Robert Ritch, M.D.

Exfoliation syndrome (XFS) is characterized by the production and progressive accumulation of a fibrillar extracellular material in many ocular tissues. When averaged across the globe, it is the most common identifiable cause of glaucoma worldwide, and in some countries accounts for the majority of glaucoma. It leads to both open angle glaucoma and angle-closure glaucoma, and has been causatively associated with cataract, lens dislocation, and central retinal vein occlusion. Eyes with XFS have a greater frequency of complications at the time of cataract extraction, such as zonular dialysis, capsular rupture, and vitreous loss. Based on the identification of accumulations in orbital tissues, skin specimens, and visceral organs, XFS appears to be a generalized disorder of the extracellular matrix. The potential ramifications of this disorder appear to be far more important than ever before realized. Two reviews of XFS have appeared in the past year. ^{47, 62}

Epidemiology

XFS occurs worldwide, although reported prevalence rates vary extensively. This reflects a combination of true differences due to racial, ethnic, or other as-yet-unknown reasons; the age and sex distribution of the patients or population group examined; the clinical criteria used to diagnose XFS; the ability of the examiner to detect early stages; the thoroughness of the examination; and the awareness of the observer. ¹ Recent studies in some countries, such as Spain and Hungary, suggest literally an order of magnitude higher prevalence of XFS in the population and in glaucoma patients than reported 30-40 years ago. This obviously represents improvement in the ability to look for and identify the material clinically.

In Scandinavia, where XFS was first described, the highest rates in studies of persons over age 60 have been reported from Iceland (about 25%), ^{8, 59} and Finland (over 20%) ^{8, 25, 26} Rates in Norway and Sweden average about half these, while those in Denmark have been reported to be much less. Russian Jewish immigrants to the United States also have a very high prevalence of XFS. ³⁰ XFS is also very common in Ireland, the Middle East, India, and Japan.

The prevalence of XFS may also vary within countries in similar environments and over short distances. Differences among ethnically homogeneous persons or between ethnic groups living in close proximity might lead to useful investigations. In four prefectures in Crete, Kozobolis et al 24 found XFS in persons over age 40 to range from 11.5% to 27%. In France, the overall prevalence over age 70 (in a report by several observers) is about 5.5%, ranging from 20.6% in Brest, to 3.6% in Toulon. ^{4, 5} Ringvold et al ⁴⁴ found rates of 10.2%, 19.6%, and 21.0% in three closely situated municipalities in central Norway. In New Mexico, Spanish-American men are nearly six times as likely to develop XFS than are non-Spanish-Americans. ¹⁷

XFS increases in prevalence with age. Men and women are probably equally affects. In the United States, whites are affected much more often than African-Americans. Genetic factors predisposing to susceptibility have barely begun to be explored, and no clear hereditary pattern has been identified. One study found a ninefold increase in prevalence in first degree relatives over age 40 compared to the general population, ² suggesting autosomal dominant inheritance. A preponderance of maternal transmission of XFS in families reported has raised the possibility of mitochondrial inheritance. ⁶

Glaucoma occurs more commonly in eyes with XFS than in those without it. 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. Exfoliative glaucoma has a more serious clinical course and worse prognosis than primary open-angle glaucoma. There is a significantly higher frequency and severity of optic nerve damage at the time of diagnosis, worse visual field damage, poorer response to medications, more severe clinical course, and more frequent necessity for surgical intervention. Persons with elevated IOP and XFS are much more likely to develop glaucomatous damage on long-term follow-up than are those without XFS.

XFS is the only common glaucoma which usually affects only one eye or affects one eye long in advance of the other. As a rule of thumb, anyone over age 50 with unilateral glaucoma should be suspected of having XFS. The terms "unilateral" and "monocular" are misleading. When only one eye is clinically involved, the fellow eye often has abnormal aqueous humor dynamics or glaucomatous damage. Since early pigment-related signs of XFS are found in the majority of unaffected fellow eyes, and since exfoliation fibers may be detected on conjunctival biopsy in virtually all unaffected fellow eyes, these cases are actually asymmetric. ^{12, 41}

Clinical Findings

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 central disc corresponding roughly to the diameter of the pupil; a granular, often layered, peripheral zone, and a clear area separating the two (Figure 1). The central zone is a homogeneous, white sheet and is often absent, while the peripheral zone is always present (Figure 2). The clear zone is created by rubbing of the iris over the surface of the lens during pupillary movement. Phacodonesis, or looseness of the lens because of damage to the zonules which hold the lens in place, is common and is one of the leading factors predisposing to an increase in complications at the time of cataract surgery. Spontaneous partial or complete dislocation of the lens can occur (Figure 3).

Iris: Iris changes are an early and well recognized clinical feature in XFS. Next to the lens, exfoliation material is most prominent at the pupillary border (Figure 4). Pigment loss from the iris sphincter region and its deposition on anterior chamber structures is a hallmark of XFS. Loss of iris pigment and its deposition throughout the anterior segment are reflected in iris sphincter region transillumination defects (Figure 5), loss of the pupillary ruff (Figure 6), pigment dispersion in the anterior chamber after pupillary dilation (Figure 7), pigment deposition on the iris surface, increased trabecular meshwork pigmentation (Figure 8), and pigment deposition on the iris surface. ⁴⁰

The blood vessels of the iris are often narrowed and may become obliterated. In advanced stages, the cells of the vessel wall degenerate completely. Fluorescein angiographic studies have shown partial occlusion of radial iris capillaries associated with hypoperfusion, a reduced number of vessels, formation of tiny new blood vessels, and diffuse, patchy fluorescein dye leakage.

Cornea: Flakes of exfoliation material may be present on the endothelium. There may be a diffuse, nonspecific pigmentation of the central endothelium, occasionally having the pattern of a Krukenberg spindle. Pigment is characteristically deposited on Schwalbe's line and sometimes as a wavy line or lines anterior to Schwalbe's line (Sampaolesi line, Figure 8). The number of corneal endothelial cells is reduced and central corneal thickness is also greater in eyes with XFS, perhaps reflecting early corneal dysfunction. ⁴³ These changes predispose to early corneal decompensation at only moderate rises of IOP or after cataract surgery. ³⁵

Other findings: Eyes with XFS often dilate poorly. Exfoliation material may be detected earliest on the ciliary processes and zonules, which are often frayed and broken. Abnormal zonular attachment to the lens or ciliary body may account for the development of lens subluxation or dislocation. Deposits of exfoliation material cover the crests of the ciliary processes in the pars plicata.

Increased trabecular pigmentation is a prominent sign of XFS and is apparent in virtually all patients with clinically evident disease. The distribution of the pigment tends to be uneven or splotchy and, in clinically unilateral cases, is almost always denser in the involved eye. There appears to be a highly significant correlation between elevated IOP and the degree of pigmentation of the meshwork. ³³ In virtually all studies of patients with unilateral involvement, the trabecular pigment is almost always denser in the involved eye. ^{27, 46} Eyes with exfoliative glaucoma tend to have greater pigmentation than eyes with XFS but without glaucoma. ^{42, 50} and eyes with exfoliative glaucoma have greater pigmentation than eyes with COAG. ^{9, 19} Marked IOP rises can occur in eyes with XFS after dilation for retinal examination. Post-dilation IOPs should be checked routinely and the anterior chamber examined for pigment liberation in all patients receiving dilating drops.

Ocular Associations: Increasing evidence suggests an causal association between XFS and cataract formation. The iris pigment epithelium and the lens surface, both coated with exfoliation material, tend to adhere (posterior synechiae), particularly when pupillary movement is inhibited by miotic therapy (Figure 9). Vigorous dilation can result in adhesion of the entire iris pigment epithelium onto the lens surface.

Patients with XFS are much more prone to have complications at the time of cataract extraction. Eyes with XFS dilate less well and have greater incidences of capsular rupture, zonular dehiscence, and vitreous loss. Pupillary diameter and zonular fragility have been suggested as the most important risk factors for capsular rupture and vitreous loss. Zonular fragility increases the risk of lens dislocation, zonular dialysis, or vitreous loss up to ten times. ^{11, 34, 36, 57} Postoperative complications of posterior capsular opacification, capsule contraction syndrome, intraocular lens decentration, and inflammation are also greater in eyes with XFS.

A possible association of XFS with retinal vein occlusion has also been suggested. ^{18, 31, 38} In clinically unilateral cases of XFS, ipsilateral pulsatile ocular blood flow 56 and carotid blood flow ⁵³ have been reported to be reduced. Eyes may be more prone to developing dry eye syndrome, especially if treated with beta-adrenergic blocking agents. ²³

Extraocular findings: Aggregates of exfoliation fibers have been identified in skin and in autopsy specimens of heart, lung, liver, kidney, gall bladder, and cerebral meninges in two patients with ocular XFS. ^{51, 58} The deposits were focally present in the interstitial fibrovascular connective tissue septa of these organs, frequently adjacent to elastic fibers, elastic microfibrils, collagen fibers, fibroblasts, and to the walls of small blood vessels.

In the Blue Mountains Eye Study (Australia), XFS correlated positively with a history of hypertension, angina, myocardial infarction or stroke, suggestive of vascular effects of the disease. ³² In another study, 50% of persons with XFS had cardiovascular disease, three times the rate of the unaffected subjects. ⁷ In another study, XFS was significantly associated with aneurysms of the abdominal aorta, but not with carotid artery occlusion. ⁵² Nevertheless, no increase in mortality in patients with XFS has been reported. ^{45, 55}

Mechanisms of Glaucoma

Open-angle glaucoma: Potential causes of elevated IOP in eyes with XFS include trabecular cell dysfunction, blockage of the meshwork by exogenous and endogenous exfoliation material, blockage of the meshwork by liberated iris pigment, trabecular cell dysfunction, and coexisting primary open-angle glaucoma. Obstruction of the trabecular meshwork either by pigment or exfoliation material or both is generally considered the most likely cause. Exfoliation syndrome can develop later in life in patients who have had bilateral pigment dispersion syndrome, and the presentation of an older patient with signs of bilateral pigment dispersion and unilateral glaucoma warrants a careful examination for the development of XFS. ^{28, 48, 61}

Angle-closure glaucoma: Although two important series noted a high incidence of narrow or occludable angles in eyes with XFS, ^{29, 63} angle-closure glaucoma was until recently considered rare in patients with XFS and was usually thought to be coincidental. Ritch ⁴⁶ found either clinically apparent XFS or exfoliation material on conjunctival biopsy in 17 of 60 (28.3%) consecutive patients with uncomplicated primary ACG or occludable angles. In another study, 5 of 18 affected patients had occludable angles. ⁷ Characteristics of eyes with XFS which predispose to angle-closure glaucoma include the predisposition to posterior synechia formation, zonular weakness and associated forward lens movement, iris stiffness and rigidity, and a smaller pupil. Patients with ACG or occludable angles and XFS tend to be more myopic and to have deeper anterior chambers than those without XFS.

Management

Glaucoma associated with XFS tends to respond less well to medical therapy than does POAG. Apraclonidine is additive to timolol in eyes with XFS and elevated IOP. ²² Dorzolamide is almost as effective as timolol and also is additive with it. ^{13, 21} Cholinergic agents are effective and probably have a greater additive effect with beta-blockers in XFS than in POAG. Not only do miotics lower IOP, but should enable the meshwork to clear more rapidly by increasing aqueous outflow and should slow the progression of the disease by limiting pupillary movement. Becker ³ has presented suggestive evidence that treatment with aqueous suppressants leads to worsening of trabecular function.

Argon laser trabeculoplasty (ALT) is particularly effective, at least early on, in eyes with XFS. The baseline IOP is usually higher than in eyes with POAG undergoing ALT and the initial drop in IOP is greater. Approximately 20% of patients develop sudden, late rises of IOP within the first two years after treatment. ^{37, 49} Continued pigment liberation may overwhelm the restored functional capacity of the trabecular meshwork, and maintenance miotic therapy to minimize papillary movement after ALT might counteract this. The increased effectiveness may be related to the increased trabecular meshwork pigmentation found in XFS. Long-term success drops to approximately 35-55% at 3-6 years.

The results of trabeculectomy are comparable to those in POAG, but complications are more frequent. IOP after trabeculectomy has been reported to be lower in eyes with exfoliative glaucoma than in eyes with POAG. ^{20, 39, 54} Trabeculotomy has been reported to have success rates of 79% at 3 years and 64% at 5 years, with medication. ⁶⁰ Jacobi and Krieglstein ¹⁴ have presented a procedure termed trabecular aspiration, designed to improve outflow facility. Trabecular aspiration combined with phacoemulsification was significantly more effective than cataract surgery alone in reducing postoperative IOP and the necessity for antiglaucoma medication. ^{10, 15} However, it is less effective than phacoemulsification combined with trabeculectomy. ¹⁶

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