Elsevier

Survey of Ophthalmology

Volume 45, Issue 4, January–February 2001, Pages 265-315
Survey of Ophthalmology

Major review
Exfoliation Syndrome

https://doi.org/10.1016/S0039-6257(00)00196-XGet rights and content

Abstract

Exfoliation syndrome (XFS) is an age-related disease in which abnormal fibrillar extracellular material is produced and accumulates in many ocular tissues. Its ocular manifestations involve all of the structures of the anterior segment, as well as conjunctiva and orbital structures. Glaucoma occurs more commonly in eyes with XFS than in those without it; in fact, XFS has recently been recognized as the most common identifiable cause of glaucoma. Patients with XFS are also predisposed to develop angle-closure glaucoma, and glaucoma in XFS has a more serious clinical course and worse prognosis than primary open-angle glaucoma.

There is increasing evidence for an etiological association of XFS with cataract formation, and possibly with retinal vein occlusion. XFS is now suspected to be a systemic disorder and has been associated preliminarily with transient ischemic attacks, stroke, systemic hypertension, and myocardial infarction. Further ramifications await discovery.

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 distinct zones that become visible when the pupil is fully dilated. Whereas the classic picture of manifest XFS has been often described, the early stages of beginning exfoliation have not been well defined. Next to the lens, exfoliation material is most prominent at the pupillary border. Pigment loss from the iris sphincter region and its deposition on anterior chamber structures is a hallmark of XFS.

Despite extensive research, the exact chemical composition of exfoliation material (XFM) remains unknown. An overproduction and abnormal metabolism of glycosaminoglycans have been suggested as one of the key changes in XFS. The protein components of XFM include both noncollagenous basement membrane components and epitopes of the elastic fiber system such as fibrillium. Regardless of etiology, typical exfoliation fibers have been demonstrated electron microscopically in close association with the pre-equatorial lens epithelium, the nonpigmented ciliary epithelium, the iris pigment epithelium, the corneal endothelium, the trabecular endothelium, and with almost all cell types of the iris stroma, such as fibrocytes, melanocytes, vascular endothelial cells, pericytes, and smooth muscle cells.

The presence of XFS should alert the physician to the increased risks of intraocular surgery, most commonly zonular dehiscence, capsular rupture, and vitreous loss during cataract extraction. Heightened awareness of this condition and its associated clinical signs are important in the detection and management of glaucoma, and preoperative determination of those patients at increased risk for surgical complications.

Section snippets

Historical Aspects and Terminology

Exfoliation syndrome was first described in 1917 by Lindberg,332, 333 who, with the aid of the newly developed slit-lamp, noted the presence of bluish-gray flecks at the pupillary margin of the iris in 50% of his patients with chronic glaucoma. Vogt621, 622 thought that it originated from the lens capsule and called it senile exfoliation of the lens capsule and, having established its frequent association with open-angle glaucoma, capsular glaucoma. Others thought that it was just deposited on

Epidemiology

The reported prevalence of XFS both with and without glaucoma has varied widely. This reflects a combination of 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.8 Many cases go undetected

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 distinct zones that become visible when the pupil is fully dilated: a relatively homogeneous central disk corresponding roughly to the diameter of the pupil; a granular, often layered, peripheral zone, and a clear area separating the two (Fig. 1). Individual variations of this classical clinical picture may result from differing

Cataract

Although the nature of the relationship is still not well characterized or understood, increasing evidence has been presented in recent years for an association between XFS and cataract formation.55, 112, 215, 222, 236, 304, 309, 323, 342, 347, 361, 369, 371, 404, 428, 487, 571, 582, 588, 629, 633 Nuclear cataract is often more frequently found in eyes with XFS than in eyes without it.215, 523, 582 A higher rate of subcapsular cataract has also been reported.428 There is a higher prevalence of

Systemic Associations

No clear-cut association of XFS with a systemic disease has yet been shown. The response of patients with XFS but without glaucoma to topical steroid testing is similar to that of the normal population.177, 417, 583 However, in one study, two out of 15 patients with bilateral, nonglaucomatous XFS responded with a pressure rise of 6 mm Hg or more, and three out of 18 patients showed the same response when 0.1% betamethasone drops were administered four times a day for 6 weeks.583 In another

Structure of exfoliation material

The abnormally produced material appears by light microscopy as periodic acid–Schiff (PAS)-positive, eosinophilic, bush-like, nodular or feathery aggregates on the anterior segment surfaces, e.g., anterior lens capsule, anterior and posterior iris surfaces, ciliary processes, zonules, chamber angle, and, occasionally, the posterior corneal and anterior hyaloid surfaces (Fig. 23A).376

By scanning electron microscopy, the nodular aggregates are composed of an irregular tangle of fibrils (Fig. 23B)

Morphologic Studies

Regardless of etiology, typical exfoliation fibers have been demonstrated electron microscopically in close association with the pre-equatorial lens epithelium (Fig. 24B and C),30, 70, 72, 129, 521, 522 the nonpigmented ciliary epithelium (Fig. 16D),128, 172, 526 the iris pigment epithelium (Fig. 25C),171, 532 the corneal endothelium (Fig 26D),510 the trabecular endothelium (Fig. 27A and B),501 and with almost all cell types of the iris stroma, such as fibrocytes, melanocytes, vascular

Lens

The light and electron microscopic appearance of diagnostically important XFM on the anterior lens capsule is dependent upon the stage of the disease and the region of the lens examined. Histopathologic studies confirm the presence of a precapsular layer in early stages and the characteristic lenticular distribution of XFM in different zones (central disk, clear intermediate zone, peripheral granular zone, preequatorial zone) in manifest XFS, which can be best visualized by scanning electron

Conjunctiva

Extraocular deposits similar to XFM have been demonstrated electron microscopically in both the bulbar and palpebral conjunctiva of affected eyes, of fellow eyes in unilateral cases, and of patients with suspected XFS without any evidence of ocular XFM in either eye422, 452, 454, 482, 552, 559 and in Tenon's capsule,533 suggesting that the conjunctiva might be an independent source of XFM that precedes clinical recognition of XFM on anterior segment structures. The XFM was found in the

Chronic open-angle glaucoma

The pathogenesis of elevated IOP in XFS remains controversial, and the debate as to whether XFS is a coincidental finding in COAG5, 582, 586, 632 or actually causes glaucoma85, 139, 205, 487, 621 has not entirely been laid to rest. The glaucoma associated with XFS is a hypertensive glaucoma associated with an increase in aqueous outflow resistance.169, 246 Glaucomatous visual field damage correlates much better with untreated IOP in exfoliative glaucoma than it does in COAG.593 Johnson and

Posterior Synechiae

The iris pigment epithelium and the lens surface, both coated with XFM, tend to adhere, particularly when pupillary movement is inhibited by miotic therapy. Bartholomew53 coined the term “iridocapsular block” for this phenomenon. Because of the strength of these adhesions, the attachment of the pupillary ruff to the lens may be stronger than its attachment to the iris stroma. The vascular abnormalities affecting the iris stroma can also affect the synechiae.

Posterior synechiae predispose to

Management

The stepwise approach to the management of the patient with XFS is similar to that for COAG, and it includes beta-adrenergic antagonists, alpha-adrenergic agonists, miotics, carbonic anhydrase inhibitors, and laser and intraocular surgery. Response to these interventions, however, differs from the response of patients with COAG.

Epidemiology

Much remains to be learned about XFS, not only at the basic levels of its production and biochemical nature, but also with regard to genetics, epidemiology, and treatment. What are the real differences in prevalence between races, ethnic groups, and even at local levels within the same population group, and why do these differences exist? Although XFS is common worldwide, its prevalence in China, with one-fifth of the world's population, is said to be quite low (Dennis Lam, MD, personal

Method of Literature Search

References have been compiled for nearly 20 years and maintained on the computers of the authors. To our knowledge, the list of references from the past 30 years is virtually complete. Except for key papers, numerous older references from before 1960 and a few references deemed to be without merit have been omitted. Additional searches were made of MEDLINE from 1976 to 2000, using the search words pseudoexfoliation, exfoliation, capsular glaucoma, and fibrillopathia.

Outline

I. Historical aspects and terminology

II. Epidemiology

A. Frequency in the general population

1. Age

2. Sex

3. Heredity

B. Frequency in glaucoma populations

C. Glaucoma in eyes with XFS

D. Asymmetry of involvement

III. Clinical Findings

A. Lens

B. Iris (including exfoliation suspects)

C. Pupil

D. Cornea

E. Zonules and ciliary body

F. Anterior chamber angle

G. Vitreous and retina

H. Optic disk

I. Extraocular findings

J. Differential diagnosis

IV. Ocular associations

A. Cataract

B. Posterior synechiae

C. Blood-aqueous

Acknowledgements

Supported in part by the Joseph and Barbara Cohen and the Irving and Rena Katz Research Funds of the New York Glaucoma Research Institute, New York City, and by the Deutsche Forschungsgemeinschaft (SFB 539).

The authors have no proprietary or commercial interest in any product or concept discussed in this article.

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