Overview of Pseudoexfoliation (pxf) Syndrome Features

Pseudoexfoliation (PXF) syndrome is a pathologic and age related accumulation of abnormal fibrillar deposits also on various ocular structures with extraocular tissues. With increasing age the extracellular matrix that may affect up to 20% of elderly population. Although the specific synthesis and pathophysiology of PXF syndrome are still unknown the concept of an elastotic process has recently been established by the discovery of the lysyl oxidase-like 1 (LOXL 1) gene is a major risk factor in people for PXF syndrome and PXF glaucoma (Thorleifsson et al., 2007). Finnish ophthalmologist named John Lindberg, in 1917 first described PXF in his doctoral thesis. With the aim of a newly developed slit-lamp, he defined as grayish flecks and the changes on the lens and over the pupillary margin of the iris in 50% of patients with chronic glaucoma. The prevalence rates vary in different populations like: general population, patients with cataract, patients with severe glaucoma, persons over a certain age. The prevalence also depends upon the examiner and the method (mydriasis or not, early stages or not). Its prevalence considerably determined between countries and even within regions or between ethnic groups within many countries. Low rates of PXF have been found in Greenland Eskimos (0%), in India (4.2% in patients older than 70 years), in the eastern part of the United States (5% in patients between 75 and 85 years old), in Germany (1.5% in patients 70-79 years of age and 6.3% in those between 80 and 89) and in Britain (2% in 70-79 and 5.4% in 80-89) (Vesti & Kivela, 2000). On the other hand, high frequencies have been reported in Iceland (31.5%), Finland (>20%),

In southwestern Greece in a cross-sectional study of admitted patients at the hospital for cataract surgery we found the prevalence of PXF syndrome to be 27.9% (Andrikopoulos et al., 2009). Pseudoexfoliation syndrome has been associated with progression of cataract, raised intraocular pressure and intraoperative difficulties like zonular or posterior capsule rupture, poorly dilating pupils, vitreous loss and postoperative fibrinoid reaction or luxation of intraocular lens implants. It is the most common identifiable cause of open-angle glaucoma, the pseudoexfoliation glaucoma. The later it is characterized by bad prognosis than primary open angle glaucoma, fast progression and higher resistance to medical therapy for glaucoma. The definite clinical diagnosis of PXF can be confirmed only in the last stages of classic PXF (fibers in the two zones) and in the stage of mini-PXF (focal defects in the precapsular layer nasal superiorly). Next to the lens PXF material deposits are most notable to the pupillary border. Other clinical signs at the slit-lamp examination are loss of melanin from the peripupillary pigment epithelium of the iris, transillumination defects in the sphincter area of iris, poor mydriasis, posterior synechiae, zonular weakness, melanin deposition and melanin dispersion (on the structures of anterior segment) after dilatation of pupil. It appears that a various kind of of epithelial and mesenchymal cells may be combined with disordered synthesis of the extracellular fibrillar substance in different sites.

The intraocular matter seems to be produced mainly in the pre-equatorial epithelium of lens, the nonpigmented ciliary epithelium and the pigment epithelium of iris and secondarily in the corneal endothelium, the trabecular endothelium and by almost all types of the iris stromacells (Ritch & Schlötzer-Schrehardt, 2001). Secondary dispersion by the aqueous humor is responsible for its passive deposition on the various structures of the anterior segment. The extraocular PXF substance has been demonstrated electron microscopically in close proximity to fibroblasts, striated and smooth muscle cells, and heart muscle cells (Schlötzer-Schrehardt et al., 1992a; Streeten et al., 1992). These kind of cells are probably involved in its synthesis in various visceral organs. There are two main theories on the pathogenesis of PXF syndrome. The first denotes the exfoliation fibers to the elastic microfibrils of the elastic system. It definees PXF syndrome as a kind of elastosis, an elastic microfibrillar dehiscence with excessive formation of elastic fiber components (Garner & Alexander, 1984; Streeten et al., 1986). The second theory explains PXF syndrome to be a generalized disorder of the basement membranes (Dickson & Ramsay, 1975), with a various basement membrane components to have been recognized with PXF material (Eagle et al., 1979; Harnisch et al., 1981; Konstas et al., 1990; Kubota et al., 1998; Schlötzer-Schrehardt et al., 1992b; Tawara et al., 1996). Growth factors (GFs) and specifically Transforming Growth Factor-β1 (TGF-β1), vicious cellular protection system with increased cellular and oxidative stress, disequilibrium between Matrix Metalloproteinases (MMPs) and Tissue Inhibitor of Metalloproteinases (TIMPs), ischemia/hypoxia, cross-linking process and collection of misfolded stressed protein particles appear to be involved in the pathogenetic concept of this fibrotic disorder with accumulation of extracellular substance (Gartaganis et al., 2001, 2002, 2005, 2007; Schlötzer- Schrehardt & Naumann, 2006; Schlötzer-Schrehardt, 2009).

The precise chemical composition of PXF material remains unknown. It seems to consist a complex of glycoprotein/proteoglycan with epitopes of the the elastic fiber system and basement membrane. The protein part of PXF material include non-collagenous basement membrane components (such as laminin, nidogen, and fibronectin), epitopes of elastic fibers (such as elastin, tropoelastin, amyloid P, vitronectin) and elements of elastic microfibrils like as fibrillin-1, emilin, , latent TGF- β binding proteins 1-2) and microfibril-associated glycoprotein-1 (Ritch & Schlötzer-Schrehardt, 2001). Other proteins are cross-linking enzymes, chaperones, glycosaminoglycans, apolipoproteins, proteolytic enzymes and their inhibitors, complement proteins, and cytokines like TGF-β1. Τhe glycosaminoglycans and proteoglycans include heparan sulfate proteoglycan, dermatan sulfate proteoglycan, chondroitin sulfate proteoglycan, keratan sulfate proteoglycan, and hyaluronan (Fitzsimmons et al., 1997; Harnisch et al., 1981; Schlötzer-Schrehardt et al., 1992b; Tawara et al., 1996). The microfibrillar susbdivisions seem to form a core surrounded by an amorphous matrix, which is advocated to represent glycosaminoglycans on the surface of the exfoliation fibrils.