardt et al., 1992a) and epitopes of the elastic fiber system, such as elastin, tropoelastin, fibrillin, amyloid P, and vitronectin,(Li et al., 1988; Li et al., 1989; Schlötzer-Schrehardt et al., 1997; Streeten et al., 1986; Vogiatzis et al., 1994) and particularly components of elastic microfibrils, such as fibrillin-1 (Figure 1D,2D), microfibril-associated glycoprotein (MAGP-1), and latent TGF-ß binding proteins (LTBP-1 and -2).(Schlötzer-Schrehardt et al., 2000; Schlötzer-Schrehardt et al., 1997; Schlötzer-Schrehardt et al., 2001) These immunohistochemical data give strong support to the current elastic microfibril theory that explains XFS as a type of elastosis particularly affecting elastic microfibrils.(Garner and Alexander, 1984; Streeten, 1993) Antibodies to elastic microfibril components (e.g. LTBP-1) have been proven particularly useful as markers for exfoliation deposits in intra- and extraocular tissues.(Schlötzer-Schrehardt et al., 2000) The elastic microfibril theory on the pathogenesis of XFS gains increasing support by molecular biologic studies confirming an overexpression of fibrillin-1 and LTBP mRNA in most tissues and cell types involved.(Schlötzer-Schrehardt et al., 2001)
B. Cellular dysfunction in exfoliation syndrome
Exfoliation fibers appear to be multifocally produced by various intra- and extraocular cell types, including epithelial cells, endothelial cells, connective tissue cells, muscle cells, and vascular wall cells. In the eye, XFM is produced primarily by the preequatorial lens epithelium (Figure 2A), nonpigmented ciliary epithelium (Figure 2B), iris pigment epithelium (Figure 2C,D), trabecular endothelium (Figure 5A), corneal endothelium, and virtually all cell types of the iris stroma and vasculature – cell types that are closely associated with the aqueous humor circulation.(Naumann et al., 1998; Ritch and Schlötzer-Schrehardt, 2001) In extraocular locations, XFM is primarily found in skin and connective tissue portions of visceral organs and seems to originate from connective tissue fibroblasts, smooth and striated muscle cells, and heart muscle cells.(Schlötzer-Schrehardt et al., 1992b; Streeten et al., 1992) All cell types involved show ultrastructural signs of active fibrillogenesis, such as formation of surface invaginations with emerging exfoliation fibrils. The pericellularly accumulating XFM successively disrupts and destroys the normal basement membrane of the cells (Figure 2C) and eventually results in degeneration of the cells involved (degenerative fibrillopathy).
1. Histopathology of ocular tissues involved in XFS
a. Lens
The classic pattern of diagnostically important exfoliation deposits on the anterior lens surface consists of three distinct zones (central disk, clear intermediate zone, peripheral granular zone). These zones are created by the topographic relation of the anterior lens surface to the iris, which deposits granular aggregates in some areas and rubs material off in others. In early stages of the disease, a diffuse precapsular layer of microfibrils can be found on the entire surface of the anterior lens capsule by electron microscopy, which appears to be a precursor of typical XFM.(Dark and Streeten, 1990; Tetsumoto et al., 1992) In manifest stages of XFS, the central disk appears to develop from the central portion of the precapsular layer and consists of loosely arranged microfibrils and scattered exfoliation fibrils. The intermediate zone discloses a smooth capsular surface that develops from abrasion of the preexisting precapsular layer by iris movements. The peripheral granular zone consists of abundant nodular aggregates, which appear to be passively deposited on the preexisting precapsular layer by the iris pigment epithelium. The clinically invisible preequatorial region is characterized by nodular excrescences covering the zonules and their attachment to the anterior lens capsule. Whereas the clinically obvious deposits in the central and midperipheral regions of the lens are considered to result from aqueous- and iris-derived passive deposition, this peripheral region is the only region of the lens with active production of exfoliation fibers by the metabolically active preequatorial lens epithelium (Bertelsen, 1974 #72; Dark 1977 #114; Naumann 1998 #381) (Figure 3A). In this area, the locally produced exfoliation fibers infiltrate and penetrate the lens capsule and erupt through the capsular surface, thereby lifting the zonular lamella off the surface of the capsule (Figure 3B).(Schlötzer-Schrehardt and Naumann, 1994)
b. Iris
Iris changes are an early and consistent feature of exfoliation eyes and involve all iris structures and cell types. XFM is produced by and accumulates on the surface of the posterior pigment epithelium, which exhibits marked degenerative changes with focally ruptured cell membranes and liberation of melanin granules (Figure 3C).(Asano et al., 1995; Shimizu and Futa, 1985) Stromal exfoliation deposits are primarily found in the anterior border layer, within sphincter and dilator muscles, and in the walls of blood vessels (Figure 3D).(Asano et al., 1995; Konstas et al., 1993c; Ringvold, 1970; Shimizu, 1985) In advanced stages, the vascular wall cells may degenerate completely, leaving acellular ghost vessels outlined by a ring of XFM. Atrophic alterations of sphincter and dilator muscle tissues may be due to the pronounced anterior chamber hypoxia occurring in XFS eyes.(Helbig et al., 1994) Subtle ultrastructural alterations, such as microfibrillar deposits in the dilator muscle or in the periphery of iris vessels can be observed in virtually all contralateral eyes in clinically unilateral cases,(Hammer et al., 2001) supporting the concept that XFS is a bilateral disease with clinically asymmetric manifestation.(Speakman and Ghosh, 1976; Prince and Ritch, 1987; Kivelä et al., 1997)
c. Ciliary body and zonules
Bush-like feathery deposits of XFM typically cover the crests of the ciliary processes and are derived from local production by the nonpigmented ciliary epithelium.(Ghosh and Speakman, 1973) In later stages, some epithelial cells seem to degenerate under the progressively accumulating exfoliation masses that destroy the basement membrane of the cells. No XFM has been found in the ciliary body stroma or vessel walls, except in the anteriormost portion of the ciliary muscle at the junction with trabecular tissue.(Ringvold and Davanger, 1977)
The zonules are typically coated and encrusted with XFM, giving them a frosted appearance. Although it is still unclear whether the zonular fibers proper are intact or degenerated, their anchorage into the defective basement membranes of ciliary body and lens is markedly impaired explaining their instability.(Schlötzer-Schrehardt and Naumann, 1994) At their attachment to the ciliary epithelium and anterior lens capsule, the zonular fibers are separated from the basement membranes by intercalating masses of exfoliation fibers locally produced by the nonpigmented ciliary epithelium on the one hand (Figure 3E,F) and the preequatorial lens epithelium on the other (Figure 3A,B), thereby loosening zonular anchorage into the ciliary body and lens.(Schlötzer-Schrehardt and Naumann, 1994)
d. Trabecular meshwork
Most deposits of XFM can be found by light and in the juxtacanalicular tissue adjacent to Schlemm’s canal (Figure 4A,B, 5B) or in the uveal meshwork (Figure 4C), while the corneoscleral portion of the meshwork appears less involved.(Benedikt and Roll, 1979; Gottanka et al., 1997b; Richardson and Epstein, 1981; Ringvold and Vegge, 1971; Roth, 1979; Schlötzer-Schrehardt and Naumann, 1995) Accumulation of XFM also occurs in the outer wall of Schlemm’s canal and in the periphery of collector channels and scleral aqueous veins.(Schlötzer-Schrehardt and Naumann, 1995) The deposits in the meshwork have been suggested to result from a combination of passive deposition in the inner uveal portions and local synthesis in the outer juxtacanalicular area, where ultrastructural evidence suggests active production of exfoliation fibers by the endothelial cells lining Schlemm’s canal (Figure 5A,D).(Schlötzer-Schrehardt and Naumann, 1995) The amount of XFM in the trabecular meshwork correlates with the presence or absence of glaucoma and correlates inversely with the axon count in the optic nerve, indicating a direct causative relationship between the buildup of XFM in the meshwork and glaucoma development.(Gottanka et al., 1997a; Schlötzer-Schrehardt and Naumann, 1995)
The progressive accumulation of XFM in the juxtacanalicular area (Figure 5B), the site of greatest outflow resistance, appears not only to impair aqueous drainage, but also to cause structural alterations of the normal tissue architecture. Normally, the entire periphery of Schlemm’s canal is encircled by a network of elastic microfibrils providing tensile strength and flexibility to the canal wall (Figure 5C). In XFS eyes, this subendothelial microfibrillar plexus is gradually disrupted and replaced by abnormal deposits of XFM (Figure 5D), which presumably results in loss of structural stability and flexibility of the canal wall.(Schlötzer-Schrehardt et al., 2002b) Loss of mechanical stability may ultimately lead to marked disorganization of the normal juxtacanalicular tissue structure and may explain the degenerative changes usually found in eyes with advanced exfoliative glaucoma, such as narrowing and focal collapse of the canal lumen, partial obliteration of Schlemm’s canal, and splitting of Schlemm’s canal into smaller channels (Figure 4D,5E). Collapse of aqueous veins due to perivascular accumulation of XFM can be also often observed (Figure 5F).(Schlötzer-Schrehardt and Naumann, 1995)
Thus, the primary cause of chronic pressure elevation appears to be the active involvement of trabecular cells and Schlemm’s canal cells in particular, in the generalized pathologic matrix process with subsequent degenerative changes of Schlemm’s canal and adjacent tissues.(Schlötzer-Schrehardt et al., 1999) However, many more factors may contribute to glaucoma development, such as dispersion and accumulation of melanin granules liberated from the degenerating iris pigment epithelium, a protein-rich aqueous humor,(Küchle et al., 1994) vascular factors,(Yüksel et al., 2001) and connective tissue alterations of the lamina cribrosa.(Netland et al., 1995) Melanin granules can be found in variable amounts throughout the meshwork, but show a high circumferential variation in density and are generally phagocytosed by trabecular endothelial cells (Figure 4C).(Schlötzer-Schrehardt and Naumann, 1995) However, pigment dispersion may cause pressure peaks after mydriasis and may represent an additional aggravating factor for the metabolically damaged cells.
Exfoliative glaucoma can be clearly differentiated from primary open-angle glaucoma (POAG) histopathologically. Whereas POAG is characterized by increased juxtacanalicular plaque material (Figure 6B) and decreased trabecular meshwork cellularity,(Alvarado et al., 1984; Rohen, 1983) both plaque material and cellularity are unchanged in exfoliative glaucoma compared to normal eyes, but there is deposition of the characteristic XFM instead (Figure 6A).(Lütjen-Drecoll et al., 1986; Schlötzer-Schrehardt and Naumann, 1995) These histopathologic differences suggest completely different pathogenetic mechanisms and underscore the need for specific therapeutic approaches.
e. Cornea
In some eyes with XFS, focal retrocorneal flakes of XFM can be observed adhering to the corneal endothelium. Ultrastructural evidence suggests local production of exfoliation fibers by corneal endothelial cells, which degenerate and detach from Descemet’s membrane. Subsequent re-endothelialization of denuded areas by neighboring fibroblastic endothelial cells leads to incorporation of exfoliation aggregates into Descemet’s membrane.(Schlötzer-Schrehardt et al., 1993a) Together with a reduced endothelial cell density, a diffuse non-guttate-like thickening of Descemet’s membrane, and marked endothelial phagocytosis of melanin granules, the involvement of the corneal endothelium in the exfoliation process lead to the concept of a specific XFS-associated keratopathy.(Naumann and Schlötzer-Schrehardt, 2000)
C. Pathogenetic factors in exfoliation syndrome
Candidate pathogenetic factors in the aqueous humor that might influence the abnormal matrix metabolism in the surrounding tissues include growth factors, proteolytic enzymes and their inhibitors, and free radicals.
1. Growth factors
Recent data indicate involvement of certain growth factors in the pathogenesis of XFS. Increased growth factor activity, as measured by 3H-thymidine incorporation, has been reported in the aqueous humor of patients with XFS.(Koliakos et al., 2000) Specifically, aqueous levels of basic fibroblast growth factor (bFGF)(Gartaganis et al., 2001) and hepatocyte growth factor(Hu and Ritch, 2001) were reported to be elevated in eyes with XFS with and without glaucoma. Moreover, transforming growth factor (TGF-ß1), both in its latent and active forms, was significantly increased in the aqueous humor of XFS patients with and without glaucoma compared to age-matched controls.(Koliakos et al., 2001b; Schlötzer-Schrehardt et al., 2001) There is evidence for enhanced local synthesis of TGF-ß1 by anterior segment tissues, suggesting a role for TGF-ß1 in the promotion of this abnormal matrix process.(Schlötzer-Schrehardt et al., 2001) In contrast, TGF-ß2 levels were significantly higher in the aqueous humor of POAG patients only but not of XFS patients.(Schlötzer-Schrehardt et al., 2001; Tripathi et al., 1994)
2. Proteolytic enzymes and their inhibitors
Excessive matrix accumulation may be due either to increased de novo synthesis or decreased turnover of matrix components or both. Aqueous humor from XFS patients had a higher level of acid phosphatase activity compared to that from cataract patients.(Mizuno et al., 1980) In a recent study, significantly increased concentrations of MMP-2, MMP-3, TIMP-1, and TIMP-2 were detected in aqueous samples from XFS patients with and without glaucoma compared to control patients with cataract; however, levels of endogenously active MMP-2 were significantly decreased and the ratio of MMP-2 to its principal inhibitor TIMP-2 was decreased, resulting in an excess of TIMP-2 over MMP-2 in XFS samples.(Schlötzer-Schrehardt et al., 2002a) These findings suggest that complex changes in the local MMP/TIMP balance and reduced MMP activity in the aqueous humor may promote the abnormal matrix accumulation in XFS.
3. Free radicals
Ultraviolet irradiation, a main source of free radicals, has been implicated in the past for the variable prevalence of XFS in various geographic locations and populations.(Taylor, 1979) Significantly reduced levels of ascorbic acid, an important free radical scavenger in the eye, have been reported in the aqueous humor of XFS patients,(Koliakos, 2002) suggesting a faulty antioxidant defense system.
D. Pathogenetic concept of exfoliation syndrome
The current pathogenetic concept of XFS suggests a TGF-ß1-stimulated excess production of elastic microfibril components and their aggregation into typical exfoliation fibrils by a spectrum of potentially elastogenic cells. Abnormal glycosylation processes may take place and other extracellular matrix components, such as basement membrane components derived from ruptured basement membranes, may interact and become secondarily incorporated into the composite exfoliation fibers. Due to an imbalance of MMPs and TIMPs and extensive cross-linking processes involved in fiber formation, the pathologic material is not degraded but progressively accumulates within the tissues over time with potentially deleterious effects in the trabecular meshwork.
III. Clinical Findings in Exfoliation Syndrome
A. Symptoms
Throughout its long and insidious course, XFS is usually clinically silent. Symptoms may arise only with the development of cataract or when glaucoma ensues. Open-angle glaucoma may remain asymptomatic and undetected until serious disability has occurred. However, in some cases it may give rise to subjective symptoms: dull eye ache, or “tension” due to high IOP; difficulty in reading, diminished peripheral or night vision, and ultimately failure of vision due to advanced glaucomatous neuropathy. High IOP in exfoliative glaucoma may also give rise to symptomatic vascular sequelae (e.g. central retinal vein occlusion) that seriously diminish vision. In a small proportion of cases, open-angle glaucoma may present in a more dramatic fashion with headache or pain owing to the development of “acute open angle glaucoma” with an IOP in excess of 50 mmHg.(Brooks and Gillies, 1988; Gillies and Brooks, 1988; Jerndal, 1986)
B. Lens
Deposits of white material on the anterior lens surface are the most consistent and important diagnostic feature of XFS. The classic pattern consists of three zones: a relatively homogeneous central disc corresponding roughly to the diameter of the pupil; a granular, often layered, peripheral zone, and a clear area separating the two (Figure 7). Individual variations may result from differing quantities of XFM deposits, different stages in the disease progress, and the topographic relationship between lens and iris. Changes in the size of the pupil (i.e. a miotic pupil or chronically dilated one) result in a smaller or larger central disc (Figure 8), respectively, whereas a distortion in the shape of the pupillary rim would also change the shape of the central disc.(Prince and Ritch, 1986; Sugar, 1984; Sunde, 1956)
The central disc or zone is a homogeneous, subtle opacification resembling a cellophane-like membrane lying on the anterior pole of the lens capsule. Its diameter varies from 1.5 to 3.0 mm and it is best visualized with oblique illumination after pupillary dilation, since its border may be hidden under the iris. The central disc may be absent in some 10-20% of cases.(Joannides et al., 1961; Layden and Shaffer, 1974, Ruprecht, 1985 #10695; Sood and Ratnaraj, 1968; Tarkkanen, 1962). Minute particles of XFM may be seen on the edge or surface of the central disc.
The peripheral zone is the most reliable sign for the diagnosis of XFS (Figure 9). It may be granular in the periphery and frosty white centrally and radial striations are often seen. Layers may be present. The granularity of the peripheral layer is consistent with undisturbed accumulation of XFM.
Examination after mydriasis is essential for the accurate diagnosis of XFS. This disorder evolves slowly, over many years. The early biomicroscopic stages have not been well defined. A precursor of XFM is thought to be initially diffusely deposited on the lens surface. A homogeneous ground-glass or matte appearance to the lens surface in one eye compared to the other may represent a very early (precapsular) stage.(Dark and Streeten, 1990; Tetsumoto et al., 1992) In a perhaps slightly later (pregranular) stage, there may be a ring of about 80 faint, radial, nongranular striae on the mid-third of the anterior capsule behind the iris (Figure 4).(Bartholomew, 1971) In a study which evaluated the value of individual signs with reference to the ultrastructural presence of XFM in the iris, the sensitivity of this sign was 100%, the specificity was 94% and the predictive value was 85%.(Konstas, 1993) In visualizing the earlier stages at the slit-lamp, placing the slit beam at 45 degrees to the axis of observation, reducing the light source, and focusing temporally about 2 to 3 mm from the center of the lens may help to highlight the subtle deposits on the lens surface.
An alternative hypothesis for the early development of the condition has been suggested by Jerndal.(Jerndal, 1985) According to this hypothesis, in stage 1 the posterior layer of the iris epithelium begins to lose pigment and tiny dots of pigment appear in radial clusters upon the lens capsule. Stage 2 is characterized by progressive loss of the pupillary ruff, transillumination defects and an incomplete granular zone with the first aggregates of XFM often intermingled with pigment. Often at this stage the outline of the granular zone is evident and demarcated with pigment. Stage 3 demonstrates the completed granular zone with XFM and more advanced transillumination defects of the iris.
The intermediate clear zone is created by rubbing of the iris over the surface of the lens during pupillary movement. As the precapsular layer becomes thicker, the iris sphincter region begins to rub against it during normal pupillary movement. Faint clefts form where XFM is rubbed away. With time, these clefts increase in size and begin to become confluent (Figure 7). Eventually, only small bridges may remain as an indication of the previous layer of XFM in the intermediate zone.
Phacodonesis due to zonular weakness is common and may be a sign of incipient lens displacement.(Bartholomew, 1970a) Mohammed and Kazmi(Mohammed and Kazmi, 1986) detected lens subluxation or dislocation in 14 of 48 patients with XFS (16%). Late lens particle glaucoma may result.(Lim et al., 2001) Phacodonesis is not always associated with iridodonesis, perhaps attributable to increased iris rigidity. It may be brought out by giving a drop of 2% pilocarpine to relax the zonules. The denser the XFM accumulation, the more likely is there to be phacodonesis.(Bartholomew, 1970b; Mohammed and Kazmi, 1986)
There appears to be a significant association between XFS and cataract formation.(Bartholomew, 1979; Dark, 1979; Hietanen et al., 1992; Hirvelä et al., 2000; Irvine, 1940; Küchle and Naumann, 1992; Küchle et al., 1989; Layden and Shaffer, 1974; Lumme and Laatikainen, 1993; Madden and Crowley, 1982; Meyer et al, 1984; Moreno Montañés et al., 1989; Moreno-Montañés et al., 1990a; Paufique and Audibert, 1958; Puska and Raitta, 1992; Puska and Tarkkanen, 2001; Roth and Epstein, 1980; Summanen and Tönjum, 1988; Tarkkanen, 1962; Taylor, 1980; Wilson, 1953; Yalaz et al., 1992) There is an increased prevalence of XFS in eyes coming to cataract surgery and an increased prevalence of cataracts in eyes with XFS.(Hietanen et al., 1992) Eyes with XFS with or without glaucoma have poorer visual acuity and more often have lens opacification (with or without pilocarpine treatment in glaucomatous eyes) than clinically uninvolved fellow eyes.(Puska, 1994) Koliakos et al(Koliakos et al., 2001a) found a significantly reduced level of ascorbic acid in the aqueous humor of patients with XFS. Since ascorbic acid plays an important role in protecting the lens from ultraviolet irradiation, this finding may provide a logical explanation for the greater incidence of cataract formation and posterior capsular opacification after cataract extraction in eyes with XFS. In a histological study, XFS was diagnosed in 33% of cataractous lenses, whereas only 16% of those cases had been diagnosed clinically prior to cataract surgery.(Krause and Tarkkanen, 1978)
C. Iris.
Iris changes are an early and well recognized clinical feature in XFS. Next to the lens, XFM is most prominent at the pupillary border (Figure 10). It is not invariably present and may be represented only by a tiny dot or two, requiring again a high index of suspicion and a careful search, or it may be extensive. In advanced stages of XFS it is a more prominent diagnostic feature. It tends to be most prominent in eyes maintained on miotic therapy. Forsius (Forsius, 1988) suggested that the open-angle glaucoma may be more severe if XFM is present on the iris in addition to the lens. The iris in eyes with XFS appears to be more rigid than in eyes without XFS.(Bartholomew, 1970a; Futa and Furuyoshi, 1989)
Iris vascular abnormalities are characteristic of XFS. Vessel dropout with collateral formation and iris hypoperfusion lead to patchy iris microneovascularization. Fluorescein angiographic studies have shown partial occlusion of radial iris capillaries associated with hypoperfusion, a reduced number of vessels, microneovascularization, and diffuse, patchy fluorescein leakage, especially in the pupillary region.(Boguszaková and Dubská, 1987; Brooks and Gillies, 1983; Brooks and Gillies, 1987; Cobb and Smith, 1971; Sakai and Kojima, 1982; Valle and Vannas, 1976; Vannas, 1969; Vannas, 1972; Vargas and Drance, 1973) Indocyanine green angiography provides better recognition of iris hypoperfusion and anastomotic vessels.(Parodi et al., 2000) Neovascularization of posterior synechiae may result in microhyphema, occasionally accompanied by elevated IOP, following pharmacologic dilation. Patients with XFS who are taking anticoagulants may be more susceptible.(Greenfield et al., 1999)
A close relationship exists between the development of the classic clinical signs of XFS and progressive atrophy of the posterior pigmented layer of the affected iris. Pigment loss from the iris sphincter region and its deposition on anterior chamber structures is a hallmark of XFS. Just as the iris scrapes XFM from the lens surface, the material on the lens causes rupture of iris pigment epithelial cells at the ruff and sphincter region with concomitant dispersion of pigment into the anterior chamber. Loss of iris pigment and its deposition throughout the anterior segment are reflected in iris sphincter region transillumination, loss of the pupillary ruff, increased trabecular meshwork pigmentation, and pigment deposition on the iris surface.(Prince and Ritch, 1986) Although mechanical friction is thought by most to be the most likely mechanism of pigment release it has also been suggested that pigment liberation may be caused by a primary vascular disturbance in the iris.(Vannas, 1969)
Pupillary ruff defects are the most common of these signs and are most striking in patients with unilateral involvement.(Prince and Ritch, 1986) Transillumination defects occur at the pupillary ruff and margin.(Aasved, 1973) However, if extensive depigmentation has occurred, defects may be noted over the entire sphincter region. Generalized peripheral iris transillumination, which appears as a diffuse “starry-sky” appearance of the defects, has also been associated with XFS,(Repo et al., 1990) but this finding is relatively uncommon.
Pigment deposition on the iris surface is a rarely noted but common finding.(Prince and Ritch, 1986) Its characteristic appearance should alert the examiner to search carefully for XFM. Pigment particles, larger than those found in pigment dispersion syndrome, are deposited in a whorl-like fashion on the anterior stroma at the sphincter.(Prince and Ritch, 1986) Pigment is deposited evenly over the iris surface, in contrast to its collection in iris furrows in pigment dispersion syndrome.
Exfoliation syndrome predisposes to formation of synechiae between the iris pigment epithelium and the anterior lens capsule, even in the absence of miotic therapy.(Bertelsen, 1966; Kristensen, 1965) Vigorous dilation can result in adhesion of the entire iris pigment epithelium onto the lens surface. Krause and Tarkkanen (Krause and Tarkkanen, 1978) described remnants of posterior synechiae adherent to the lens in 5 eyes with histologically proven XFS. Posterior synechiae are more prone to form between the iris and intraocular lens postoperatively.(Brazitikos and Roth, 1991)
Exfoliation ‘suspects’ were initially defined as patients in whom one or both eyes exhibited one or more signs related to pigment dispersion (see above) in the absence of clinically identifiable XFM on the anterior lens capsule or pupillary margin.(Prince et al., 1987) Transmission electron microscopy of conjunctival biopsy specimens from patients previously diagnosed to have either primary open-angle glaucoma or ocular hypertension revealed exfoliation fibers in 8/23 suspect eyes. In another prospective series,(Konstas, 1993) 4 of 18 suspects previously diagnosed to have primary open-angle glaucoma had exfoliative glaucoma by ultrastructural investigation of iridectomy specimens. These pigment-related signs also correlated with the presence of extraocular exfoliation fibrils in 7 of 12 eyelid skin specimens in the absence of any clinically visible intraocular XFM.(Schlötzer-Schrehardt et al., 1993)
D. Pupil
Eyes with XFS often dilate less than eyes of age-matched individuals without XFS.(Bartholomew, 1970a; Carpel, 1988; Drolsum et al., 1993; Lundvall and Zetterström, 1993; Tarkkanen, 1986; Watson et al., 1995; Zetterström et al., 1992) In patients with clinically unilateral XFS, the difference in response between the involved and fellow eyes to pharmacologic dilation may be significant.(Carpel, 1988) Eyes with XFS may also constrict less well to topical 4% pilocarpine.(Lundvall and Zetterström, 1993) Even without mydriatics, the pupil in the involved eye may be smaller (suggesting a defective dilator muscle, reduced sympathetic innervation or increased parasympathetic innervation). In patients with newly diagnosed, untreated, unilateral exfoliative glaucoma, the pupil in the involved eye was smaller in all cases.(Hahnenberger, 1984)
Small pigment particles can be seen floating in the aqueous in the undilated eye. Pigment dispersion in the anterior chamber is common after pupillary dilation and may be profuse. This pigment is released from the posterior pigment epithelium of the iris as the pupil dilates, and is more common and more marked in eyes with XFS than in eyes with POAG.(Krause et al., 1973) Tarkkanen(Tarkkanen, 1962) found pigment dispersion only in eyes with XFS.
Marked IOP rises can occur in these eyes after pharmacologic dilation with a positive correlation between the extent of IOP rise and the amount of pigment liberated. (Mapstone, 1981b; Nanba et al., 1978) Krause et al (Krause et al., 1973) noted the pigment in the anterior chamber to be maximal at one to two hours after mydriasis and to disappear in 12 to 24 hours. IOP rises usually reach a maximum after two hours. (Kristensen, 1968) In some patients, however, we have found that IOP may begin to rise only after three to four hours after mydriasis (unpublished data). Since IOP is rarely measured at this late a time, possible further glaucomatous damage in compromised eyes may occur. Post-dilation IOPs should be checked routinely in all XFS patients receiving mydriatics.
E. Cornea.
Scattered flakes of XFM may be observed on the endothelial surface and may be erroneously interpreted as inflammatory precipitates (figure 11).(Chern et al., 1994) Pigment deposition usually causes a diffuse, nonspecific pigmentation of the central endothelium, occasionally having the pattern of a Krukenberg spindle.(Prince and Ritch, 1986) More frequently, one or several undulating pigmented lines can be observed in the inferior peripheral cornea anterior to Schwalbe’s line.(Sampaolesi, 1959; Sampaolesi et al., 1988).
Specular microscopy demonstrates a significantly reduced endothelial cell density, even with normal IOP, together with morphologic changes in size and shape of the endothelial cells in both affected eyes and uninvolved fellow eyes.(Hattori, 1990; Knorr et al., 1991; Seitz et al., 1995; Setälä, 1980; Stefaniotou et al., 1992; Vannas et al., 1977; Wang et al., 1999; Wirbelauer et al., 1998). Decreased endothelial cell density does not necessarily correlate with the severity of glaucoma or duration of treatment,(Vannas et al., 1977) but it has been correlated with the extent of pigment dispersion.(Kohno et al., 1993) Central corneal thickness is also greater in eyes with XFS, perhaps reflective of early corneal dysfunction.(Puska et al., 2000) Although these morphologic changes may be related to XFS itself, changes in aqueous humor composition and dynamics, possibly related to XFM-induced iris hypoperfusion, may also be responsible.(Brooks et al., 1987) A greater than normal frequency of cornea guttata in eyes with XFS has been suggested.(Drolsum et al., 1993)
Naumann and Schlötzer-Schrehardt(Naumann and Schlötzer-Schrehardt, 1994; Naumann and Schlötzer-Schrehardt, 2000) have suggested that a true keratopathy, distinct from Fuchs’ dystrophy and from pseudophakic bullous keratopathy, can be found in eyes with XFS, predisposing some patients with XFS to develop early corneal endothelial decompensation at only moderate rises of IOP or after cataract surgery.
F. Ciliary body and zonules
Exfoliation material may be detected early on the ciliary processes and zonules. Zonular XFM may predate development of the peripheral granular zone and may appear as subtle striations of XFM and/or pigment on the surface of the lens.(Bartholomew, 1973) Cycloscopy in patients with apparently unilateral involvement revealed XFM on the ciliary processes in all affected eyes and on the zonule or ciliary processes or both in 77% of fellow eyes in which XFM was not clinically visible on the lens surface or pupillary border.(Mizuno and Muroi, 1979) Whether the zonules are just coated with XFM or actually replaced by it, they are often frayed and broken (Figure 12).(Chijiiwa et al., 1989; Dark et al., 1977; Futa and Furuyoshi, 1989; Mizuno and Muroi, 1979; Takei and Mizuno, 1978; Thomassen, 1949) Abnormal zonular attachment to the lens or ciliary body may provide a more convincing explanation for the development of lens subluxation or dislocation.
G. Anterior Chamber Angle
Narrow or closed angles occur in a large proportion of patients with XFS.(Kunishi et al., 1998; Layden and Shaffer, 1974; Wishart et al., 1985) Of 100 patients with XFS and glaucoma, only 21 of whom had been correctly diagnosed prior to referral, 23% had grade 2 or narrower angles.(Layden and Shaffer, 1974) Wishart et al(Wishart et al., 1985) found 32% of 76 patients with XFS (73 of whom had glaucoma) to have narrow angles. Eighteen percent were considered occludable and 14% had peripheral anterior synechiae.
Bartholomew(Bartholomew, 1980) found no significant difference in anterior chamber depth between normals and XFS patients. The decrease in anterior chamber depth between the supine and prone position is greater in eyes with XFS than in fellow eyes.(Lanzl et al., 2000) This decrease in depth and also in angle recess area has been documented with ultrasound biomicroscopy.(Esaki et al., 2001) Gharagozloo et al(Gharagozloo et al., 1992) found anterior chamber volume to be significantly smaller in both affected and unaffected eyes of patients with XFS compared to controls.
Increased trabecular pigmentation is prominent and is apparent in virtually all patients with clinically evident disease. It may be an early diagnostic finding preceding the appearance of XFM on the pupillary margin or anterior lens capsule.(Krause et al., 1973; Prince et al., 1987; Wishart et al., 1985) Unlike that in pigment dispersion syndrome, the distribution of the pigment tends to be uneven or splotchy and less well defined.
In virtually all studies of patients with clinically unilateral XFS, the trabecular pigment is almost always denser in the involved eye.(Kunishi et al., 1998; Ritch, 1994a) Eyes with exfoliative glaucoma tend to have greater pigmentation than both eyes with XFS but without glaucoma.(Puska, 1995; Rouhiainen and Teräsvirta, 1990) and eyes with POAG.(Futa et al., 1992; Konstas and Dutton, 1991) All 76 patients with XFS in the series of Wishart et al had increased trabecular pigmentation and 84% had more advanced glaucomatous damage on the side with greater pigmentation.(Wishart et al., 1985) No patient had less pigment in the eye with greater glaucomatous damage. There appears to be a highly significant correlation between elevated IOP and the degree of pigmentation of the meshwork.(Moreno-Montañés et al., 1990b) The extent of pigmentation, however, does not always correlate with IOP and the severity of glaucoma.(Konstas et al., 1993b; Layden and Shaffer, 1974)
Pigment is characteristically deposited on Schwalbe’s line and sometimes as a wavy line or lines anterior to Schwalbe’s line (Sampaolesi line)(Figure 14).(Amalric et al., 1960; Sampaolesi, 1959) This, too, is an early and consistent sign of XFS. In a study of the pigmentary signs in patients with XFS, the best predictive value for the diagnosis was found for the gonioscopic presence of Sampaolesi line.(Konstas, 1993)
Flecks of XFM may also be seen in the anterior chamber angle during gonioscopy, usually on the posterior trabecular meshwork. The reported occurrence of XFM in the angle has varied between 5.6% and 50%.(Joannides et al., 1961; Konstas and Dutton, 1991; Tarkkanen, 1962) Exfoliation material in the angle is not pathognomonic for raised IOP or exfoliative glaucoma since it may be found in normotensive patients with XFS. When seen it has no typical pattern of appearance, but is usually observed in the inferior angle(Prince and Ritch, 1986) sometimes mingled with pigment.
H. Vitreous and Retina
After cataract extraction, XFM may be found deposited upon the anterior vitreous face or on vitreous strands when the face is ruptured, on the posterior capsule, and on intraocular lenses, indicating that the presence of the lens is unnecessary for its continued formation. Two recent studies found a positive correlation between XFS and macular degeneration.(Kling and Colin, 2001; Kozobolis et al., 1999a) One reason might be that both disorders increase in incidence with age and altitude.(Kozobolis et al., 1999a) Another study found no correlation after correcting for age.(Allingham et al., 2001) One study has reported abnormalities of pattern electroretinographic findings and oscillatory potentials in eyes with XFS.(Spadea et al., 1997)
In clinically unilateral cases of XFS, ipsilateral pulsatile ocular blood flow(Sibour et al., 1997) and carotid blood flow(Scullica et al., 1993) have been reported to be reduced. Patients with exfoliative glaucoma had greater decreases in blood flow velocities determined by color Doppler imaging than those with XFS.(Yüksel et al., 2001) Blood flow of the lamina cribrosa and neural rim decreased with increasing glaucomatous damage.(Harju and Vesti, 2001) Another study found no differences between eyes with XFS, exfoliative glaucoma, and normal controls.(Mistlberger et al., 2000) In the Blue Mountains study, XFS was a risk factor for the development of disc hemorrhage.(Healey et al., 1998).
An association of XFS with retinal vein occlusion has been documented.(Meyer et al, 1984; Pohjanpelto, 1985; Saatci et al., 1999) Gillies and West(Gillies and West, 1977) reported 17 cases with central retinal vein occlusion in a retrospective series of 250 patients with XFS. Pohjanpelto(Pohjanpelto, 1985) documented retinal vein occlusion in five of 42 eyes with exfoliative glaucoma compared to two of 46 eyes with POAG. In another series, approximately 33% of all eyes enucleated for neovascular glaucoma caused by central retinal vein occlusion had coexistent XFS.(Karjalainen et al., 1987) Of 113 patients with XFS in one series, four had had a branch retinal vein occlusion.(Meyer et al, 1984) Conversely, in a retrospective review of charts of patients with branch or central retinal vein occlusion, XFS was found in 6.0% and 6.9% respectively.(Cursiefen et al., 1997)
I. Optic disc
In a prospective study of untreated ocular hypertension, the percent area of optic disc pallor was significantly greater in eyes with XFS than in eyes without despite a lack of differences in IOP or in the visual field.(Linnér et al., 1989) The disc area has been reported to be smaller in eyes with XFS, with or without glaucoma, than in controls.(Budde and Jonas, 1999; Jonas and Papastathopoulos, 1997; Tuulonen and Airaksinen, 1992) In one study, disc area, neural rim area, rim/disc ratio, cup area, and cup volume values analyzed with the Imagenet (Topcon) nerve head analyzer did not differ significantly between normotensive eyes with XFS and clinically uninvolved fellow eyes.(Puska and Raitta, 1992) In eyes with unilateral exfoliative glaucoma and no clinical evidence of XFS in the fellow eye, pairwise comparisons showed no difference in size of peripapillary crescents.(Puska and Raitta, 1993) The area of peripapillary atrophy correlated significantly with IOP and the extent of glaucomatous damage.(Puska and Raitta, 1993) Peripapillary chorioretinal atrophy areas in POAG and XFS patients were not significantly different from each other.(Tezel and Tezel, 1993) Cupping tends to be diffuse, compared to POAG, in which the most prominent neural rim defects occur at the inferotemporal and superotemporal sectors.(Tezel and Tezel, 1993)
J. Extraocular findings
Clinically, the conjunctiva is normal. However, fluorescein angiography of the conjunctiva reveals loss of the regular limbal vascular pattern and areas of neovascularization in advanced cases, as well as congestion of the anterior ciliary vessels.(Laatikainen, 1971) Lower scores in Schirmer testing and tear film break-up time have been found in eyes with XFS and it was suggested that these eyes may be more prone to developing xerophthalmia, especially if treated with beta-adrenergic blocking agents.(Kozobolis et al., 1999b)
K. Systemic associations
One of the most interesting differences between exfoliative glaucoma and POAG is the lack of change in IOP following topical steroid administration. Patients with XFS respond to topical steroid testing similarly to the normal population, whereas steroid-induced elevation of IOP occurs in the majority of patients with POAG.(Gillies, 1970; Pohjola and Horsmanheimo, 1971)
Psilas et al(Psilas et al., 1991) found a much lower prevalence of XFS in diabetics with retinopathy, particularly those with proliferative retinopathy. Konstas et al (Konstas et al., 1998) confirmed this finding by reporting also a lower prevalence of diabetes in patients with exfoliative glaucoma requiring surgery than in those with POAG.
A few reports have found a correlation between Alzheimer’s disease and XFS. Hagadus et al(Hagadus et al., 1989) found a greater proportion of patients with early Alzheimer’s disease to have XFS compared to age-matched controls. Linnér et al(Linnér et al., 2001) found 11/39 patients with dementia and cognitive impairment to have XFS. A relationship between Alzheimer’s disease and age-related macular degeneration has also been suggested. (Klaver et al., 1999)
An association of XFS with transient ischemic attacks has been reported.(Oruç et al., 2001; Repo et al., 1995; Repo et al., 1993) Patients with exfoliative glaucoma have been reported to have lower baseline fingertip cutaneous capillary perfusion than those with POAG or controls, longer time to maximal cold-induced flow reduction, and longer recovery time. (Holló et al., 1998) An association has been reported with abdominal aortic aneurysms. (Naumann et al., 1998; Schumacher et al., 2001) However, another study found the presence of XFS in patients operated for abdominal aortic aneurysms to be similar to that of the general population of the same age.(Hietanen et al, 2000) In the Blue Mountains Eye Study, XFS correlated positively with a history of hypertension, angina, myocardial infarction or stroke, suggestive of vascular effects of the disease.(Mitchell et al., 1997) However, Allingham et al,(Allingham et al., 2001) in 6 Icelandic families, found no correlation with cardiovascular or cerebrovascular disease, while two other reports found no increase in mortality rates in persons with XFS compared to those without.(Ringvold et al., 1997; Shrüm et al., 2000)
III. Pathogenesis of Glaucoma in Exfoliation Syndrome
A. Chronic Open-angle glaucoma
1. Natural history and prognosis
The prevalence of XFS in glaucoma cohorts is significantly higher than in age-matched nonglaucomatous populations. Elevated IOP with or without glaucomatous damage occurs in approximately 25% of persons with XFS, or about 6 to 10 times the rate in eyes without XFS.(Aasved, 1971c; Kozart and Yanoff, 1982; Kozobolis et al., 1997; Ringvold et al., 1991) Glaucoma in XFS has a more serious clinical course and worse prognosis than primary open-angle glaucoma (POAG). At the time of diagnosis, IOP is higher than in POAG and there is a higher frequency and severity of optic nerve damage, worse visual field damage, poorer response to medications, more rapid progression, more severe clinical course, and more frequent necessity for surgical intervention.(Aasved, 1971a; Aasved, 1971b; Futa et al., 1992; Konstas et al., 1993a; Konstas et al., 1997b; Konstas et al., 1998; Lindblom and Thorburn, 1982; Lindblom and Thorburn, 1984; Moreno-Montañés et al., 1990a; Pohjanpelto, 1986; Tarkkanen, 1965) In patients with clinically unilateral XFS and bilateral glaucoma, IOP is higher in the eye with XFS.(Aasved, 1971c) The diurnal fluctuation in IOP is greater in eyes with exfoliative glaucoma than in those with POAG. (Konstas et al., 1997a) Ocular hypertensives with XFS are more likely to develop glaucomatous damage than are those without XFS. (Henry et al., 1987; Pohjanpelto, 1986; Thorburn, 1988). The proportion of patients with XFS shows a steady increase when measured in cohorts with open-angle glaucoma without optic nerve damage, in those with damage, in those undergoing surgery, and in those with absolute glaucoma.(Aasved, 1971a; Konstas and Allan, 1989; Konstas et al., 1993b)
2. Asymmetry of Involvement
For unknown reasons, patients can present with either unilateral or bilateral involvement, which can be equal in appearance between the two eyes or markedly asymmetric. Binocular involvement is more common in European reports, with ratios as high as 3:1. (Hirvelä et al., 2000; Kozobolis et al., 1997; Madden and Crowley, 1982; Moreno Montañés et al., 1989; Ruprecht et al., 1985; Stefaniotou et al., 1990; Summanen and Tönjum, 1988). Other series, including most American ones, have reported unilateral involvement to predominate, again with ratios as high as 3:1. (Aasved, 1971d; Brooks and Gillies, 1988; Crittendon and Shields, 1988; Esmail, 1991; Futa et al., 1992; Henry et al., 1987; Klemetti, 1988; Layden and Shaffer, 1974; Shimizu et al., 1988). Patients with bilateral XFS tend to be slightly older than those with unilateral XFS, but the age difference is often small.(Aasved, 1971d; Gifford, 1957; Hiller et al., 1982; Kozart and Yanoff, 1982; Tarkkanen, 1962)
Histopathologically, both eyes are involved, XFM being almost invariably present in the conjunctiva of the clinically uninvolved fellow eye.(Prince et al., 1987; Speakman and Ghosh, 1976) Clinically unilateral involvement is often a precursor to bilateral involvement, but this may take years or not occur at all during the patient’s lifetime. Ultrastructural and immunohistochemical alterations typical of XFS were observed in anterior segment tissues, particularly the iris, of all apparently uninvolved fellow eyes.(Hammer et al., 2001; Kivelä et al., 1997) Early iris changes noted in fellow eyes may account for the clinical signs characteristic of early stages, such as pigment dispersion, peripupillary atrophy, trabecular pigmentation, and insufficient mydriasis.(Hammer et al., 2001; Prince et al., 1987)
Why some persons present with unilateral exfoliation and others with bilateral (i.e., asymmetric disease) remains to be explained. Bilateral involvement is not always preceded by unilateral involvement. It remains unknown as to whether the clinical involvement of one or two eyes early in the disease is influenced by infectious, genetic or immune factors or even by the existence of subtypes of the disease. The question also remains as to why only some eyes with XFS develop glaucoma. Possible causative factors may be simply the amount of XFM present, interindividual differences in managing the metabolic disturbance, and genetic factors.
3. Open-angle glaucoma in eyes with XFS
Exfoliative glaucoma is associated with an increase in aqueous outflow resistance and elevated IOP.(Gharagozloo et al., 1992; Johnson and Brubaker, 1982) The possible mechanisms responsible include blockage of the meshwork by XFM or by liberated iris pigment or both, trabecular cell dysfunction, and concomitant POAG.
Trabecular obstruction and localized damage, as stated earlier, is considered the most likely cause of elevated IOP. Correlations have been made between the presence and severity of glaucoma and the amount of both pigment and XFM in the trabecular meshwork. Increased trabecular pigmentation is a prominent sign of XFS and may be an early diagnostic finding preceding the appearance of XFM on the pupillary margin or anterior lens capsule.(Prince et al., 1987; Wishart et al., 1985) In patients with clinically unilateral involvement, trabecular pigment is almost always denser in the involved eye.(Kunishi et al., 1998; Ritch, 1994a) Elevated IOP has been correlated with the degree of trabecular pigmentation,(Moreno-Montañés et al., 1990b) and eyes with glaucoma tend to have greater pigmentation than eyes without glaucoma.(Puska, 1995; Rouhiainen and Teräsvirta, 1990) or eyes with POAG.(Futa et al., 1992; Konstas and Dutton, 1991) Glaucomatous damage is usually more advanced in the eye with greater trabecular pigmentation.(Wishart et al., 1985) Traumatic loss of iridolenticular contact may protect against the development of glaucoma.(Konstas and Diafas, 1999) The extent of pigmentation, however, does not always correlate with IOP and the severity of glaucoma.(Konstas et al., 1993b; Layden and Shaffer, 1974)
In one study, the presence of glaucoma correlated significantly with the amount of XFM in both the total filtration area and the juxtacanalicular tissue, and also with the average thickness of the juxtacanalicular tissue and the mean cross-sectional area of Schlemm’s canal.(Schlötzer-Schrehardt and Naumann, 1995) In another, the amount of XFM correlated with IOP and optic nerve damage.(Gottanka et al., 1997a) Disorganization of juxtacanalicular tissue and Schlemm’s canal was not observed in eyes with mild or moderate glaucoma and may be associated with advanced disease stages.(Gottanka et al., 1997a) The major pathology appears to involve accumulation of XFM in the juxtacanalicular tissue as well as degenerative changes of Schlemm’s canal and juxtacanalicular area.(Richardson and Epstein, 1981; Ringvold and Vegge, 1971; Schlötzer-Schrehardt and Naumann, 1995) In addition to mechanical obstruction of the meshwork by XFM of extratrabecular origin, production of XFM by trabecular cells may also cause trabecular dysfunction,(Schlötzer-Schrehardt and Naumann, 1995) although this has been disputed.(Gottanka et al., 1997a)
The XFM aggregates may serve as a nidus for nonspecific accumulation of serum proteins and further decrease outflow facility. Increased amounts of albumin have been detected immunohistochemically in the trabecular meshwork of XFS eyes.(Küchle et al., 1996; Schlötzer-Schrehardt et al., 1999)
Patients with normal-tension glaucoma may develop signs of XFS and subsequently develop elevated IOP. These patients must be considered at particular risk of more rapid progression of glaucomatous damage in such circumstances. Although exfoliative glaucoma is characteristically a high pressure disease, non-IOP-dependent risk factors may be present just as in patients with POAG.
There has been some suggestion that XFS itself predisposes to glaucomatous damage even in the absence of elevated IOP. At any specific IOP level, eyes with XFS are more likely to have glaucomatous damage than are eyes without XFS.(Davanger et al., 1991) Abnormalities of laminar elastic tissue cannot be ruled out. (Netland et al., 1995; Pena et al., 1998). In a prospective study, Puska et al(Puska et al., 1999) found that in patients with clinically unilateral involvement in whom IOP was unchanged throughout the follow-up period, disc changes took place only in the clinically involved eye. In normotensive eyes with no visual field loss, the greater the IOP of the involved eye compared to the fellow eye, the smaller were the rim-to-disc radius ratios in the inferotemporal quadrant.(Tomita et al., 1994)
Although 25% of patients with XFS have elevated IOP or glaucoma, 75% do not. Most patients with XFS never develop elevated IOP. Extensive deposits of XFM may be found in the meshwork in the presence of a normal IOP.(Benedikt and Roll, 1979) Whether additional predisposing factors exist for the development of glaucoma in eyes with XFS remains to be determined.
4. Angle-Closure Glaucoma in eyes with XFS
Until recently, the association between ACG and XFS was considered rare and usually thought to be coincidental, only sporadic cases having been
reported over the last half century,(Awan, 1984; Bartholomew, 1981; Franks et al., 1990; Gillies, 1978; Gillies and Brooks, 1988; Gnanadoss and Parasuraman, 1972; Gradle and Sugar, 1940; Gradle and Sugar, 1947; Herbst, 1976; Hørven, 1948; Iizuka et al., 1991; Layden and Shaffer, 1974; Lin et al., 1996; Lowe, 1964; Ross, 1949; Tarkkanen, 1962; von der Lippe et al., 1993) despite the fact that two series noted a high incidence of narrow or occludable angles in eyes with XFS.(Layden and Shaffer, 1974; Wishart et al., 1985) In one electron microscopic study of iridectomy specimens of eyes undergoing trabeculectomy, only one of 31 eyes with ACG had clinical and pathological evidence of XFS. (Konstas et al., 1993b) More recently, however, Ritch(Ritch, 1994a) found either clinically apparent XFS or XFM on conjunctival biopsy in 17 of 60 (28.3%) consecutive patients with uncomplicated primary ACG or occludable angles. Subsequent retrospective studies have found XFS associated with angle-closure or occludable angles.(Gross et al., 1994; Kasner et al., 1997)
Herbst(Herbst, 1976) first suggested a causal relationship between ACG and XFS in a myopic black patient with bilateral XFS and unilateral ACG, which responded to medical treatment, including pilocarpine, consistent with pupillary block. Franks et al(Franks et al., 1990) reported two cases of acute ACG, one precipitated by pilocarpine and the other developing after central retinal vein occlusion, and suggested zonular weakening causing forward lens movement. Von der Lippe et al(von der Lippe et al., 1993) described 2 patients with unilateral ciliary block (malignant glaucoma) and bilateral XFS.
Several characteristics of eyes with XFS predispose to the development of ACG. Pupillary block may be caused by a combination of posterior synechiae, increased iris thickness or rigidity, or anterior lens movement secondary to zonular weakness.
The iris pigment epithelium and the lens surface, both coated with XFM, tend to form posterior synechiae, particularly when pupillary movement is
inhibited by miotic therapy. Bartholomew(Bartholomew, 1981) coined the term “iridocapsular block” for this phenomenon. Posterior synechiae predispose to miotic-induced ACG, the development of which can be further stimulated by zonular weakness. Because the iris is more rigid than normal, aqueous pressure in the posterior chamber causes it to bulge at the iris root, the weakest point, leading to a pseudoplateau configuration on gonioscopy and, if untreated, chronic ACG. After iridotomy, the angle opens widely, as opposed to true plateau iris, in which the ciliary processes maintain the plateau configuration.(Pavlin et al., 1992; Ritch, 1992)
Weakening of zonular support and subsequent laxity of the lens allow it to move anteriorly, predisposing to pupillary block, particularly in the prone position. In extreme cases, the lens may come sufficiently forward to induce ciliary block.(von der Lippe et al., 1993) Miotics may exacerbate both pupillary block and forward movement of the lens-iris diaphragm. Pilocarpine decreases anterior chamber depth and increases lens axial length, even in elderly patients.(Abramson et al., 1974; Abramson et al., 1976; Abramson et al., 1972; Abramson et al., 1973; Mapstone, 1981a; Poinoosawmy et al., 1976; Wilkie et al., 1969) After pilocarpine administration, the decrease in anterior chamber depth is greater in eyes with XFS than with uninvolved fellow eyes.(Ritch, 1994a) Patients with ACG or occludable angles and XFS tend to be more myopic than those without XFS, men more so than women.(Ritch, 1994a) Eyes with acute ACG are often more myopic than their fellow eyes, reflecting cataract progression and/or a slight forward shift in lens position.(Lowe and Ritch, 1989)
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