The management of exfoliative glaucoma

Introduction

Exfoliation syndrome (XFS) is an age-related, generalized disorder of the extracellular matrix characterized by the production and progressive

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accumulation of a fibrillar extracellular material in many ocular tissues (Ritch and Schlo¨tzerSchrehardt, 2001). It is the most common identifiable cause of open-angle glaucoma worldwide, accounting for the majority of cases of this disease in some countries (Ritch, 1994). It has been estimated that between 60 and 70 million people are affected throughout the world, making it a leading cause of blindness and a disease of global importance (Ritch et al., 2003).

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XFS leads not only to severe, chronic openangle glaucoma, but also to lens subluxation, angle-closure, blood–aqueous barrier impairment, and serious complications at the time of cataract extraction, such as zonular dialysis, capsular rupture, and vitreous loss. There is increasing evidence for an etiological association of XFS with cataract formation and with retinal vein occlusion. Systemic associations, primarily ischemic vascular disease, are being increasingly reported. Plasma, aqueous humor, and tear fluid homocysteine levels are elevated in XFS with and without glaucoma (Leibovitch et al., 2003; Vessani et al., 2003; Bleich et al., 2004; Puustja¨rvi et al., 2004; Altintas et al., 2005; Roedl et al., 2007a, b). The recent discovery of two polymorphisms in the lysyl oxidase-like 1 (LOXL1) gene that confer susceptibility to exfoliative glaucoma, primarily through XFS (Thorliefsson et al., 2007) will hopefully open the door for much more research on this understudied disease and lead to new approaches to treatment.

Epidemiology

The reported prevalence of XFS both with and without glaucoma has varied widely. This reflects true differences due to racial, ethnic, or other as- yet-unknown factors; the age and sex distribution of the patient cohort or population group examined; the clinical criteria used to diagnose XFS; the ability of the examiner to detect early stages and/or more subtle signs; the method and thoroughness of the examination; and the awareness of the observer (Aasved, 1969). Although long and erroneously thought peculiar to Scandinavia, XFS comprises over half the open-angle glaucoma in such diverse countries as Norway, Ireland, Greece, Saudi Arabia, and India. Previously thought rare in Africa, recent reports suggest that it is common in Ethiopia, where 25% of open-angle glaucoma patients had XFS (Bedri and Alemu, 1999). It is also found in Navajo Indians and in Australian Aborigines and in South African Zulus. In the United States, it is much more common in Caucasians than in persons of African ancestry, comprising about 12% of glaucoma populations (Gradle and Sugar, 1947; Roth and Epstein, 1980;

Horns et al., 1983). There are geographic and ethnic variations, being less in the southern United States and in African-Americans. Although common in Japan and Mongolia, it is rare in southern China.

The prevalence of XFS increases steadily with age in all populations. About two-thirds of patients have clinically unilateral involvement, but XFS can be diagnosed prior to the clinically visible appearance of classic exfoliation material (XFM) on the lens surface by conjunctival biopsy, showing that the disease is present microscopically before it is detected clinically in the fellow eye (Prince et al., 1987). The reasons for this presentation remain unknown, but it may be analogous to that of uveitis, which is also often clinically unilateral or markedly asymmetric.

Ethnic and local variations also exist. In New Mexico, Spanish-American men develop XFS six times as often as Anglo-Americans (Jones et al., 1992). In France, XFS is much more common in Brittany, the population of which has Celtic origins, than in southeastern France (Colin et al., 1988). It accounts for about 60% of the openangle glaucoma in Ireland and in the Isle of Man, but only 10% in neighboring England. In central Norway, the prevalence in two adjacent towns (20%) was twice that in a third, adjacent town. Interestingly, the prevalence of XFS in both members of 343 married couples (3.2%) was significantly higher (P ¼ 0.022) than would be expected, suggesting the possibility of an infectious origin (Ringvold et al., 1988). In Nepal, XFS was found in 12% of members of one ethnic group, the Gurung, and only 0.24% of non-Gurung of similar ages (Shakya et al., 2004). Other examples exist and why this is so has yet to be explained.

The prevalence of XFS in glaucoma cohorts is significantly higher than in age-matched nonglaucomatous populations. In 100 consecutive patients with XFS, Kozart and Yanoff (1982) found glaucomatous optic nerve or visual field damage in 7% and ocular hypertension in 15%. This is approximately six times the chance of finding elevated IOP in eyes without XFS. Similar figures for elevated IOP with or without glaucomatous damage have been reported in XFS patients in Europe (Moreno Montan˜e´s et al., 1989; Kozobolis

et al., 1997), Australia (Mitchell et al., 1999), and Japan (Shimizu et al., 1988).

The prognosis of exfoliative glaucoma (XFG) is more severe than that of primary open-angle glaucoma (POAG). Patients with XFS are twice as likely to convert from ocular hypertension to glaucoma and when glaucoma is present, to progress (Leske et al., 2003; Bengtsson and Heijl, 2005). The mean IOP is greater in normotensive patients with XFS than in the general population and greater in XFG patients at presentation than in POAG patients. At any specific IOP level, eyes with XFS are more likely to have glaucomatous damage than are eyes without XFS. There is greater 24-h IOP fluctuation, greater visual field loss, and optic disc damage at the time of detection, poorer response to medications, more rapid progression, greater need for surgical intervention, and greater proportion of blindness.

Clinical findings

XFS is diagnosed by the presence of typical XFM on the anterior lens surface or pupillary border (Fig. 1). All anterior segment structures are involved. The classic pattern of deposition on the lens consists of three distinct zones that become visible when the pupil is fully dilated, a central disc, intermediate clear zone created by the iris rubbing XFM from the lens surface during its

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physiologic excursions, and a granular peripheral zone. XFM is often found at the pupillary border.

Just as the iris scrapes XFM from the lens surface, the material on the lens causes rupture of iris pigment epithelial cells with concomitant pigment dispersion into the anterior chamber, leading to iris transillumination defects, loss of the ruff, and trabecular hyperpigmentation (Figs. 2 and 3). Pigment dispersion after pupillary dilation may be profuse. Marked intraocular (IOP) rises can occur and IOP should be measured routinely in all patients after dilation.

The diagnosis should be suspected in the absence of XFM in the presence of these signs, which define patients as ‘‘exfoliation suspects’’

Fig. 2. Loss of iris pigment ruff in XFS. Exfoliation material is present on the pupillary border. (See Color Plate 15.2 in color plate section.)

Fig. 1. Classic appearance of XFM on the anterior lens surface consists of a central disc, intermediate clear zone, and granular peripheral zone. (See Color Plate 15.1 in color plate section.)

Fig. 3. Hyperpigmentation of the trabecular meshwork. Pigment is also found on Schwalbe’s line and on the peripheral corneal shelf (Sampaolesi line). (See Color Plate 15.3 in color plate section.)