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(Prince and Ritch, 1986; Prince et al., 1987). Transmission electron microscopy of conjunctival biopsy specimens from such patients, who had previously been diagnosed to have POAG, revealed XFM in 8/23 suspect eyes. These pig- ment-related signs also correlated with the presence of XFM in eyelid skin (Schlo¨tzer-Schrehardt et al., 1993).

The zonules are often frayed and broken (Fig 4). Phacodonesis is common, and spontaneous lens subluxation can occur. Complications of cataract surgery are more common. Zonular fragility, poor pupillary dilation, and posterior synechiae increase the risk of lens dislocation, zonular dialysis, and vitreous loss.

Ocular and systemic associations

Ocular associations

Cataract and XFS are etiologically associated. Aqeous humor ascorbic acid concentrations are reduced in XFS (Koliakos et al., 2002), and malondialdehyde concentrations are much higher (Yilmaz et al., 2005), suggesting a faulty antioxidant defense system. Increased 8-iso-Prostaglandin F2a suggests a role for free radical-induced oxidative damage (Koliakos et al., 2003).

Ocular ischemia is the rule and iris abnormalities can be detected both on angiography

Fig. 4. Fragmented zonules in XFS. (See Color Plate 15.4 in color plate section.)

(Laatikainen, 1971) and histopathologically (Hammer et al., 2001), not only in affected eyes, but in unaffected fellow eyes of patients with clinically unilateral involvement. Vessel lumens are often narrowed and may become obliterated, with marked alteration of the iris vasculature in advanced cases. Vessel dropout with collateral formation and iris hypoperfusion lead to anterior chamber hypoxia and patchy iris microneovascularization (Ritch and Schlo¨tzer-Schrehardt, 2001; Schlo¨tzer-Schrehardt and Naumann, 2006). There is chronic breakdown of the blood–aqueous barrier and increased protein in the anterior chamber.

Retinal vein occlusion has been associated with XFS at variable frequencies and based upon retrospective studies, which employed either slitlamp examination or histopathology (Saatci et al., 1999; Cursiefen et al., 2001). Elevated IOP and glaucoma have been suggested as a cause for the association of XFS with CRVO.

Systemic associations

An emerging clinical spectrum of associations with cardiovascular and cerebrovascular diseases elevates XFS to a condition of general medical importance. Deposits of XFM have been identified in the walls of posterior ciliary arteries, vortex veins, and central retinal vessels as they exit the optic nerve. Ocular, retrobulbar, and cerebral blood flow are reduced in patients with XFS both with and without glaucoma (Yu¨ksel et al., 2001; Yu¨ksel et al., 2006). Blood flow of the lamina cribrosa and neural rim decreases with increasing glaucomatous damage (Harju and Vesti, 2001). In clinically unilateral cases, ipsilateral pulsatile ocular blood flow and carotid blood flow are reduced (Scullica et al., 1993; Sibour et al., 1997). Recently, pathological carotid artery function as well as altered parasympathetic vascular control increasing with both age and higher homocysteine levels was reported (Visontai et al., 2006). In a large study, XFS was reported to be an important risk factor for coronary artery disease (Andrikopoulos et al., 2007). Patients with exfoliative glaucoma had lower baseline fingertip cutaneous capillary perfusion than those with POAG or