XFM – Glaucoma research

During my trials with glaucoma, I did a lot of questioning of so many people. Finally, Dr Robert Rich sent me this information just to help me understand better. If you have any interest at all, I hope that this saves you doing the kind of legwork that I had to do just to be better enlightened about my condition.

I put here the information in its entirety as it was presented to me, and you can take what you wish from here if it helps you. Again, I am not a doctor, and not telling you what to do other than to seek medical advice immediately if you have any symptoms of any eye problem.

EXFOLIATION SYNDROME

 

Robert Ritch, M.D.

Ursula Schlötzer-Schrehardt, Ph.D.

 

From the Glaucoma Service, Department of Ophthalmology, The New York Eye and Ear Infirmary, New York City, and the Department of Ophthalmology, University Erlangen-Nürnberg, Erlangen, Germany

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)

Running title: Ritch/Exfoliation

 

Reprint requests to: Robert Ritch, M.D., Professor and Chief, Glaucoma Service, the New York Eye and Ear Infirmary, 310 East 14th Street, New York, New York 10003.

  

OUTLINE

I. Introduction

            1.1 Historical aspects; terminology

            1.2 Increasing significance

II. Epidemiology

            2.1 Frequency in the general population

            2.2 Frequency in glaucoma populations

            2.3 Glaucoma in eyes with XFS

            2.4 Asymmetry of involvement

III. Clinical Findings

            3.1 Lens

            3.2 Iris (including exfoliation suspects)

            3.3 Pupil

            3.4 Cornea

            3.5 Zonules and ciliary body

            3.6 Anterior chamber angle

            3.7 Vitreous

            3.8 Optic disc

            3.9 Extraocular findings

            3.10 Differential diagnosis

IV. Ocular Associations

            4.1 Cataract

            4.2 Posterior synechiae

            4.3 Blood-aqueous barrier dysfunction

            4.4 Ischemia

V. Systemic Associations

VI. Pathogenesis of exfoliation syndrome

            6.1 Structure of exfoliation material

            6.2 Nature of exfoliation material

            6.3 Origin of exfoliation material

            6.4 Theories of pathogenesis

VII. Clinical-histopathologic Correlations

            7.1 Lens

            7.2 Iris

            7.3 Aqueous humor

            7.4 Ciliary body and zonules

            7.5 Cornea

            7.6 Trabecular meshwork

            7.7 Extraocular occurrence

VIII. Mechanisms of glaucoma development

            8.1 Chronic open-angle glaucoma

            8.2 Acute glaucoma

            8.3 Angle-closure glaucoma

IX. Management

            9.1 Medical therapy

            9.2 Laser surgery

            9.3 Glaucoma surgery

            9.4 Cataract surgery

X. Overview and future progress

 

Abstract

 

            Exfoliation syndrome (XFS) is an age related disease characterized by the production and progressive accumulation of a fibrillar extracellular material in many ocular tissues. It has only recently been recognized to be the overall most common identifiable cause of glaucoma, and in some countries accounts for the majority of the glaucoma. Its ocular manifestations affect all of the structures of the anterior segment as well as conjunctiva and orbital structures. New insights have increased the importance of accurate diagnosis.

Glaucoma occurs more commonly in eyes with XFS than in those without it. The prevalence of XFS in glaucoma cohorts is significantly higher than in age-matched nonglaucomatous populations. In persons with XFS, the risk of developing glaucoma is cumulative over time. Glaucoma in XFS has a more serious clinical course and worse prognosis than in 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. Glaucomatous damage progresses more rapidly in patients with XFS and glaucoma than in patients with primary open-angle glaucoma. Persons with XFS are also predisposed to develop angle-closure glaucoma.

            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. Just as the iris scrapes XFM from the lens surface, the material on the lens causes rupture of iris pigment epithelial cells at the ruff and sphincter region with concomitant dispersion of pigment into the anterior chamber. Loss of iris pigment and its deposition throughout the anterior segment are reflected in iris sphincter region transillumination, loss of the pupillary ruff, increased trabecular meshwork pigmentation, and pigment deposition on the iris surface.

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.

Despite extensive research, the exact chemical composition of XFM remains unknown. An overproduction and abnormal metabolism of glycosaminoglycans have been, therefore, suggested as one of the key changes in XFS. The protein components of XFM include both non collagenous basement membrane components such as laminin, nidogen/entactin, and fibronectin and epitopes of the elastic fiber system such as alpha-elastin, tropoelastin, fibrillin, amyloid P, vitronectin, and probably the elastin associated glycoprotein gp115/emilin. 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. Predisposing factors include zonular fragility, poor pupillary dilation, phacodonesis, and posterior synechia formation. 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.

 

 

I. INTRODUCTION

 

            Exfoliation syndrome (XFS) is an age related disease characterized by the production and progressive accumulation of a fibrillar extracellular material in many ocular tissues. It has only recently been recognized to be the overall most common identifiable cause of glaucoma, and in some countries accounts for the majority of the glaucoma.452 Similar material has also been detected in skin and connective tissue portions of various visceral organs. In the eye, XFS is characterized clinically by small, white deposits of material in the anterior segment, most commonly on the pupillary border and anterior lens capsule. Making the diagnosis often requires a careful slit-lamp examination after pupillary dilation, and it frequently goes undiagnosed, leading to unexpected problems in management and during surgery. In addition to the exfoliation deposits, important signs of pigment liberation and deposition throughout the anterior segment aid in the diagnosis.

            Despite its wide prevalence and clinical importance, the pathogenesis of XFS and the exact composition of the material remain unknown. Based on the recent identification of accumulations of exfoliation material (XFM) in orbital tissues,480 skin specimens,536, 545 and visceral organs,478, 539 XFS has now been recognized as a generalized or systemic disorder of the extracellular matrix. It may eventually prove to be a conformational disorder rather than a biochemically abnormal material. The pathophysiological manifestations in other organs remain undefined.

 

1.1 Historical aspects and terminology

            Exfoliation syndrome was first described in 1917 by Lindberg,318, 319 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. Vogt595, 596 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 the normal lens capsule.86, 334 The view of a degenerated, exfoliated lens capsule or zonular lamella57, 168, 219, 595 was opposed by the theory of precipitation from the aqueous humor.86, 132, 547 The material was described on the iris, trabecular meshwork, ciliary body, zonules, and cornea, and within the conjunctiva. That the lens is unnecessary for pathogenesis was finally proven by the appearance of XFM many years after intracapsular cataract extraction in aphakic eyes.87, 167, 410, 543 and on intraocular lens implants in pseudophakic eyes.93, 143, 279, 441, 451, 532

            The terms ‘senile uveal exfoliation’601 and ‘glaucoma senilis’,603 emphasized the relationship of XFS to aging. To differentiate XFS from true exfoliation of the lens capsule, Dvorak Theobald131 coined the term ‘pseudoexfoliation of the lens’, while Sunde547 proposed ‘exfoliation syndrome’. Others have used ‘iridociliary exfoliation with capsular pseudoexfoliation’, 30 ‘exfoliation of the pseudocapsule’,239 ‘fibrillopathia epitheliocapsularis’,67 ‘complex pigmentary glaucoma’,514 ‘basement membrane exfoliation syndrome’,133 ‘exfoliation of the lens capsule’,65 ‘oxytalanosis of the aqueous’,162 and ‘ocular elastosis’.534 Since the disease may occur both with and without glaucoma, we use the terms ‘exfoliation syndrome’ and ‘exfoliative glaucoma’.

 

 1.2 Increasing significance of exfoliation syndrome

            The awareness of the importance of XFS has increased considerably in recent years. It causes not only severe, chronic open angle glaucoma, but also lens subluxation, angle-closure glaucoma, blood aqueous barrier impairment, and serious complications at the time of cataract extraction, such as zonular dialysis, capsular rupture, and vitreous loss.365 It appears now that XFS is etiologically responsible for cataract formation and may also play a role in central retinal vein occlusion. Preliminary information suggests a relationship with transient ischemic attacks, stroke, and heart disease.346, 419

            American ophthalmologists historically have put little emphasis on making an accurate diagnosis of XFS. Reasons for this include the assumption that it is a disease found primarily in Scandinavia and northern Europe and that, since the associated glaucoma is treated identically to chronic open-angle glaucoma (COAG), it is unimportant to differentiate it. The first point is a serious misconception, while the second, although perhaps formerly true, is becoming less so and will eventually sound absurd. Recent epidemiological studies in some countries have suggested literally an order of magnitude higher prevalence of XFS in the elderly population and in glaucoma patients than detected in studies a generation earlier.352, 552

            New insights have increased the importance of accurate diagnosis. Taking all epidemiologic studies as a whole, XFS appears to account for about 20-25% of open-angle glaucoma, making it the most common identifiable cause worldwide.452 Glaucoma in XFS tends to be more severe than COAG. Exfoliation-like fibrils have been found in many organs by electron microscopy, suggesting it to be a systemic disorder, long recognized only in the eye because of its visibility on slit-lamp examination and the fact that it causes glaucoma. It can be diagnosed prior to the clinically visible appearance of classic exfoliation material (XFM) on the lens surface. Finally, new understanding of pathophysiologic mechanisms should lead to new approaches to treatment and, eventually, prevention or elimination of the disorder.

 

II. 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 reasons; 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.1 Many cases go undetected because of failure to dilate the pupil or to examine the lens with the slit-lamp after dilation.309, 463 For example, the diagnosis was missed by the referring ophthalmologist in 60% of 42 patients with exfoliative glaucoma referred to one glaucoma center,103 and 79% to another.309

            Prevalence studies have been conducted on diverse populations, including general populations, persons over a certain age, patients taken from eye clinics or general medical clinics, patients with cataracts, glaucoma patients, hospitalized glaucoma patients, and glaucoma patients undergoing surgery. These differences have produced much confusion in the literature and should be taken into account when comparing series. Reports dealing with the prevalence of XFS in glaucoma patients and the prevalence of glaucoma in persons with XFS suffer from these drawbacks and also from variability in the definition of glaucoma, making comparisons difficult even when age-specific rates are available.

            The prevalence of XFS increases progressively among the following groups: a) the general population; b) persons over age 50; c) ocular hypertensives; d) glaucoma patients; e) glaucoma patients admitted to the hospital; f) glaucoma patients undergoing surgery; g) patients blind from glaucoma or who have absolute glaucoma. It is important also to distinguish cohorts of clinic patients and cohorts of cataract patients and patients without cataracts.

 

2.1 Frequency in the General Population

            Exfoliation syndrome occurs worldwide, although reported prevalence rates vary extensively.59, 140, 519.1, 8, 25, 35, 39-41, 47, 51, 69, 70, 76, 91, 98, 101, 139, 145, 146, 148, 149, 205, 214, 226, 246, 255, 277, 278, 303, 305, 306, 316, 331, 339, 352, 373, 438, 439, 468, 505, 523, 525, 541, 546, 550, 556, 565, 607, 609 For reviews of the epidemiology of XFS, the reader is referred to previous publications.121, 146, 351, 434, 435, 556 What stands out is that the reported prevalence rates in a country can vary threefold or more depending on the examiner. In Scandinavia, the highest rates in studies of persons over age 60 have been reported from Iceland (about 25%),145, 550 and Finland (over 20%)145, 278, 280 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.312

            The most significant comparisons are those made among different populations by the same observer. Aasved8 found prevalences of 6.3%, 4.0%, and 4.7% in persons over age 60 in nursing homes in Norway, England, and Germany respectively. Forsius,145 looking at persons over age 60 in varied groups, including Lapps, Eskimos, Icelanders, Peruvian Indians, and Tunisians, found prevalences ranging from 0% in Greenland Eskimos to 21% in Icelanders. Lantukh306 found a low prevalence in native Siberian Tchutchee, but a much higher rate among immigrants to the area.

            The reported prevalence in the United States is generally similar to that in Western Europe. In the Framingham Eye Study, age-specific rates for persons not specifically identified as having glaucoma rose from 0.6% for ages 52 to 64 to 5.0% for ages 75 to 85.214, 316 The figure may be lower in Caucasian populations in the southern United States. XFS was present in only 1.6% of 2121 nonglaucomatous persons over age 60.90, 91 American blacks have a much lower prevalence of XFS than do whites.40, 41, 90, 91 

            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 al277 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.100, 101 Ringvold et al439 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.240 In Australia, persons from Greece, the Baltic states, and India were most likely to have XFS.174

            The reasons underlying true variations, both from one population to another and within more-or-less homogeneous populations remain to be explained. Geographic distribution patterns may perhaps be explained either by regional gene pools or by environmental influences. Persons living at lower latitudes (Greece, Saudi Arabia, Iran) appear to develop XFS at younger ages.435 Exposure to sunlight (ultraviolet radiation) may146, 563, 565 or may not205 be implicated, as may dietary factors.381 Forsius and Luukka147 found no XFS in Eskimos versus 20% of Lapps living at the same latitude. Persons living at higher altitude had a greater prevalence in two series277, 350 but not in a third.145 In one series, eyes with blue irides were significantly more detected to have XFS than those with brown irides.259

            In a given population, the actual prevalence of XFS is probably about twice that which is visible on clinical examination. Of 100 lenses of 98 patients examined by electron microscopy after intracapsular cataract extraction, XFM was found in 33%; only half of these had been diagnosed preoperatively.282 Larsen307 examined 100 postmortem eyes of 50 patients over age 70 and found that while 12% had light microscopic evidence of XFM, only 3% had slit-lamp evidence of the disease.

 

Age: In all series, the prevalence of XFS increases with age. Patients with XFS who have glaucoma tend to be older than those who do not. Forsius146 found its incidence to double every decade after age 50. The reported prevalence in older individuals ranges from 0% among Eskimos145 to as high as 38% in Navaho Indians over age 60.139 In a Finnish population, XFS was found in 10% of patients aged 60 to 69, 21% of those aged 70 to 79, and 33% of those aged 80 to 89.278 In Japan, Iizuka et al226 found prevalence rates of 0.7% in persons from ages 50 to 60 and 7.3% in persons over age 80.

            Early onset of XFS has been found in certain population subgroups. Bartholomew50 described what he termed the pregranular stage at about age 40 in a South African Bantu tribe of whom 6.4% in the 30-39 age group were already affected. Other groups with early onset include Skolt Lapps, Icelanders at Husquik, and Australian aborigines.556 The youngest reported patient, who had had intraocular surgery in infancy, was 17 years of age.267

 

Sex: Women have predominated in some series of XFS without glaucoma.5, 103, 135, 137, 191, 214, 226, 250, 345, 346, 556 Others have found equal352, 505, 531, 546 or greater prevalence in men.54, 146, 227, 277, 373, 524, 607 Glaucoma may develop earlier, more frequently, and more severely in men.146, 173, 226, 273, 333, 353, 552, 607 However many studies have found no sex predilection in patients with glaucoma.1, 2, 72, 101, 191, 221, 465, 546, 550, 556, 586 However, if XFS is more common in women, then an equal number of men and women affected by glaucoma could be construed as a greater predilection for men to develop glaucoma. Women also live longer than men in most countries and comprise a greater proportion of the elderly.

 

Heredity: Genetic factors predisposing to susceptibility have barely begun to be explored, and no clear hereditary pattern has been discerned.394, 560 Examining first degree relatives over age 40 in 25 families, Aasved7 found 9.4% affected individuals, versus 1% of persons detected in a mass screening, and suggested an autosomal dominant inheritance. Both concordant and discordant homozygous twins have been reported.438, 566 Loss of heterozygosity, suggestive of the presence of a gene located in the same region that could be implicated in the development or progression of a disease, was found to be significantly higher in XFS patients than in controls.274 A preponderance of maternal transmission of XFS in families reported has raised the possibility of mitochondrial inheritance.105, 106

One study found a higher frequency of HLA Bw35 in exfoliative glaucoma in Swedish patients than in controls,378 but another found no association.517 More recently, an HLA association with XFS was identified for 14 antigens, four of which were strongly associated, with odds ratios of over 7.5.144

 

2.2 Frequency in Glaucoma Populations

            The prevalence of XFS in glaucoma cohorts is significantly higher than in age-matched nonglaucomatous populations. Reported prevalence rates range from practically zero to as high as 93%, with the highest rates in Scandinavia. Representative values are 46-57% in Iceland,550 28-47% in Finland,386, 586 33-60% in Norway,2, 436 66% in Sweden,322 and 26% in Denmark.377 Forsius146 has provided an extensive list of references in this regard.

            There is also a high incidence of XFS in open-angle glaucoma populations in other European countries. In the Isle of Man, 55% of glaucoma patients had XFS, a much higher figure than in mainland England.96 In Ireland, two-thirds of open-angle glaucoma patients had XFS.333 These figures suggest a higher prevalence of XFS in populations of Celtic descent. Even more revealing are series from countries in which XFS was previously thought to be uncommon or rare. This applies also to countries in Africa and Asia.122, 155, 331, 525, 607 In the United States, 3 series have reported prevalences of 12% in glaucoma populations.309, 463 In the South, the prevalence seems to be lower, with blacks involved less often than whites.40, 90, 91, 103

 

2.3 Glaucoma in Eyes with Exfoliation Syndrome

            Glaucoma occurs more commonly in eyes with XFS than in those without it. In 100 consecutive patients with XFS, Kozart and Yanoff273 found glaucomatous optic nerve or visual field damage in 7% and ocular hypertension in 15%. This is approximately 6 times the chance of finding elevated IOP in eyes without XFS. XFS was unilateral in 76% and bilateral in 24%. Men comprised 21% and women 79% of eyes with XFS without glaucoma, while there was no sex difference for those with glaucoma.

            Aasved4 found elevated IOP with or without glaucomatous damage in 22.7% of patients with XFS detected on screening, as opposed to 1.2% of those without XFS. In Norway, Ringvold et al436 found 30% and 4.8%, respectively, while Kozobolis et al277 found 28.8% and 5.4% in Crete. Similar high figures for elevated IOP with or without glaucomatous damage have been reported in XFS patients in other studies in Europe,101, 136, 137, 250, 251, 352, 531, 556 the Middle East,546, 607 Australia,83, 345 and Japan.505

            In persons with XFS, the risk of developing glaucoma is cumulative over time. Henry et al203 found the 5- and 10-year cumulative probabilities of initially nonglaucomatous eyes with XFS developing glaucoma to be 5.3% ± 0.1% and 15.4% ± 2%, respectively, a significantly higher rate than would be expected in a similar group of patients without XFS. In their population, therefore, XFS patients would have approximately a 40% chance of either having initially or developing ocular hypertension or glaucoma within ten years, approximately a ten-fold increased risk when compared to the general population. Still, patients with XFS have also been observed for long periods of time without developing glaucoma.192

            Glaucoma in XFS has a more serious clinical course and worse prognosis than COAG. 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.2, 3, 159, 258, 268, 269, 320, 321, 354, 393, 557 In a prospective study, Puska et al408 found that in patients with clinically unilateral involvement in whom IOP was equal throughout the follow-up period, disc changes took place only in the involved eye, suggesting that the exfoliative process itself may be a risk factor for optic disc changes.

            In normotensive eyes with XFS, mean IOP is higher than in eyes without XFS.4, 119, 154, 193, 214, 250, 277, 281, 333, 345, 546 In clinically unilateral XFS and bilateral glaucoma, IOP is higher in the eye with XFS.[Aasved, 1971 #3317 In one series, even in normotensive eyes with no visual field loss, the greater the IOP of the involved eye compared to the fellow eye, the smaller were the rim-to-disc radius ratios in the inferotemporal quadrant.574 In patients with elevated IOP, mean IOP is higher at the time of detection in patients with XFS than in those with COAG.4, 268 Persons with elevated IOP and XFS are more likely to progress to glaucomatous damage than are those with elevated IOP without XFS.224

           Glaucomatous damage progresses more rapidly in patients with XFS and glaucoma than in those with COAG.3, 159, 320, 321, 354, 393, 557 This probably reflects the effects of the higher IOP on the optic nerve, but abnormalities of the lamina cribrosa relating to elastic tissue cannot be ruled out.368, 385 At any specific IOP level, eyes with XFS are more likely to have glaucomatous damage than are eyes without XFS.118 The diurnal fluctuation in IOP is greater in eyes with exfoliative glaucoma than in those with COAG.264 Visual field defects are more severe at the time of diagnosis268, 320 and when studied longitudinally over a period of 5 years, visual field loss was more severe than in a group of comparable patients with COAG.379 Ocular hypertensives with XFS are much more likely to develop glaucomatous damage on long-term follow-up than are those without XFS.203, 393, 571

            Glaucoma in XFS is more resistant to medical therapy than is COAG, responds for a shorter period of time, and fails more often.15, 74, 83, 138, 268, 309, 379 In addition, the proportion of patients with XFS shows a steady increase when measured in cohorts with open-angle glaucoma without optic nerve damage, in those with damage, in those undergoing surgery, and in those with absolute glaucoma.2, 255, 261 

 

2.4 Asymmetry of Involvement

            A review of the literature comparing the frequency of monocular versus binocular involvement in various series is particularly confusing. Binocular involvement is more common in the European literature than elsewhere. Many series have reported bilateral involvement to be more common, with ratios as high as 3:1.277, 333, 352, 467, 531, 546 Other series, including most American ones, have reported unilateral involvement to predominate, again with ratios as high as 3:1.5, 83, 103, 137, 203, 250, 309 This is apparently true in Japan as well where 80% have monocular involvement.159, 505

Patients with bilateral XFS tend to be slightly older than those with unilateral XFS, but the age difference is often small.5, 168, 214, 273, 556 Klemetti250 found an average age of 66.3 years in unilateral patients, and 68.0 years in bilateral cases. Patients with bilateral disease tend to have a higher prevalence of ocular hypertension or glaucoma when compared to unilateral cases.273 When glaucoma develops in patients with bilateral XFS there is a tendency for it to occur in both eyes simultaneously or within a limited period of time.6 Tarkkanen556 found that patients with unilateral XFS and glaucoma show a high proportion of men, myopes, a family history of glaucoma, marked pigmentary changes, and a large proportion of high initial IOP when compared to bilaterally affected patients.

            When only one eye is involved, the fellow eye often has abnormal aqueous humor dynamics or glaucomatous damage, which, when it is present, is almost always less marked than the involved eye.163, 389, 556 In one series, 73.9% of patients had unilateral XFS, but 38.9% of the fellow eyes had abnormalities related to glaucoma.159 In 5 of 16 of Kozart's patients with unilateral XFS and elevated IOP, the fellow eye also had elevated IOP.273

            Electron microscopic observations have revealed XFM in the conjunctiva of the clinically uninvolved fellow eye almost invariably.400, 528 These findings suggest early development of XFS in the fellow eye, although why this asymmetry occurs remains unknown. However, clinically unilateral involvement is often a precursor to bilateral involvement. Results of series in the literature show highly variable outcomes. Although Tarkkanen556 described unchanged unilateral occurrence in 47 patients followed 5 years, Hansen and Sellevold192 found XFS to develop in the second eye in 40.8% of men and in 31% of women over the same time period, and Aasved2 found that 43% developed binocular involvement after 6 or 7 years. Others have reported similar findings.4, 371, 375, 463, 516, 556 Using life-table analysis, Henry et al203 found the probability of XFS developing in the second eye to be 6.8% after 5 years and 16.8% after 10 years, while Klemetti250 found 14.4% with a mean time to conversion of 4.5 years.

            The terms "unilateral" and "monocular" are misleading. Since early pigment-related signs (see below) of XFS are found in the majority of unaffected fellow eyes, and since XFM may be detected on conjunctival biopsy400, 528 and orbital tissues480 in virtually all unaffected fellow eyes, these cases are actually asymmetric. Subtle ultrastructural and immunohistochemical alterations typical of XFS were observed in anterior segment tissues, particularly the iris, of all apparently uninvolved fellow eyes.189, 249 However, since these terms have been used for so long a time, they will be retained here specifically to describe those patients who have clinically visible XFM in only one eye on slit-lamp examination, with the understanding that both eyes are actually affected by the process.

 

III. CLINICAL FINDINGS

3.1 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 disc 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 quantities of XFM deposits, different stages in the disease progress, and the topographic relationship between lens and iris.    

            The central zone is a homogeneous, white sheet lying on the anterior pole of the lens capsule. Its diameter varies from 1.5-3.0 mm, and is it usually slightly smaller than the physiologic pupil. The edges of the central disc are often rolled anteriorly (Fig. 2). The central disc is absent in 20%309 to 60%467 of cases. It is often initially overlooked, but with careful examination after dilation, a subtle area of XFM may be noted, especially when compared to the adjacent intermediate clear zone. Computerized image enhancement can increase the visibility of the material.407 Scheimpflug photography may be used to pick up XFM on the surface of the lens before it is visible clinically.178

            The peripheral zone is always present (Fig. 3).219 It may be granular in the periphery and frosty white centrally, and radial striations are often seen. Layers may be present. Axially it is bounded partly by curled edges, and partly by tongue-shaped projections. Equatorially it extends as granular tongue-shaped projections which merge into the normal capsule before reaching the anterior zone of insertion of the zonular fibers. The peripheral band may be situated close to the equator in some eyes and more axially in others. The granularity of the peripheral layer is consistent with undisturbed accumulation of XFM. In eyes treated with miotics, the central disc may similarly develop a granular appearance.

            Whereas the classic picture of manifest XFS has been often described, the early stages of beginning exfoliation have not been well defined. A precursor of XFM is thought to be initially diffusely deposited on the lens surface. A homogeneous ground-glass or matte appearance to the lens surface in one eye compared to the other may represent a very early (precapsular) stage.108, 567 In a perhaps slightly later (pregranular) stage, there may be a ring of about 80 faint, radial, nongranular striae on the mid-third of the anterior capsule behind the iris (Fig. 4).50 Ultrastructurally, the precapsular layer at this stage consists of microfibrils, but not mature exfoliation fibers.108, 567 Degenerated zonular fragments have been occasionally found interspersed in, and sometimes merged with microfibrils of the precapsular layer.614 In visualizing the earlier stages at the slit-lamp, placing the slit beam at 45 degrees to the axis of observation, reducing the light source, and focusing temporally about 2 to 3 mm from the center of the lens may help to highlight the subtle deposits on the lens surface.

            The intermediate clear zone is created by rubbing of the iris over the surface of the lens during pupillary movement. As the precapsular layer becomes thicker, the iris sphincter region begins to rub against it during normal pupillary movement. Faint clefts begin to form where XFM is rubbed away in what will eventually become the clear zone (Fig. 5). With time, these clefts increase in size and begin to become confluent. Eventually, only small bridges may remain as an indication of the previous layer of XFM in the intermediate zone. In some patients, the central disc may become thick enough to peel away in sheets from the lens, as may the peripheral zone, giving rise to the appearance of a true exfoliation syndrome (Fig. 6). Chronic pupillary dilation also permits undisturbed accumulation of XFM (Fig. 7).

            Phacodonesis is common, yet not always associated with iridodonesis, perhaps attributable to increased iris rigidity.48, 49, 159, 186, 344, 349 It may be brought out by giving a drop of 2% pilocarpine to relax the zonules. Spontaneous subluxation or dislocation of the lens can occur.151, 156, 168, 581 Phacodonesis and lens dislocation have been attributed to weakness of the zonules, with a varying incidence reported. The denser the XFS, the more likely is there to be phacodonesis.49, 350

 

3.2 Iris.

            Iris changes are an early and well recognized clinical feature in XFS. Next to the lens, XFM is most prominent at the pupillary border (Fig. 8). Deposits of XFM on the iris sphincter and pupillary margin can be found in 32% to 94% of patients.166 It is not invariably present and may be represented only by a tiny dot or two, requiring again a high index of suspicion and a careful search, or it may be extensive (Fig. 8). It tends to be most prominent in eyes maintained on miotic therapy. In some eyes, more prominent excrescences can be seen. Forsius146 suggested that the open-angle glaucoma may be more severe if XFM is present on the iris in addition to the lens. The iris in eyes with XFS appears to be more rigid than in eyes without XFS.48, 156

            Pigment loss from the iris sphincter region and its deposition on anterior chamber structures is a hallmark of XFS. Just as the iris scrapes XFM from the lens surface, the material on the lens causes rupture of iris pigment epithelial cells at the ruff and sphincter region with concomitant dispersion of pigment into the anterior chamber. Loss of iris pigment and its deposition throughout the anterior segment are reflected in iris sphincter region transillumination, loss of the pupillary ruff, increased trabecular meshwork pigmentation, and pigment deposition on the iris surface.399

            Pupillary ruff defects are the most common of these signs and are most striking in patients with unilateral involvement (Fig. 9).399 Their frequency increases significantly with age and they are more common in eyes with XFS than in clinically uninvolved fellow eyes or in normal eyes.6, 372 How the pigment ruff, which often extends slightly anteriorly from the pupillary border, scrapes against the XFM remains to be elucidated. We have noted that the ruff becomes inverted, placing it in contact with the anterior lens surface.

            Transillumination defects occur at the pupillary ruff and margin (Fig. 10).6 However, if extensive depigmentation has occurred, defects may be noted over the entire sphincter region. Generalized peripheral iris transillumination, which appears as a diffuse "starry-sky" appearance of the defects, has also been associated with XFS.421

            Pigment deposition on the iris surface is a rarely noted but common finding.399 Its characteristic appearance should alert the examiner to search carefully for XFM. Pigment particles, larger than those found in pigment dispersion syndrome, are deposited in a whorl-like fashion on the anterior stroma at the sphincter.399 Pigment is deposited evenly over the iris surface, in contrast to its collection in iris furrows in pigment dispersion syndrome (Fig. 11).

            Exfoliation ‘suspects’ were initially defined as patients in whom one or both eyes exhibited one or more signs related to pigment dispersion (see above) in the absence of clinically identifiable XFM on the anterior lens capsule or pupillary margin in either eye.400 Transmission electron microscopy of conjunctival biopsy specimens from patients previously diagnosed to have either COAG or ocular hypertension revealed XFM in 8/23 suspect eyes. These pigment-related signs also correlated with the presence of extraocular exfoliation fibrils in 7 of 12 eyelid skin specimens in the absence of any clinically visible intraocular XFM.479

 

3.3 Pupil

            Eyes with XFS often dilate poorly, even when miotics have never been used.48, 88, 128, 330, 561, 600, 613 In patients with clinically unilateral XFS, the difference in response between the involved and fellow eyes to pharmacologic dilation is significant.88 Eyes with XFS may also constrict less well to topical 4% pilocarpine.330 Even without mydriatics, the pupil in the involved eye may be smaller; in patients with newly diagnosed, untreated, unilateral exfoliative glaucoma, the pupil in the involved eye was smaller in all cases.187

            Two studies examined histological changes in the iris sphincter and dilator muscles by light and electron microscopy and found fibrotic, disorganized or degenerative muscle tissue in most XFS and exfoliative glaucoma specimens, but not in controls.26, 418

            Small particles can be seen floating in the aqueous in the undilated eye. Pigment dispersion in the anterior chamber is common after pupillary dilation and may be profuse.6, 14, 38, 46, 160, 168, 281, 283, 287, 336, 388, 399, 417, 556, 585, 595 This pigment is released from the posterior pigment epithelium of the iris as the pupil dilates (Fig. 12)14 and is more common and more marked in eyes with XFS than in eyes with COAG.281 Tarkkanen556 found pigment dispersion only in eyes with XFS.

            Marked IOP rises can occur in these eyes after pharmacologic dilation with a positive correlation between the extent of IOP rise and the amount of pigment liberated.336, 361 Krause et al281 noted the pigment in the anterior chamber to be maximal at one to two hours after mydriasis and to disappear in 12 to 24 hours. IOP rises usually reach a maximum after two hours.284 In some patients, however, we have found that IOP may begin to rise only after three to four hours after dilation (unpublished data). Since IOP is rarely measured at this late a time, possible further glaucomatous damage in compromised eyes may occur. Post-dilation IOPs should be checked routinely in all patients receiving mydriatics.

 

3.4 Cornea.

            Scattered flakes of XFM may be observed on the endothelial surface of the cornea (Fig. 13). These may be erroneously interpreted as inflammatory precipitates.94 Pigment deposition usually causes a diffuse, nonspecific pigmentation of the central endothelium, only occasionally having the pattern of a Krukenberg spindle (Fig. 14).399 More frequently, one or several undulating pigmented lines can be observed in the peripheral cornea anterior to Schwalbe's line.470, 472

            Specular microscopy demonstrates a significantly reduced endothelial cell density, even with normal IOP, together with morphologic changes in size and shape of the endothelial cells in both affected eyes and uninvolved fellow eyes.197, 252, 495, 501, 530, 590, 599, 604 Decreased endothelial cell density does not necessarily correlate with the severity of glaucoma or duration of treatment,590 but it has been correlated with the extent of pigment dispersion.253 Although these morphologic changes may be related to XFS itself, changes in aqueous humor composition and dynamics, possibly related to XFM-induced iris hypoperfusion, may be responsible.84 Corneal endothelial changes may help in early diagnosis347 and in preoperative assessment prior to cataract extraction.197 A greater than normal frequency of cornea guttata in eyes with XFS has been suggested.128

            Naumann and Schlötzer-Schrehardt363, 364 have suggested that a true keratopathy, distinct from Fuchs’ dystrophy and from pseudophakic bullous keratopathy, can be found in eyes with XFS, predisposing them to develop early corneal endothelial decompensation at only moderate rises of IOP or after cataract surgery. The percentage of cells lost during cataract surgery in eyes with XFS does not appear to differ from that in those without.604

            Bartholomew52 reported a significant association of exfoliation syndrome with spheroidal degeneration of the cornea in men, but not in women. Associations with climatic droplet keratopathy have been noted.422, 564. Both of these associations may be environmental.  A patient with lattice degeneration of the cornea and XFS but without amyloidosis has been described.493

             

 

3.5 Zonules and ciliary body.

            Exfoliation material may be detected earliest on the ciliary processes and zonules (Fig. 15). Zonular XFM may predate development of the peripheral granular zone and may appear as subtle striations of XFM and/or pigment on the surface of the lens.51 Cycloscopy in patients with apparently unilateral involvement revealed XFM on the ciliary processes in all affected eyes and on the zonule or ciliary processes or both in 77% of fellow eyes in which XFM was not clinically visible on the lens surface or pupillary border.349

            Deposits of XFM on the zonules may explain the tendency to spontaneous subluxation or dislocation of the lens in advanced cases. Whether the zonules are just coated with XFM or actually replaced by it, they are often frayed and broken (Fig. 16A).95, 109, 156, 349, 553, 570 Abnormal zonular attachment to the lens or ciliary body may account for the development of lens subluxation or dislocation (see below).

 

3.6 Anterior Chamber Angle       

            Despite the previously reported rarity of angle-closure glaucoma in eyes with XFS, narrow angles occur in a large proportion of patients.300, 309, 605 Of 100 patients with XFS and glaucoma, only 21 of whom had been correctly diagnosed prior to referral, 23% had grade 2 or narrower angles.309 Four of these presented with acute angle-closure glaucoma, but were also being treated with echothiophate, which could have been contributory. Wishart et al605 found 32% of 76 patients with XFS (73 of whom had glaucoma) to have narrow angles. Eighteen percent were considered occludable and 14% had peripheral anterior synechiae. Dense trabecular pigmentation in the absence of clinically visible XFM was noted in the fellow eye of patients with unilateral XFS.

            Bartholomew55 examined anterior chamber depth in 34 normotensive eyes of patients with XFS and 334 normal controls. He found a decreased anterior chamber depth with age but no significant difference between normals and XFS patients. Gharagozloo et al163 found anterior chamber volume to be significantly smaller in both affected and unaffected eyes of patients with XFS compared to controls.

            Increased trabecular meshwork pigmentation is a prominent sign of XFS and is apparent in virtually all patients with clinically evident disease (Fig. 17). Unlike pigment dispersion syndrome, the distribution of the pigment tends to be uneven or splotchy, and less well defined. It may be an early diagnostic finding preceding the appearance of XFM on the pupillary margin or anterior lens capsule.400, 605

            In virtually all studies of patients with unilateral involvement, the trabecular pigment is almost always denser in the involved eye.300, 451 Eyes with exfoliative glaucoma tend to have greater pigmentation than eyes with XFS but without glaucoma.404, 464 and eyes with exfoliative glaucoma have greater pigmentation than eyes with COAG.159, 260 All 76 patients with XFS in the series of Wishart et al had increased trabecular pigmentation and 84% had more advanced glaucomatous damage on the side with greater pigmentation.605 When the pigment was markedly asymmetric, unilateral XFS with glaucoma was common in the more pigmented eye, and no patient had less pigment in the eye with greater glaucomatous damage. There appears to be a highly significant correlation between elevated IOP and the degree of pigmentation of the meshwork.357 In one series, the IOP was greater in the eye with greater pigment in all persons and the greater the difference, the greater the difference in IOP.357 The extent of pigmentation, however, does not always correlate with IOP and the severity of glaucoma.261, 309

            Electron-microscopic studies of conjunctival biopsy specimens of clinically uninvolved fellow eyes consistently show the presence of fibrils resembling those of intraocular exfoliation material.400, 528 Pigment is characteristically deposited on Schwalbe's line and sometimes as a wavy line or lines anterior to Schwalbe's line (Sampaolesi line).19, 470 This, too, is an early sign of XFS. Flecks of XFM may also be seen in the anterior chamber angle during gonioscopy, usually on the posterior trabecular meshwork.

 

3.7 Vitreous and Retina

            After cataract extraction, XFM may be found on the vitreous face (Fig. 18), on vitreous strands when the face is ruptured (Fig. 19), on the posterior capsule (Fig. 20), and on intraocular lenses (Fig. 21), indicating that the presence of the lens is unnecessary for its continued formation. Kozobolis et al275 found a positive correlation between XFS and macular degeneration, attributing this to both disorders increasing in incidence with age and altitude. One study has reported abnormalities of pattern electroretinographic findings and oscillatory potentials in eyes with XFS.526

 

3.8 Optic disc

            In a prospective study of untreated ocular hypertension, the percent area of optic disc pallor was significantly greater in exfoliative than in nonexfoliative eyes despite a lack of differences in IOP or in the visual field.323 The mean disc area has been reported to be smaller in eyes with XFS, with or without glaucoma, than in controls.85, 238 There were no significant differences in neural rim area or extent of peripapillary atrophy despite higher mean IOPs in the exfoliation groups. Although mean values of disc areas in eyes with COAG and exfoliative glaucoma are similar, small discs may be more frequently found in eyes with exfoliative glaucoma.580

            In one study, disc area, neural rim area, rim/disc ratio, cup area, and cup volume values analyzed with the Imagenet (Topcon) nerve head analyzer did not differ significantly between normotensive eyes with XFS and clinically uninvolved fellow eyes.405 In eyes with unilateral exfoliative glaucoma and no clinical evidence of XFS in the fellow eye, pairwise comparisons showed no difference in size of peripapillary crescents.406 The area of peripapillary atrophy correlated significantly with IOP and the extent of glaucomatous damage.406 Peripapillary chorioretinal atrophy areas in COAG and XFS patients were not significantly different from each other.569 Cupping tends to be diffuse, compared to COAG, in which the most prominent neural rim defects occur at the inferotemporal and superotemporal sectors.569

 

3.9 Extraocular findings

            Clinically, the conjunctiva is normal. However, fluorescein angiography of the conjunctiva reveals loss of the regular limbal vascular pattern and areas of neovascularization in advanced cases, as well as congestion of the anterior ciliary vessels.302 Lower scores in Schirmer testing and tear film break-up time have been found in eyes with XFS and it was suggested that these eyes may be more prone to developing xerophthalmia, especially if treated with beta-adrenergic blocking agents.276

 

3.10 Differential Diagnosis

            When clinical signs of XFS are prominent, the diagnosis is readily apparent. Common conditions associated with pigment deposition in the anterior segment and/or angle include pigment dispersion syndrome, uveitis, diabetes, and chronic angle-closure glaucoma. Patients with pigment dispersion syndrome are younger and more myopic, have a more heavily pigmented trabecular meshwork pigment band, mid-peripheral iris transillumination defects, and Krukenberg spindles. 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.308, 359, 559 The trabecular meshwork in patients with uveitis tends to have splotchy pigment, with peripheral anterior synechiae. The angle structures in patients with chronic angle-closure glaucoma are often hidden by peripheral anterior synechiae or iris apposition, but after iridectomy, the widened angle may have visible areas of increased pigmentation. Other conditions characterized by pigment changes, such as Fuchs' heterochromic iridocyclitis, pigmentation of the chamber angle with aging or after surgery, and pigmentation secondary to intraocular tumors can usually be readily distinguished.

            True exfoliation of the lens capsule is a rare clinical entity associated with exposure to high temperatures, and is associated with cataract, but not glaucoma.23 Histopathologic studies have shown actual splitting of the superficial lens capsule.242 Angle-closure glaucoma may occur with this entity also.510 Cashwell et al89 reported 11 eyes of 7 patients with true exfoliation, none of whom had had prolonged exposure to heat, infrared irradiation, or trauma, and suggested that this condition might be underdetected.

            Clinically, the ocular findings in primary familial and non-familial amyloidosis may resemble XFS. Amyloid deposition occurs on the lens surface, along the iris surfaces, and in the trabecular meshwork. Several authors have described patients with both primary familial amyloidosis and exfoliation based upon the clinical and ultrastructural appearances.157, 248, 341, 491, 577 However, differences have been noted between this amyloid material and XFM, both ultrastructurally and histochemically577 and clinically.157 Increased trabecular pigmentation can occur in these eyes.24, 157, 473

            Secondary glaucoma can occur in eyes with amyloidosis. Multiple mechanisms, including angle-closure, outflow obstruction and elevated episcleral venous pressure resulting from perivascular amyloid deposits, have been implicated.43, 367 Ultrastructural findings include intertrabecular amyloid accumulation and trabecular cell degeneration.513 What should be appreciated is that a fibrillar material which is secreted, deposited, or polymerized on the lens surface develops into an anatomic pattern determined by relationships between the lens, iris, and aqueous currents.

 

IV. OCULAR ASSOCIATIONS

4.1 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.54, 107, 208, 228, 292, 297, 309, 327, 333, 344, 352, 354, 383, 405, 463, 546, 556, 564, 603, 607 Nuclear cataract is often more frequently found in eyes with XFS than in eyes without it.208, 499, 556 An increased rate of subcapsular cataract has also been reported.405 There is an increased prevalence of XFS in eyes coming to cataract surgery and an increased prevalence of cataracts in eyes with XFS.208 Eyes with XFS with or without glaucoma have poorer visual acuity and more often have lens opacification (with or without pilocarpine treatment in glaucomatous eyes) than clinically uninvolved fellow eyes.403 We hypothesize that cataract formation is related to ocular ischemia and that the virtually constant association we have noted clinically between unilateral cataract and asymmetric exfoliation syndrome, the two occurring in the same eye, is indicative of greater ischemia in the involved eye. Studies implicating glaucoma as a risk factor for cataract formation did not look for XFS as a unifying factor.194

            Patients with XFS are much more prone to have complications at the time of cataract extraction.16, 32, 34, 48, 88, 152, 186, 247, 327, 329, 356, 362, 366, 382, 412, 413, 488, 515 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.362, 366, 398 Zonular fragility increases the risk of lens dislocation, zonular dialysis, or vitreous loss up to ten times.177, 223, 356, 362, 366, 387, 515, 613 The presence of phacodonesis has been related to poor mydriasis, cataract, presence of glaucoma, and trabecular pigmentation, all a reflection of the severity of involvement, and should serve as a warning sign to the surgeon.356 Küchle298 found an intraoperative complication rate of 13.4% in eyes with anterior chamber depths of less than 2.5 mm and 2.8% in eyes with anterior chamber depth of 2.5 mm or greater, and suggested that a shallow anterior chamber may indicate zonular instability. Postoperatively, transient IOP elevations are more common.398

            Posterior capsular opacification is increased in eyes with XFS compared to those without XFS.289, 522 Late postoperative decentration of intraocular lenses and capsular bags was reported to be significantly higher in eyes with XFS and was also related to zonular weakness.31 Capsule contraction syndrome is an exaggerated reduction in capsular opening and capsular bag diameter after cataract extraction and is much more common after capsulorhexis.120, 161 It is particularly common in eyes with XFS, particularly if the capsulorhexis is small, and can lead to IOL displacement.78, 120, 198

            Published series regarding the rate of complications during phacoemulsification remain few, although reports of small series have suggested a lower complication rate than with extracapsular cataract extraction.99, 126, 130, 207 In one large series of over 1000 patients, those with XFS had over 5 times the complication rate as those without.492

            Despite involvement of the lens capsule in XFS, one study found no significant differences in mean capsular thickness between XFS and normals.466 Capsular elasticity is also normal and XFS does not preclude nucleus extraction through a capsulorhexis.28, 29

 

4.2 Posterior Synechiae

            Exfoliation syndrome predisposes to formation of synechiae between the iris pigment epithelium and the anterior lens capsule, even in the absence of miotic therapy.66, 283 Vigorous dilation can result in adhesion of the entire iris pigment epithelium onto the lens surface (Fig. 22). Krause and Tarkkanen282 described remnants of posterior synechiae adherent to the lens in 5 eyes with histologically proven XFS. Posterior synechiae are more prone to form between the iris and intraocular lens postoperatively.77

 

4.3 Blood-aqueous Barrier Dysfunction

            Inflammation after cataract extraction is more common in eyes with XFS than in those without, and a transitory fibrinoid reaction, attributed to breakdown of the blood aqueous barrier, may occur.42, 380, 598 Evidence of blood-aqueous barrier impairment in eyes both with and without glaucoma has been suggested by studies using fluorescein angiography,80, 81, 97 fluorophotometry,80, 415 and the laser flare-cell meter.290, 293-295, 299, 599 Immunohistochemical staining for albumin suggests that barrier impairment is primarily localized at the level of the iris and to a lesser extent, the ciliary body.299 Breakdown of the blood-aqueous barrier following intraocular surgery is significantly higher in eyes with XFS.293, 369, 489 The finding of alpha1-lipoprotein and ceruloplasmin in the aqueous humor of eyes with XFS led Baba36 to suggest increased vascular permeability.

 

4.4 Ischemia

            Iris blood vessel abnormalities are the rule in XFS.22, 81, 123, 133, 166, 195, 202, 229, 266, 425, 427, 443, 498, 506, 507, 529 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 patchy iris microneovascularization. Fluorescein angiographic studies have shown partial occlusion of radial iris capillaries associated with hypoperfusion, a reduced number of vessels, microneovascularization, and diffuse, patchy fluorescein leakage, especially in the pupillary region.75, 80, 81, 97, 469, 587-589, 591 Similar findings may rarely occur in the iridocorneal angle. Due to iris hypoperfusion, the partial pressure of oxygen in the anterior chamber of eyes with XFS is significantly reduced.202 Friedburg and Bischof153 found rubeosis in 50% of eyes with XFS, with an increased incidence in patients over age 65. Neovascularization of posterior synechiae may result in microhyphema, occasionally accompanied by elevated IOP, following pharmacologic dilation. Patients with XFS who are taking anticoagulants may be more susceptible.183

In clinically unilateral cases of XFS, ipsilateral pulsatile ocular blood flow512 and carotid blood flow494 have been reported to be reduced. In the Blue Mountains study, XFS was a risk factor for the development of disc hemorrhage.200

            A possible association of XFS with retinal vein occlusion has also been suggested.344, 392 Gillies and West174 reported 17 cases with a central retinal vein occlusion in a retrospective series of 250 patients with XFS. Pohjanpelto392 documented retinal vein occlusion in five of 42 eyes with exfoliative glaucoma compared to two of 46 eyes with COAG. Of 113 patients with XFS in the series of Meyer et al,344 four had had a branch retinal vein occlusion. Conversely, in a retrospective review of charts of patients with branch or central retinal vein occlusion, XFS was found in 6.0% and 6.9% respectively.104 In another series, approximately 33% of all eyes enucleated for neovascular glaucoma caused by central retinal vein occlusion had coexistent XFS.241

 

V. SYSTEMIC ASSOCIATIONS

            No clear-cut association of XFS with a systemic disease has yet been shown. Patients with XFS but without glaucoma respond to topical steroid testing similarly to the normal population.170, 395 However, in one study, 2 out of 15 patients with bilateral, non-glaucomatous XFS responded with a pressure rise of 6 mmHg or more, and 3 out of 18 patients showed the same response when 0.1% betamethasone drops were administered four times a day for six weeks.558 In another study, IOP was reduced in six of eight patients after steroid administration.374

            Blood group markers have also been investigated. Blika et al73 determined ABO and Rh (D-antigen) in 236 consecutive glaucoma patients, using local factory workers for controls. Patients with exfoliative glaucoma had significant differences from COAG but not from controls. Brooks and Gillies82 reported a significant decrease in AH secretors and increase in HB secretors in exfoliative glaucoma compared to COAG. Most recently, in the Middle-Norway study, Ringvold et al437 reported finding no significant differences in blood group distribution in persons with XFS, but that the development of glaucoma in these persons is strongly influenced. These authors concluded that a person with blood group A1 has seven times the chance of developing glaucoma when that person is K1 positive as opposed to K1 negative.437

            Mariam et al338 found antinuclear antibodies in preoperative serum and aqueous humor in 34.4% of patients with XFS as opposed to none of controls. Meretoja340 described a syndrome consisting of snowflake dystrophy of the corneal endothelium associated with a high incidence of XFS, oculocutaneous pigment disturbances, and malabsorption. Three of 12 patients with XFS had increased IgA antibodies to gluten and gliadin, suggesting barrier breakdown in the gut wall.447

            Other associations have thus far been inconclusive. Psilas et al402 found a much lower prevalence of XFS in diabetics with retinopathy, particularly those with proliferative retinopathy, and Konstas et al269 found a lower prevalence of diabetes in patients with exfoliative glaucoma than in those with COAG. Repo et al420 evaluated iris photographs of 62 patients with transient ischemic attacks and found a significantly higher prevalence of abnormal iris transillumination defects and twice the frequency of XFS as in the age-matched general population. They interpreted this data to support a potential role of hypoperfusion in the development of XFS. Using color Doppler imaging of ophthalmic arteries of patients with a history of transient ischemic attacks, the same group found a significantly greater frequency of XFS than in controls and greater resistivity indices for the ophthalmic arteries of patients with XFS.419 Patients with exfoliative glaucoma have been reported to have lower baseline fingertip cutaneous capillary perfusion than those with COAG or controls, longer time to maximal cold-induced flow reduction, and longer recovery time.216

            In the Blue Mountains Eye Study (Australia), XFS was found to correlate positively with a history of hypertension, angina, myocardial infarction or stroke, suggestive of vascular effects of the disease.346 Others, however, have found no increase in mortality rates in persons with XFS compared to those without.440, 511 In a small pilot study, XFS was significantly associated with aneurysms of the abdominal aorta, but not with carotid artery occlusion.365

 

VI. PATHOGENESIS OF EXFOLIATION SYNDROME

6.1 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).358

            By scanning electron microscopy, the nodular aggregates are composed of an irregular tangle of fibrils (Fig. 23B). Transmission electron microscopy shows the aggregates to be composed of randomly arranged, electron dense, fuzzy fibrils that run straight, curved, or bent with occasional ramifications. Generally, two types of exfoliation fibrils can be distinguished:535 Type A fibrils have a diameter of 18-25 nm, a length up to 1 µm, and a prevailing periodic banding pattern of about 50 nm, less frequently of about 25 nm (Fig. 23C). Type B fibrils are shorter (0.3 0.5 µm), thicker (30 45 nm), more electron dense, with a less distinct banding pattern (Fig. 23D). These highly characteristic exfoliation fibrils are intermingled with and apparently composed of microfibrils that are 3 7 nm or 8 10 nm in diameter, tubular in cross section, and have a microperiodicity of 10 12 nm. The microfibrillar subunits seem to form a core by lateral aggregation (Fig. 23E), which is surrounded and masked by an electron dense fuzzy material with side excrescences at regular intervals corresponding to the cross bands of exfoliation fibers.113-115 The composite exfoliation fibrils are embedded in an amorphous interfibrillar ground substance.111-113, 117 Most likely, glycosaminoglycans are present on the surface of the exfoliation fibrils and represent the interfibrillar matrix.111-113, 116

            Although extraocular exfoliation fibers often have a less distinct banding pattern and increased amounts of interfibrillar matrix,478, 539 the ultrastructural criteria of both intra- and extraocular fibers are highly characteristic and clearly distinguishable from any other known form of extracellular matrix product, supporting the notion of a pathognomonic material.

 

6.2 Nature of Exfoliation Material

 

            Despite extensive research, the exact chemical composition of XFM remains unknown. Biochemical analyses are impeded by insufficient amounts of available material, by the insolubility of the material, and by lack of experimental models. Indirect histochemical and immunohistochemical evidence suggests a complex glycoprotein/proteoglycan structure composed of a protein core surrounded by glycoconjugates, probably glycosaminoglycans, also forming the amorphous ground substance.111-113 XFM is resistant to degradation by most enzymes including collagenase, trypsin, pepsin, and papain.68, 497

 

Carbohydrate Components: Numerous studies have demonstrated staining of XFM with histochemical stains for glycosaminoglycans, including PAS, Alcian blue, and ruthenium red.37, 117, 358 The presence of glycosaminoglycans has also been shown by application of the sulfate binding dye cuprolinic blue and by immunohistochemistry, giving evidence for the presence of heparan sulfate proteoglycan, chondroitin sulfate proteoglycan, dermatan sulfate proteoglycan, and hyaluronan.142, 196, 286, 475, 562 An overproduction and abnormal metabolism of glycosaminoglycans have been, therefore, suggested as one of the key changes in XFS.37, 475 This hypothesis is supported by the finding of higher levels of hyaluronan in the aqueous humor of XFS patients.304

            Lectin histochemical studies have shown a complex mixture of glycoconjugates containing alpha-mannosyl , ß galactosyl , N acetyl D galactosaminyl , N acetyl D glucosaminyl , and terminal sialic acid residues.20, 209-212, 538 Moreover, the HNK 1 epitope, a 3 sulphoglucuronic acid-containing carbohydrate moiety present on many cell adhesion-related glycoproteins, could be demonstrated in intraocular XFM.286, 288, 409, 583, 584 The HNK-1 epitope has been suggested to be involved in the adhesiveness of XFM deposits on intraocular surfaces.288 Kivelä et al249 found HNK-1 positive deposits in the periphery of iris blood vessels of involved and fellow eyes in clinically unilateral XFS, but not in normal control eyes, and suggested an asymmetric rather than a unilateral involvement, supporting previous electron microscopic findings in conjunctival biopsy studies.400, 528 HNK-1 negativity on extraocular XFM aggregates indicates a difference in composition of intraocular and extraocular XFM.288, 409 While XFM from the skin and lens had the same lectin binding characteristics in one study,20 intra  and extraocular XFM deposits appeared to have different carbohydrate composition in others.212, 288, 409

 

Protein Components: The protein components of XFM include both non collagenous basement membrane components such as laminin, nidogen/entactin, and fibronectin256, 266, 475 and epitopes of the elastic fiber system such as alpha-elastin, tropoelastin, fibrillin, amyloid P, vitronectin, and probably the elastin associated glycoprotein gp115/emilin.313, 314, 479, 537, 594 An immunoelectron microscopic study demonstrated fibrillin-1, the main component of elastic microfibrils, on exfoliation fibers and their microfibrillar subunits, often in immediate proximity to cellular surfaces, and suggested an excessive production and abnormal aggregation of fibrillin-containing microfibrils in the extracellular matrix in XFS.487 Other components of elastic microfibrils, the latent TGF-ß-binding proteins LTBP-1 and LTBP-2 were shown to be associated with all XFM deposits in intra- and extraocular locations and to colocalize with latent TGF-ß1 on exfoliation fibers.482 The results suggest a dual role for LTBPs, both as a structural component of exfoliation fibers and as a means of matrix anchorage of latent TGF-ß1 to XFM. The collagen types I, II, III, IV, VI, and VIII are not present, nor are amyloid A, ß-amyloid, amyloid precursor protein, and transthyretin (Schlötzer-Schrehardt U, unpublished data).196, 475, 533 The apolipoproteins A-1, B, E, and LP were also suggested to be associated with XFM.190

 

Biochemical Studies: The only amino acid analysis performed on XFM is compatible with amyloid, non collagenous basement membrane components, and elastic microfibrils, but not with collagen.431 An electrophoretic analysis of extracted lens capsules demonstrated two specific polypeptides with molecular weights of 14.4 and 16.3 kD, the latter of which was faintly present in aqueous humor samples as well.445 The elemental composition of XFM was analyzed by energy filtering transmission electron microscopy and revealed the presence of nitrogen, sulfur, chlorine, and zinc in exfoliation fibers and calcium in the fiber periphery.272

 

Comparison of intra- and extraocular XFM: Despite slight variations in carbohydrate composition,212, 288, 409 both intra- and extraocular exfoliation fibers share epitopes for elastin, vitronectin, fibrillin-1, fibronectin, laminin, nidogen, amyloid P, and heparan sulfate and chondroitin sulfate proteoglycans,21, 479, 487 indicating basic identity of the protein cores and a common underlying pathogenetic process.

 

6.3 Origin of Exfoliation Material

Morphologic studies: Regardless of etiology, typical exfoliation fibers have been demonstrated electron microscopically in close association with the pre-equatorial lens epithelium (Fig. 24 B,C),27, 65, 67, 124, 496, 497 the nonpigmented ciliary epithelium (Fig. 16D),123, 165, 502 the iris pigment epithelium (Fig. 25C),166, 508 the corneal endothelium (Fig 26D),476 the trabecular endothelium (Fig. 27A,B),486 and with almost all cell types of the iris stroma, such as fibrocytes, melanocytes, vascular endothelial cells, pericytes, and smooth muscle cells.26 Based on electron microscopic criteria, the authors suggested a local production of XFM by the various cell types involved. The intraocular XFM, therefore, appears to be multifocally produced, while secondary distribution by the aqueous humor is responsible for passive deposition on the central anterior lens capsule, the zonules, the anterior hyaloid surface and artificial lenses. In extraocular tissues, the typical fibers could be identified in close proximity to fibroblasts, vascular wall cells, smooth and striated muscle cells, and heart muscle cells (Fig. 28A,D).478, 539

            All cell types involved disclose common signs of fibrillogenesis and ultrastructural indications for a local synthesis of exfoliation fibers: 1) The cells are characterized by an irregular surface outline forming extracellular concavities and compartments which contain exfoliation fibers and basement membrane fragments (Fig. 29A/Initial figure 27A/New fig 27 Ursula). 2) The exfoliation fibrils apparently arise perpendicularly from the cell surface interrupting the continuity of the basement membrane (fig. 29B-D). 3) The emerging exfoliation fibers frequently show a “maturation” or aggregation process from microribrils to thicker composite fibers (fig. 29B). 4) Direct cell-fiber contacts are restricted to minute foci characterized by coated pits of the cell membrane (Fig. 29B-D). 5) Clusters of coated cytoplasmic vesicles containing amorphous material fuse with the cell membrane in the region of the concavities and open toward the extracellular space (Fig. 29B,D). 6) The cells involved disclose elaborate secretory organelles, e.g., rough endoplasmic reticulum, giving the appearance of a metabolically activated state (Fig. 29C).

            Comparable ultrastructural features, such as fiber formation within infoldings of cellular surfaces, are known from the secretion of other extracellular matrix elements, e.g., elastic fibers and collagen fibers.

            Exfoliation fibers have never been observed intracellularly, but appear to form extracellularly close to the cell surface. The progressively accumulating XFM successively detaches, destroys, and replaces the normal extracellular matrix, e.g. the basement membranes of the cells, and finally results in degeneration (possibly basement membrane-loss-induced degeneration) of the cells involved.508

            Thus, it appears that a variety of unrelated epithelial and mesenchymal cell types may have a common metabolic lesion resulting in the excessive and disordered synthesis of extracellular fibrillar material at multiple sites.

Although the glycoprotein thrombospondin-1 could not be detected in XFM, iris and corneal stromal fibroblasts were found to express this molecule in XFS specimens, indicating that stromal fibroblasts in XFS are altered at the molecular level.215

 

In Vitro Studies: In search of metabolic defects corresponding to the production of exfoliation fibers, a number of cell culture experiments with tissues from exfoliation patients have been performed. Abnormal fibrils resembling exfoliation fibers could be detected in primary cultures after some time in vitro in association with iris pigment epithelial cells,225, 446 lens epithelial cells,477 and Tenon's capsule fibroblasts.453 However, cultured conjunctival fibroblasts derived from patients with and without XFS, did not show differences in morphology and metabolic behavior as demonstrated by amino acid incorporation.188, 370

 

6.4 Theories of Pathogenesis

            The previous biochemical and (immuno)histochemical approaches toward clarification of the composition of XFM gave rise to three major theories regarding the pathogenesis of XFS:

 

Amyloid Theory: Although there was initially a positive labeling of XFM with a crude anti amyloid A antiserum,444 more sophisticated tests using Congo Red staining109, 358 or monoclonal antibodies against beta-amyloid,433, 540 amyloid A, amyloid precursor protein, thransthyretin (unpublished data), and immunoglobulin light chains109 have yielded negative results. Therefore, although some cases with XFS and primary amyloidosis have been described, the amyloid theory could not be substantiated.342

 

Basement Membrane Theory: Production of XFM has been suggested to result from disturbed basement membrane metabolism, as supported by frequent association of XFM with defective basement membranes of various cell types123, 133, 425 and immunohistochemical evidence of basement membrane epitopes, e.g., laminin, nidogen, and heparan sulfate proteoglycan, in XFM.196, 256, 475

 

Elastic Microfibril Theory: This theory was based on the frequent structural association of exfoliation fibers with components of the elastic system, e.g., zonular fibers and other elastic microfibrils (oxytalan), elastic fibers, and elastotic material, on ultrastructural indications for the development of degenerating elastic microfibrils into XFM, and on similar histochemical staining properties of XFM and zonules.95, 162, 168, 458, 533-535, 553 There is also a marked localized elastosis of the elastic fibers in the lamina cribrosa of XFS eyes.368, 385 This theory was further supported by the immunohistochemical demonstration of various epitopes of elastic components, e.g., elastin, fibrillin, vitronectin, and amyloid P, in XFM.313, 314, 479, 537, 594 In particular, the prominent labeling of microfibrillar subunits of XFM at intra- and extraocular sites for fibrillin-1 and LTBP-1by immunoelectron microscopy indicated excessive production and abnormal aggregation of elastic microfibrils in XFS.482, 487

            Whereas the amyloid theory lacks any conclusive evidence, both the elastic microfibril  and the basement membrane theory appear to describe part of the pathological process.533 Although an abnormal aggregation of elastic microfibrils into exfoliation fibers appears plausible, other extracellular matrix components, such as basement membrane components and glycosaminoglycans, may interact and become equally incorporated into the composite XFM. At present it is still unknown which of the various constituents represent primary products of disordered cellular metabolism or which become secondarily incorporated into the abnormal matrix aggregates. Possible pathogenetic mechanisms include an abnormal stimulus (e.g. growth factors) towards an enhanced expression of matrix components, abnormal glycosylation processes, abnormal enzymatic processes,484 or even a possible genetic defect in any of the involved matrix components.

 

Evidence for an infectious origin: In the Middle Norway eye-screening study, Ringvold et al438 found the prevalence of XFS in both members of 343 married couples (3.2%) to be significantly higher (P=0.022) than one would expect. Ringvold432 also noted a striking morphologic similarity between the fibrillar material of scrapie and the exfoliation fibers, suggesting the possibility of a viral disorder.

            Further evidence for the possibility of an infectious agent comes from reports of younger patients developing XFS after intraocular surgery. A few younger patients (ages 17, 22, 31) have developed XFS years after intraocular surgery or trauma with iris surgery in infancy and childhood.222, 267, 270, 542 There has been an increasing number of reports of younger patients developing XFS after penetrating keratoplasty from elderly donors.222, 270, 292, 471

 

VII. CLINICAL-HISTOPATHOLOGIC CORRELATIONS

7.1 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 disc, clear intermediate zone, peripheral granular zone, preequatorial zone) in manifest XFS, which can be best visualized by scanning electron microscopy (Fig. 30).109, 110 The posterior capsular surface appears normal. The lens capsule itself has been reported to be of normal466 or increased thickness.164

 

Precapsular layer: In up to 70% of patients with clinically diagnosed early exfoliation stages ("exfoliation suspects"), a precapsular layer (0.5 3.5 µm thick) composed of microfibrils (3 6 nm and 8 10 nm in diameter) can be found on the surface of the anterior lens capsule by electron microscopy (Fig. 31A).108, 337, 567 Scanning electron microscopy reveals a delicate microfibrillar network with rolled up edges suggesting loose attachment. This loosely arranged microfibrillar layer does not contain typical exfoliation fibers, but can be immunostained for fibrillin, laminin, and entactin/nidogen.108, 567 Although it may be common in older patients in general, it is suggested to represent a precursor of typical exfoliation accumulations on the lens surface and may be deposited by sedimentation from the aqueous humor. Its occurrence is significantly correlated with clinically observed pigmentary abnormalities of the iris.567

 

Central disc: In the pupillary area, the lens capsule in manifest XFS is covered by a homogenous, matted, fibrillar layer (1.5 3.5 µm thick) that frequently shows rolled up edges suggesting loose attachment (Fig. 31C).109, 110, 497 The underlying lens capsule and lens epithelium appear essentially normal. The central disc, which resembles the precapsular layer of early stages, can be also immunostained for fibrillin537 and consists of loosely arranged microfibrils and scattered single exfoliation fibers that seem to originate by aggregation of the microfibrils (Fig. 31B).114, 485 It is, therefore, suggested that the central disc develops from the central portion of the precapsular layer.485

 

Intermediate zone: This 1-2 mm wide zone discloses a smooth capsular surface that is largely devoid of XFM deposits (Fig. 31D). It develops from abrasion of the preexisting precapsular film by iris movements. The lens capsule is also normal in this region.27

 

Peripheral granular zone: This zone consists of abundant nodular exfoliation aggregates deposited on a continuous fibrillar basal layer (Fig. 31D). This layer often shows centrally rolled up edges and may detach from the capsular surface as a continuous lamella.110 The exfoliation aggregates frequently contain melanin granules. The underlying lens capsule and lens epithelium do not show any alterations. The fibrillar basal lamella is considered analogous to the central disk110 and the exfoliation aggregates appear to be passively deposited on this pre-existing precapsular layer by the iris pigment epithelium.485, 542 The topographic relationship between iris and lens may be also responsible for the formation of a second or even third granular zone central to the first one, containing smaller and less densely packed exfoliation vegetations (Fig. 30). Since the dilating properties of the iris are gradually reduced in exfoliation eyes, the second granular zone is supposed to result from a subsequent deposition of XFM by the posterior iris.485 Occasionally, posterior synechiae form with XFM interposed between the posterior iris surface and the lens capsule.109, 582

 

Preequatorial zone: This region, which is clinically hidden by the iris, may be separated from the granular zone by an inconspicuous agranular zone and is characterized by abundant nodular exfoliation excrescences covering the zonules and their attachment to the anterior lens capsule, the zonular lamella (Fig. 24A). This region corresponds to the proliferative zone of the lens epithelium and displays pathological alterations of the lens epithelium and the lens capsule proper. Intracapsular XFM forms a deep fibrogranular layer that may occupy up to two thirds of the capsule's thickness (Fig. 24B)27, 65, 67, 109 and is in fact arranged in discoid plaques of 10 150 µm diameter.496, 497 This fibrogranular layer contains vertical striations which consist of bundles of exfoliation fibrils, that arise from pit like surface invaginations of the pre-equatorial lens epithelial cells and aggregate within the capsule from 10 15 nm microfibrils to typical exfoliation fibers 18 25 nm in diameter (Fig. 24C). These ultrastructural observations led to the conclusion that the intracapsular XFM is locally produced in this area.65, 67, 109, 164, 496, 497 This active production process by residual lens epithelial cells appears to continue after extracapsular cataract extraction and intraocular lens implantation.551

            The obviously locally produced exfoliation fibers appear to infiltrate and traverse the capsule and seem to erupt through its surface, thereby lifting the zonular lamella off the surface of the capsule (Fig. 24B).483 Futa et al158 showed exfoliation fibrils to continue from the lens epithelial pits to the surface of the lens capsule in serial sectioning. The lens capsule proper discloses a rather loose and lamellar structure in this area.65 The horizontal fibrillar, 50 nm banded capsular inclusions, that are normally present in the preequatorial region of the aging lens capsule, are larger and increased in quantity in exfoliation eyes.123, 164

 

Theories on the origin of lenticular XFM: Historically, the origin of XFM on the surface of the lens was explained by secondary deposition from the aqueous humor86, 132, 547 or from the iris pigment epithelium,123 or by local formation from a degenerating lens capsule or zonular lamella27, 168, 595 or from the epithelium of the germinative zone67 as a source of XFM. Today, the clinical obvious exfoliation deposits in the central and peripheral regions are considered to result from aqueous  and iris derived passive deposition, whereas the clinically invisible material in the preequatorial zone of zonular attachment is actively produced by the lens epithelium.485 The characteristic distribution pattern is primarily created by the topographic relation to the iris, whose contact with the anterior lens capsule deposits granular aggregates in some areas and whose movement rubs material off in others.358

            In addition, disruption of the superficial capsular layers with true delamination of capsular material may occur,65, 109 possibly indicating an occasional coincidence of true exfoliation and (pseudo)exfoliation in the same eye.89, 291

 

7.2 Iris

                        By light microscopy, bush shaped aggregates of XFM cover the surface of the posterior pigment epithelium, which shows atrophic alterations and a characteristic serrated appearance, especially in the periphery (Fig. 25A). By scanning electron microscopy, exfoliation fibers bridge the concentric folds on the posterior iris surface, giving rise to the saw tooth appearance of the pigment epithelium (Fig. 25B). In the anterior border layer, XFM deposition is most common in furrows and crypts and on the pupillary sphincter.

            Numerous transmission electron microscopic studies on iris specimens have demonstrated accumulations of XFM on the posterior pigment epithelium, within the stromal connective tissue and the anterior border layer, and in the walls of stromal blood vessels.22, 123, 166, 245, 265, 425, 426, 429, 443, 502, 506-508, 529 Additional association of exfoliation fibers with stromal melanocytes and smooth muscle cells of sphincter and dilator muscles has been shown in a more recent study.26

            The posterior pigment epithelial cells exhibit marked degenerative changes with focally ruptured cell membranes and liberation of melanin granules, producing transillumination defects and anterior chamber pigment dispersion. Shimizu and Futa508 correlated progressive disruption of the pigment epithelial cells and pigment epithelial basement membrane to the severity of XFS. Exfoliation fibrils appear to be extruded from irregular membrane infoldings and are intermingled with disorganized basement membrane material (Fig. 25C).166, 502 These events may be related to normal aging processes, since some of the changes, such as reduplication of the basal lamina or formation of cell surface invaginations, are also seen in normal iris specimens of older patients.244 Degenerative changes of sphincter and dilator muscle tissues and apparent involvement of the muscle cells in exfoliation fiber formation have been described and may be contributing factors to poor pupillary dilation in eyes with XFS.26

            Stromal XFM deposits are found in close proximity to fibroblasts429 and are particularly prominent in the adventitia of part of the blood vessels.425, 507, 529, 589 The vessels affected show basement membrane abnormalities and a gradual degeneration of vascular wall cells, progressing from adventitial (pericytes, smooth muscle cells) to endothelial cells (Fig. 25D).202, 265 In advanced stages, the vascular wall cells degenerate completely, leaving an acellular vessel wall outlined by a ring of XFM ("ghost vessels"). Obliteration of the lumen by XFM or degenerating endothelial cells in some areas (Fig. 25D) and new vessel formation has been also described.443 These changes may explain the fluorescein angiographic findings of vessel dropout, microneovascularization, and fluorescein leakage. Tracer studies visualized the leakage of endogenous serum proteins through the structurally altered iris vessels into the iris stroma, along the anterior surface of the iris and in the anterior chamber.299 Defects in the barrier integrity, leading to a significant increase in aqueous flare values,290, 293, 294 could be also localized to a lesser extent at the level of the ciliary epithelium.

            Further functional implication of the iris vasculopathy is a significantly reduced oxygen partial pressure in the anterior chamber of eyes with XFS.202 The accompanying tissue hypoxia may contribute to the atrophic changes of the iris stroma and muscle tissues. Subtle ultrastructural alterations, such as XFM deposits in the dilator muscle or accumulations of microfibrils and reduplicated basement membrane material in the periphery of iris vessels, were documented in all contralateral eyes in clinically unilateral XFS.189 These findings support the concept that XFS is a generalized, basically bilateral disease with clinically markedly asymmetric manifestation.

 

7.3 Aqueous Humor

            Johnson and Brubaker237 had found reduced aqueous flow in eyes with exfoliative glaucoma, but later attributed these results to a residual effect of timolol.163

            Functional defects in the blood aqueous barrier integrity are felt to result in altered aqueous humor composition. Total aqueous protein concentrations were significantly higher in eyes with XFS than in eyes with cataract or COAG290, 293, 294 or age-matched controls.254 A high concentration of IgG has been noted in the aqueous humor in exfoliative glaucoma, but not in COAG615 or eyes with cataract.520 Whereas in eyes with XFS without glaucoma only the albumin concentration was increased, albumin and IgG concentrations were significantly higher in eyes with glaucoma, indicating a more severe barrier defect.355 The calculation of the total IgG index ruled out a local IgG production and the possibility of immunological mechanisms in eyes with XFS. Changes in the aqueous levels of alpha1-¬lipoprotein and ceruloplasmin,36 apoprotein-J and cystatin,102 alpha1-antitrypsin,520 one transferrin isoform,254 and cellular and plasma fibronectin592 have been described in XFS. A ferning pattern developing during crystallization of aqueous humor in eyes with XFS was attributed to aggregates of exfoliation material.416

            Electrophoretic analyses of aqueous humor proteins demonstrated a prominent band (MW 12.5 kDa) in aqueous humor and serum of 56% of patients with XFS in one study290 and a weak exfoliation specific band (MW 16.3 kDa) in another.445 Aqueous humor from XFS patients had a 2 5 times higher level of acid phosphatase activity than aqueous humor from normal cataract patients, probably derived from ruptured uveal epithelial cells.348

 

7.4 Zonules and Ciliary Body

            Bush like, feathery depositions of XFM cover the crests of the ciliary processes in the pars plicata of the ciliary body, whereas the posterior half of the pars plana is generally devoid of exfoliation accumulations (Fig. 16B,C). By electron microscopy, the exfoliation fibers appear to emanate from irregular surface invaginations of the nonpigmented epithelial cells and are intermixed with microfibrils and basement membrane fragments (Fig. 16D).123, 165, 502 In a later stage of the disease, some epithelial cells seem to degenerate under the progressively accumulating exfoliation masses.553 No XFM has been found in the stroma or vessel walls of the ciliary body, except at the junction of ciliary muscle with trabecular tissue.442

            Most investigators reported on a normal and intact appearance of the zonular fibers, which were merely coated by easily removable XFM in the pars plicata region (Figs. 16C, 32A).27, 109 However, the zonular fibers of lenses which showed phacodonesis or lens dislocation prior to cataract extraction disclosed marked degenerative changes and fragmentation.156 In lenses with XFS which did not show phacodonesis clinically, the zonules were partially fragmented and covered with XFM, but did not appear to have degenerated.156 Others observed a gradual transition between zonular fibers and XFM.95, 553

            One study explained the clinically observed instability of the zonular fibers by histopathological alterations of the zonular fibers themselves and their impaired anchorage in the defective basement membranes of ciliary body and lens:483 At their origin and anchorage in the ciliary body, the zonular bundles were separated from the disrupted basement membrane of the nonpigmented epithelium by locally produced intercalating XFM (Fig. 32B). The zonular bundles passing alongside the ciliary processes were focally infiltrated by XFM leading to zonular ruptures (Fig. 32C). Zonular disintegration may be facilitated by proteolytic mechanisms, since lysosomal enzymes, particularly cathepsin B, could be immunohistochemically demonstrated within XFM. At their attachment to the anterior lens capsule, the zonular lamella was focally lifted off and ruptured by masses of XFM which seem to propagate from the lens epithelium and erupt through the capsular surface (Figs. 24B, 32D).

 

7.5 Cornea

 

            By light microscopy, some eyes with XFS show focal retrocorneal aggregates of XFM that adhere loosely to the endothelium or are incorporated into Descemet's membrane, forming posterior protrusions or warts (Fig. 26B).476 Whereas the retrocorneal accumulations were previously regarded as aqueous-¬borne depositions (Fig. 26A),544 one recent study provided ultrastructural evidence for a local production of XFM by corneal endothelial cells (Fig. 26D).476 In the affected areas, the endothelial layer appeared irregular and discontinuous with detaching, degenerating endothelial cells that appeared to produce exfoliation fibers. Subsequent reendothelialization of denuded areas of Descemet's membrane by neighbouring fibroblastic endothelial cells led to the incorporation of XFM, cellular debris, and pigment granules into Descemet's membrane (Fig. 26C).

            Rather nonspecific ultrastructural changes of the endothelial cells include rarefaction and thinning of the cells, cytoplasmic vacuolization, focal degeneration and proliferation, phagocytosis of melanin granules, and abnormal extracellular matrix production, e.g., multilamellar basement membrane.476 These changes are consistent with specular microscopic findings of a reduced endothelial cell density and morphologic alterations.84, 252, 347, 495, 590 The resulting corneal endotheliopathy increases the risk of early corneal endothelial decompensation.363, 364 Sampaolesi's line could be histopathologically correlated to aggregates of intracellular melanin granules phagocytosed by the peripheral endothelial cells.472

            A recent study provides clinical and histopathologic evidence of a distinct type of keratopathy in XFS,364 which can be differentiated from Fuchs’ endothelial dystrophy. It is characterized by a diffuse, irregular thickening of Descemet’s membrane, focal accumulations of XFM onto or within Descemet’s membrane, and a prounounced melanin phagocytosis of the rarefied endothelial cells.

 

7.6 Trabecular Meshwork

            XFM has been found by electron microscopy in the intertrabecular spaces, within the trabecular beams, and in the periphery of Schlemm's canal.60, 301, 448, 460, 462, 472 Independent of the presence of glaucoma, and regardless of the fixation procedure, most deposits were found in the juxtacanalicular tissue beneath the inner wall endothelium of Schlemm's canal and in the uveal meshwork, while the corneoscleral portion of the meshwork appeared largely uninvolved.180, 423, 486 Accumulation of XFM was also reported in the periphery of the collector channels branching from Schlemm's canal and of the scleral aqueous veins.486 The XFM accumulation in the trabecular meshwork was suggested to result from a combination of passive deposition in the inner meshwork and local production in the outer portions, as judged by ultrastructural indications.486

            In the uveal meshwork, clumps of XFM are found both within intertrabecular spaces (Fig. 27A) and within the connective tissue cores of the trabecular beams together with multilamellar basement membrane material. The XFM in the uveal meshwork has been suggested to be partly derived from local production by trabecular endothelial cells and partly from the aqueous humor.486 The greatest amounts of melanin are localized in the innermost uveal portions of the meshwork.472 Melanin granules can also be found to a lesser extent in the corneoscleral meshwork, juxtacanalicular tissue, and the walls of Schlemm’s canal, but are generally phagocytosed by trabecular endothelial cells.

            Pathologic changes appear to affect primarily the outer meshwork, however423, 486. In the juxtacanalicular tissue, XFM has been found within vacuole like spaces448 and surface invaginations of the endothelial cells, suggesting local production by the endothelial cells lining Schlemm's canal (Fig. 27B).486 There are no indications for phagocytosis of XFM by endothelial cells or for transport into the lumen of Schlemm's canal resulting in a progressive accumulation of XFM in the subendothelial area. In eyes with advanced exfoliative glaucoma, masses of XFM accumulate along the whole periphery of Schlemm's canal causing a considerable disorganization of the normal tissue architecture, including narrowing and focal collapse of the canal lumen, disruption of its endothelial lining, splitting and fragmentation into smaller channels, and partial obliteration by XFM and detached endothelial cells (Fig. 27C,D).423, 486 Additional changes in glaucomatous eyes, such as thickening of trabecular lamellae, compression of intertrabecular spaces, and accumulation of long spacing collagen448, 472 probably represent nonspecific secondary changes due to high pressure and antiglaucomatous medication.

            Occasionally, proliferating and migrating corneal endothelial cells produce a pretrabecular sheet of abnormal extracellular matrix including exfoliation masses, collagen fibers, and multilamellar basement membrane, that covers the inner surface of the uveal meshwork.133, 235, 486

 

7.7 Extraocular occurrence

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 eye400, 428, 430, 458, 528, 534 and in Tenon’s capsule,509 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 conjunctival stroma in close association with elastic and oxytalan fibers, with elastotic materials, with stromal fibroblasts, and with the adventitia of conjunctival vessels.

 

Orbital tissues: Extraocular exfoliation fibers have been identified by electron microscopy in the walls of posterior ciliary arteries and vortex veins, in extraocular rectus and oblique muscles, in orbital connective tissue septa, in the optic nerve sheaths, and in the walls of the central retinal vessels as they exit the optic nerve.133, 296, 480 The findings could be established both in eyes with typical ocular exfoliation and in clinically uninvolved fellow eyes.480

 

Skin: In 1990, Sugino545 described fibrils structurally resembling XFM in the dermis of the skin of the lateral canthus in three of nine patients and microfibrils indicating the immature form of XFM, but not mature fibrils, in the other six. Similar deposits have been further observed by electron microscopy in eyelid skin (Fig. 28A), even in exfoliation suspects with no evidence of ocular XFM,479 and in skin sites distant from the eye.536 The material was found primarily associated with elastic fibers (Fig. 28B), elastotic materials, collagen fibers (Fig. 28C), and fibroblasts. The finding of XFM in the eyelid skin tissue of suspects indicates that the extraocular development of XFS precedes its clinical appearance within the eye.

 

Visceral organs: Aggregates of XFM were identified by electron microscopy in autopsy specimens of heart (Fig. 28D), lung (Fig. 28E), liver, kidney, gall bladder, and cerebral meninges in two patients with ocular XFS.478, 539 The causes of death were dissecting aortal aneurysm in one case and esophageal rupture in the other. In both, the lung was most affected, followed by heart and liver. 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 (Fig. 28E). In myocardium, the XFM aggregates were closely apposed to the myocardial cells and their interrupted basement membranes (Fig. 28D).

            These findings provide evidence for the systemic nature of XFS, which may involve an abnormal extracellular matrix process of connective tissues throughout the body. Although minor variations in structure and carbohydrate composition of intra- and extraocular XFM exist and full proof of identity is still not available, basic ultrastructural and immunohistochemical similarities support equivalence of the materials and a common pathogenetic mechanism.21, 479, 482, 487 Interestingly, the abnormal extracellular matrix deposits in XFS and Alzheimer’s disease share some components, such as amyloid P, fibrillin, microfibril-associated glycoprotein, and cathepsin B.540

 

VIII. MECHANISMS OF GLAUCOMA DEVELOPMENT

8.1 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 COAG3, 556, 561, 606 or actually causes glaucoma83, 136, 199, 463, 596 has not entirely been laid to rest. The glaucoma associated with XFS is a hypertensive glaucoma associated with an increase in aqueous outflow resistance.163, 237 Glaucomatous visual field damage correlates much better with untreated IOP in exfoliative glaucoma than it does in COAG.568 Johnson and Brubaker237 had found aqueous flow to be reduced by 20% in eyes with exfoliative glaucoma, but these eyes were also being treated with topical medications. In XFS eyes without glaucoma, the same group found no difference in aqueous humor flow between affected, unaffected, and control eyes.163 Exfoliative glaucoma has been almost universally reported as occurring in the presence of an open anterior chamber angle and an anterior chamber of normal depth.4, 55, 309, 325, 556

            Potential mechanisms of glaucoma in XFS include trabecular cell dysfunction, blockage of the meshwork by XFM, blockage of the meshwork by liberated iris pigment, and concomitant COAG. There has been a great deal of argument as to whether the XFM or pigment particles or both block aqueous outflow and lead to elevated IOP.

            Obstruction of the trabecular meshwork either by pigment or XFM or both is generally considered the most likely cause of elevated IOP.199, 261, 281, 333, 451, 596 Traumatic loss of iridolenticular contact may protect against the development of glaucoma.257 Most patients with XFS never develop elevated IOP. Extensive deposits of XFM may be found in the meshwork in the presence of a normal IOP.60 While this latter finding was based on a single trabeculectomy specimen, which may not be representative of the entire meshwork, a relationship between the amount of XFM in the trabecular meshwork and the presence of glaucoma was established in studies examining whole eyes.180, 448, 486 In an electron microscopic-morphometric study of XFS eyes with and without glaucoma, the presence of glaucoma correlated significantly with the amount of XFM in both the total filtration area and the juxtacanalicular tissue, and also with the average thickness of the juxtacanalicular tissue and the mean cross-sectional area of Schlemm’s canal.486 In a larger series of glaucomatous and nonglaucomatous XFS eyes, the amount of XFM correlated with IOP and optic nerve damage.180 Sampaolesi et al472 reported that, while in pigmentary glaucoma the pigment is located throughout the trabecular meshwork, extending to the outer wall of Schlemm’s canal and the collector channels, the pigment particles in XFS, being larger and stickier, are restricted to the inner meshwork.

            Regardless of the fixation technique applied, most XFM has been reported to accumulate in the subendothelial area of Schlemm’s canal and the major pathology appears to involve accumulation of XFM in the juxtacanalicular tissue as well as degenerative changes of Schlemm’s canal and juxtacanalicular area.423, 448, 486 In addition to mechanical obstruction of the meshwork by XFM of extratrabecular origin, active involvement of the trabecular cells in the abnormal extracellular matrix process and local production of XFM by trabecular cells has been suggested as a contributory factor of outflow obstruction,486 although this has been disputed.180 Disorganization of juxtacanalicular tissue and Schlemm’s canal was, however, not observed in XFS eyes with mild or moderate glaucoma and may be associated with advanced disease stages only.180

            The XFM aggregates may serve as a nidus for nonspecific accumulation of serum proteins and thereby further decrease outflow facility. Increased amounts of albumin have been detected immunohistochemically in the trabecular meshwork of XFS eyes.299, 481 Nevertheless, the question remains as to why only some eyes with XFS develop glaucoma. Possible causative factors may be simply the amount of XFM present, interindividual differences in managing the metabolic disturbance, additional predisposing factors, or the factors of time and follow up.

            Exfoliative glaucoma is well differentiated from COAG, not only clinically, but also histopathologically. Whereas a significant increase in juxtacanalicular plaque material459 and a decrease in trabecular meshwork cellularity18 have been reported in COAG, no differences in plaque concentration and cellularity from normal eyes have been found in exfoliative glaucoma.332, 486 These morphometric data indicate fundamental differences in nature of the two entities.

 

            8.2 “Acute” Glaucoma in Exfoliation Syndrome

            Patients with XFS and open-angle glaucoma may present with an external clinical picture mimicking acute ACG, with a red eye, corneal edema, and IOP often over 50 mmHg.83, 173, 174 In one series of 250 patients with XFS and glaucoma, although many patients presented with "acute" glaucoma, only 2 actually had ACG.174 Gillies and Brooks173 described 139 cases of "acute" glaucoma, comprising fully 25% of their patients with XFS and glaucoma. Of these, 86 had open-angle glaucoma, 21 neovascular glaucoma, 14 absolute glaucoma, and 18 acute ACG. In all acute ACG eyes, the anterior chamber depth was ≤2.2 mm, but few cases with acute open-angle glaucoma had a shallow anterior chamber (P<0.001).

 

8.3 Angle-Closure Glaucoma in eyes with XFS

            Until recently, angle-closure glaucoma was considered rare in patients with XFS and was usually thought to be coincidental, only sporadic cases having been reported over the last half century.33, 56, 150, 172, 173, 176, 181, 182, 204, 220, 226, 309, 317, 325, 461, 556, 597 Many authors have found ACG in XFS to be less than or equal to its occurrence in the general population.1 Series from East Asia show a greater proportion of ACG, although the published numbers have been small.300, 609

            Although two important series noted a high incidence of narrow or occludable angles in eyes with XFS,309, 605 the prevalence of XFS in eyes with ACG has only rarely been mentioned and has even been regarded as unusual.325 Of 250 patients with ACG, of whom 215 presented acutely, only 7 had XFS.325 In the same clinic, 19 of 88 patients with open-angle glaucoma had XFS.169 Konstas et al261 performed electron microscopy on iridectomy specimens of 100 patients undergoing trabeculectomy for open-angle glaucoma. All 22 patients with XFS and 4 of 18 XFS suspects had ultrastructural evidence of XFM. As controls, they examined 15 acute and 16 chronic ACG patients. Only one (3.2%) had clinical and pathologic evidence of XFS. More recently, however, Ritch451 found either clinically apparent XFS or XFM on conjunctival biopsy in 17 of 60 (28.3%) consecutive patients with uncomplicated primary ACG or occludable angles. Other small retrospective studies have found associations between XFS and angle-closure or occludable angles.185, 243

 

Etiologic Considerations in Eyes with angle-closure and XFS

            Not only is an association between ACG and XFS not rare, but a number of characteristics of eyes with XFS predispose to the development of ACG. Pupillary block may be caused by a combination of posterior synechiae, increased iris thickness or rigidity, or anterior lens movement secondary to zonular weakness or dialysis.

            Herbst204 was the first to suggest a causal relationship between ACG and XFS in a myopic black patient with bilateral XFS and unilateral ACG, which responded to medical treatment, including pilocarpine, consistent with pupillary block. The angle in the opposite eye was grade III. Franks et al150 reported two cases of acute ACG, one precipitated by pilocarpine and the other developing after central retinal vein occlusion, and suggested zonular weakening causing forward lens movement. Bartholomew56 suggested that posterior synechia formation led to pupillary block. Von der Lippe et al597 described 2 patients with unilateral ciliary block (malignant glaucoma) and bilateral XFS.

            Patients with ACG or occludable angles and XFS tend to be more myopic than those without XFS, men more so than women.451 Eyes with acute ACG are often more myopic than their fellow eyes, reflecting cataract progression and/or a slight forward shift in lens position.326 In a series of 127 eyes with primary ACG, 7 (5.5%) were myopes, of whom 4 had myopia of ≤1 diopter and 42 eyes (33.1%) had hyperopia of ≤1 diopter.326 Anterior chamber depth and volume are smaller in hyperopes than in emmetropes.310

 

Characteristics of Eyes with XFS which Predispose to angle-closure glaucoma

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. Bartholomew56 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 (Figure 36).

            Posterior synechiae predispose to miotic-induced angle-closure glaucoma, the development of which can be further stimulated by zonular weakness. Because the iris is more rigid than normal, aqueous pressure in the posterior chamber causes it to bulge at the weakest point, which is the iris root. This localized bombé narrows the angle, gives a pseudoplateau configuration on gonioscopy, and leads to chronic angle-closure glaucoma. After iridotomy, the angle opens widely, as opposed to true plateau iris, in which the ciliary processes are unusually anterior and maintain the plateau configuration.384, 450

 

Zonular Weakness. The zonules are affected early in the course of XFS. The zonular fibers may separate from their attachments to the ciliary body and lens and produce a characteristic inferior displacement of the lens. 48 Weakening of the zonular support and subsequent laxity of the lens allow it to move anteriorly, predisposing to pupillary block, particularly in the prone position. In extreme cases, the lens may come sufficiently forward to induce ciliary block.597 Miotics may exacerbate both pupillary block and forward movement of the lens-iris diaphragm. Pilocarpine decreases anterior chamber depth and increases lens axial length, even in elderly patients.10-13, 335, 396, 602 Overtreatment with pilocarpine can exacerbate attacks of angle-closure glaucoma that are unresponsive to initial medical treatment.454 Pilocarpine may cause attacks of angle-closure glaucoma.71, 179, 343, 424 Miotic-induced angle-closure is more common in eyes with XFS as opposed to eyes without XFS (unpublished data).

 

 

IX. MANAGEMENT

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

 

9.1 Medical therapy.

            Glaucoma associated with XFS tends to respond less well to medical therapy than COAG, to be more difficult to treat, to require surgical intervention more commonly, and to have a worse prognosis.309

            Although elevated IOP in eyes with XFS was reported to respond less favorably to timolol therapy than in COAG,9 others suggest an equal554 or greater271 ocular hypotensive effect in eyes with exfoliative glaucoma. However, despite a greater initial IOP reduction in the XFS patients, they still had a higher IOP and greater fluctuation in the diurnal IOP curve that patients with COAG. Apraclonidine is additive to timolol and eliminates these differences.263

            Dorzolamide is almost as effective as timolol and also is additive with it.201, 262 Some authors have reported good pressure-lowering effects,376 whereas others have noted a poorer response compared to COAG.557 A greater additive effect of epinephrine with timolol has been reported in XFS than in COAG.376

            Cholinergic agents are effective and probably have a greater additive effect with beta-blockers in XFS than COAG.15 Miotics, however, have multiple beneficial actions in eyes with XFS. Not only do they lower IOP, but by increasing aqueous outflow, they should enable the trabecular meshwork to clear more rapidly, and by limiting pupillary movement, should slow the progression of the disease. Aqueous suppressants, on the other hand, by decreasing aqueous secretion, result in decreased aqueous flow through the trabecular meshwork. Becker58 has presented suggestive evidence that treatment with aqueous suppressants leads to worsening of trabecular function. In organ culture, reduced perfusion results in failure of the meshwork to survive.236 Continued administration of oral acetazolamide produced a reduction in outflow facility and treated and an elevation of IOP to greater than baseline after discontinuation.58

             Theoretically, miotics should be the first line of treatment. However, many patients have nuclear sclerosis and miotics may reduce visual acuity or dim vision sufficiently to create difficulty. The long-term use of miotics may lead to the development of posterior synechiae. The incidence of significant pigment release into the anterior chamber, worsened by the use of miotics,503 is particularly hazardous in XFS. Pilocarpine Ocuserts can achieve excellent reduction of pupillary movement while often maintaining a 3 to 4 mm pupil and are well tolerated by many elderly patients. In one study, 2% pilocarpine drops were significantly less effective in exfoliative glaucoma than in COAG and had a shorter duration of action, while no differences were found using P-40 Ocuserts.79

                       

9.2 Laser surgery. Argon laser trabeculoplasty (ALT) is particularly effective, at least early on, in eyes with XFS.134, 175, 218, 315, 324, 390, 401, 456, 457, 490, 504, 548, 549, 572, 576, 579, 610 The baseline IOP is usually higher than in eyes with COAG undergoing ALT and the initial drop in IOP is greater.213, 411, 449, 578, 579 Postlaser IOP rises have been reported to be higher in eyes with XFS.311 The increased effectiveness may be related to the increased trabecular meshwork pigmentation found in XFS.61 A prospective study of primary ALT with a 2-year follow-up showed a favorable effect of initial laser treatment versus medical treatment with pilocarpine on IOP and progression of glaucomatous damage.62-64 Others have reported a gradual reduction in success over time.184

Long-term success drops to approximately 35-55% at 3-6 years.206, 572, 573

            Prior to the development of apraclonidine, IOP rise of greater than 10 mm Hg were noted to occur in 8-20% of patients.548, 549 Eyes with XFS may have a greater postlaser inflammatory reaction than eyes without.141 Approximately 20% of patients develop sudden, late rises of IOP within the first two years after treatment.455 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. Pohjanpelto391 treated 97 eyes with exfoliation and demonstrated 10 late failures, 2 of which had neovascular glaucoma from unrelated causes. Spaeth and Baez527 reported a 50% failure rate at one year, compared to a 19% rate in COAG.

            Laser iridotomy is the procedure of choice for angle-closure glaucoma. Angle-closure glaucoma caused by anterior lens movement or subluxation may not be cured by iridotomy alone and may require argon laser peripheral iridoplasty to mechanically pull the iris away from the trabecular meshwork.449

 

9.3 Glaucoma surgery. The results of trabeculectomy are comparable to those in COAG. Patients with exfoliative glaucoma have been reported to progress less frequently than those with COAG after surgery.575 However, surgical complications are more common. Markedly elevated preoperative IOP may predispose to choroidal hemorrhage or effusion. Weakened zonular support may allow marked intraoperative anterior lens movement or subluxation, leading to inadvertent lens damage during iridectomy, vitreous loss, or late incarceration of vitreous into the internal ostium. Previously undetected iris neovascularization may lead to intraoperative or delayed hyphema from the surgical iridectomy. Patients with XFS are more likely to have progression of cataract after trabeculectomy.593 These complications probably occur with greater frequency in patients whose disease is more advanced or of longer duration.414

            Intraocular pressure after trabeculectomy has been reported to be lower in eyes with exfoliative glaucoma than in eyes with chronic open-angle glaucoma.261, 397, 500

            Trabeculotomy, performed with the rationale that it may bypass mechanical blockage of the trabecular meshwork, has been reported to be successful.171, 217, 360, 608 Tanihara et al555 examined the effect of trabeculotomy as a primary procedure prospectively (none had had ALT), reporting success rates of 79% at 3 years and 64% at 5 years, with medication. The higher the initial IOP, the less likelihood for success. Along similar lines of reasoning, Jacobi and Krieglstein230, 232-234 have presented a procedure termed trabecular aspiration, designed to improve outflow facility. In 12 patients with medically uncontrolled IOP undergoing trabecular aspiration as a primary procedure, mean IOP of 37.4 mmHg was reduced to a mean of 18.3 mmHg 15 months after surgery, with reduced medications.234 Trabecular aspiration combined with phacoemulsification was significantly more effective than cataract surgery alone in reducing postoperative IOP and the necessity for antiglaucoma medication.231

 

9.4 Cataract surgery. Patients with XFS are elderly and often have coexisting cataract.107 The two proven risk factors for vitreous loss are XFS and insufficient mydriasis.186 Poor dilation is common in XFS.515 Zonular fragility increases the risk of lens dislocation or zonular dialysis up to ten times.177, 223, 356, 387, 515, 613 Vitreous loss has been reported to be 5 times more common than in normal patients (9.0% vs 1.8%)362, 366 This is related to an increased incidence of zonular dialyses, lens dislocation, and capsular rupture.186 Although the posterior capsule is of normal thickness in XFS,67 capsular rupture is more common and has been reported to occur in 27% of XFS eyes as compared to 2% of control eyes.177 This may be related to a degenerate capsule48, 49 or excessive "stickiness" of the remaining cortical material and increased difficulty in irrigation and aspiration.17 A Flieringa ring may decrease the incidence of vitreous loss.366

            Posterior synechialysis or lysis of more peripheral iridocapsular adhesions and pupillary enlargement may be necessary. Because of chronic sphincter fibrosis, it is advisable not to enlarge the pupil as much as possible, since it often will remain dilated, predisposing to pupillary capture. Avoidance of mechanical pressure on the lens is important and the nucleus should be freely rotatable after hydrodissection. An endocapsular fixation ring may be useful in preventing collapse of the capsular bag in areas of weakened zonules. Spontaneous lens displacement, which may not be visible preoperatively, may worsen considerably upon entering the eye or beginning anterior capsulorhexis.515 The presence of subtle iridodonesis or phacodonesis indicates loose or ruptured zonules.515 Cryoextraction is useful for subluxed or dislocated lenses.186

            The choice of intraocular lens is also important in eyes with XFS. Heparin surface modified posterior chamber intraocular lenses (PCIOLs) were found to result in fewer postoperative fibrinoid reactions, less frequent pigment and cellular deposits on the lenses, and a lower incidence of posterior synechia formation than regular polymethylmethacrylate (PMMA) lenses.415, 612 Lens decentration is more common even when the lens is entirely in the capsular bag, primarily due to decentration of the entire bag.31 Subluxation of the IOL can occur if the zonules break or the capsular bag dislocates.412 Posterior chamber lenses my be implanted in the ciliary sulcus despite the presence of a small capsular break or area of zonular dehiscence, provided enough support still exists for the implant.515

            Postoperatively, these patients are at greater risk for developing an immediate elevation of IOP.474 All viscoelastic should be removed from the eye at the time of surgery. Patients with extensive visual field loss or severe glaucomatous optic atrophy should have tonometry performed 4 to 6 hours after surgery and any acute rise in IOP treated.125 Postoperative breakdown of the blood-aqueous barrier is signficantly greater in eyes with XFS.293, 369, 489 Inflammation is more common in eyes with XFS and a transitory fibrinoid reaction may occur.42, 127, 129, 380, 398, 598, 613 A giant cell reaction has been associated with the presence of XFS.328 Long-term protein deposition on intraocular lenses appears to be more common in eyes with XFS, and we prefer to maintain these patients indefinitely on a topical steroid, such as prednisolone acetate, three times weekly.

            The management of glaucoma after cataract surgery usually requires the continued use of antiglaucoma medications. Raitta412 reported good success in controlling IOPs after extracapsular cataract extraction with posterior chamber intraocular lenses in patients that had been controlled preoperatively. Cataract surgery does not seem to shorten the duration of clinical response to prior ALT.474 Combined cataract and glaucoma surgery decreases the incidence of an acute postoperative rise in IOP285 and may improve long-term control of IOP.

            A reduction in IOP after cataract surgery, whether extracapsular or phacoemulsification, with posterior chamber intraocular lens implantation has been well noted. No difference in IOP reduction after phacoemulsification in nonglaucomatous eyes with XFS compared to eyes without has been reported in a small series.604 Eyes with glaucoma had a large reduction of IOP after intracapsular cataract extraction.53

 

X. OVERVIEW AND FUTURE PROGRESS

 A. 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 communication, December, 1999). More studies are needed here and in other Asian and African populations, in which almost no information exists.

            Do genetic differences underlie differences in prevalence rates between ethnic groups within particular countries? For instance, populations of Celtic origin appear to have a much greater prevalence of XFS than neighboring populations. The much higher prevalence in the Isle of Man may reflect the Celtic origin of the Manx, while the mainland of England has similar prevalences to the populations of Germany and Denmark. Ireland has a similarly high prevalence. In France, the prevalence in Brittany, which has a high Celtic admixture and which was also settled by Vikings, is higher than in other areas.

            Do populations which are genetically related have similar prevalences? For instance, the relatedness between distant populations can be determined through similarities in linguistics and HLA antigens.44, 45, 92, 518, 521 Even within countries which are relatively "homogeneous", there are genetic gradients. Zei et al611 investigated surname distributions in Italy in order to reconstruct human migration patterns and observed similarity between spatial patterns of surnames, genes, and dialects. Could such a phenomenon play a role in disease prevalence?

 

 B. Are there subtypes of exfoliation syndrome?

            Why some persons present with unilateral exfoliation and others with bilateral (i.e., asymmetric disease) remains to be explained. Bilateral involvement is not always preceded by unilateral involvement. The percentage of patients going on to develop clinical XFS in the fellow eye is actually quite small when compared to the proportion in most series of persons having unilateral versus bilateral involvement.2, 203, 516 In most series which have looked at the question, there is only a small difference between the mean ages of patients with unilateral and bilateral involvement.

            These data could be explained by the hypothesis that whether one or two eyes are clinically involved early in the disease is influenced by other, still unknown, factors. They are not inconsistent with the hypotheses of either an infectious origin of XFS or a variable role of the immune system in retarding the process in the second eye. It is also possible that subtypes of XFS exist which have different patterns of progression. Meyer et al344 noted variability in distribution patterns of XFM and suggested that genetic variability might underlie these.

 

 C. Development and treatment of glaucoma

            What, if any, predisposing factors exist for the development of glaucoma in eyes with XFS above and beyond interference with aqueous humor outflow? How important is pigment dispersion to the development of glaucoma? Do all patients with moderate pigmentation develop glaucoma or are some either more susceptible or more protected? Does pigment dispersion help to explain the more severe prognosis of the disease? Prospective studies are needed to examine the risk factors more precisely.

            Understanding of the mechanisms leading to elevated IOP could allow us to develop new approaches to therapy. The successful elimination of XFS by inhibiting its production or dissolving or depolymerizing it would eliminate a large percentage of the world’s glaucoma. We cannot yet do that. But we can at the present time immobilize the pupil, preventing progressive pigment liberation. Patients treated medically are more likely to fail than are those with COAG.15, 74, 83, 138, 309, 379 Is this failure in part due to continued pigment liberation while on medical therapy? A prospective randomized trial of treatment to increase aqueous outflow (and also, in the process, immobilize the pupil with miotic therapy) versus aqueous suppression in patients with might elucidate whether inhibition of pupillary movement would decrease the incidence of glaucoma and also provide evidence as to whether or not aqueous suppression worsens the status of the trabecular meshwork over time.

 

 D. Systemic factors: What are the systemic manifestations of XFS? What are the ramifications of finding XFS in a patient and does it portend vascular or other systemic disease? This area has only begun to be explored.

             

 

Method of Literature Search

 

            References have been compiled for nearly 20 years and maintained on the computers of the authors. To our knowledge, this list is virtually complete. Only a few references deemed to be without merit have been omitted. Additional searches were made of MEDLINE from 1976 to 2000 for pseudoexfoliation, exfoliation, capsular glaucoma, and fibrillopathia.

 

 

References

 

 

1.         Aasved H: The geographical distribution of fibrillopathia epitheliocapsularis Acta Ophthalmol 47:792-810, 1969.

 

2.         Aasved H: The frequency of fibrillopathia epitheliocapsularis (so-called senile exfoliation or pseudoexfoliation) in patients with open-angle glaucoma Acta Ophthalmol 49:194-210, 1971.

 

3.         Aasved H: The frequency of optic nerve damage and surgical treatment in chronic simple glaucoma and capsular glaucoma Acta Ophthalmol 49:589-600, 1971.

 

4.         Aasved H: Intraocular pressure in eyes with and without fibrillopathia epitheliocapsularis Acta Ophthalmol 49:601-610, 1971.

 

5.         Aasved H: Mass screening for fibrillopathia epitheliocapsularis Acta Ophthalmol 49:334-343, 1971.

 

6.         Aasved H: Incidence of defects in the pigmented pupillary ruff in eyes with and without fibrillopathia epitheliocapsularis Acta Ophthalmol 51:710-715, 1973.

 

7.         Aasved H: Study of relatives of persons with fibrillopathia epitheliocapsularis (pseudoexfoliation of the lens capsule) Acta Ophthalmol 53:879-886, 1975.

 

8.         Aasved H: Prevalence of fibrillopathia epitheliocapsularis (pseudoexfoliation) and capsular glaucoma Trans Ophthalmol Soc UK 99:293-295, 1979.

 

9.         Aasved H, Seland JH, Slagsvold JE: Timolol maleate in the treatment of open-angle glaucoma Acta Ophthalmol 57:700-708, 1979.

 

10.        Abramson DH, Chang S, Coleman DJ, et al: Pilocarpine-induced lens changes: An ultrasonic biometric evaluation of dose response. Arch Ophthalmol 92:464-468, 1974.

 

11.        Abramson DH, Chang S, Coleman J: Pilocarpine therapy in glaucoma: effects on anterior chamber depth and lens thickness in patients receiving long term therapy. Arch Ophthalmol 94:914-918, 1976.

 

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15.        Airaksinen PJ: The long-term hypotensive effect of timolol maleate compared with the effect of pilocarpine in simple and capsular glaucoma Acta Ophthalmol 57:425-434, 1979.

 

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36.        Baba H: Investigation of the pathogenesis of glaucoma capsulare with special discussion of alpha/1 lipoprotein and ceruloplasmin    in aqeuous humor Graefes Arch Clin Exp Ophthalmol 218:283-286, 1982.

 

37.        Baba H: Histochemical and polarization optical investigation for glycosaminoglycans in exfoliation syndrome Graefes Arch Clin Exp Ophthalmol 221:106-109, 1983.

 

38.        Baba H, Hara K, Migita H: Appearance of gelatinous substance in the anterior chamber in 3 cases of exfoliation syndrome following mydriasis Jpn J Clin Ophthalmol 33:259-263, 1976.

 

39.        Backhaus B, Lorentzen SE: Prevalence of pseudoexfoliation in non-glaucomatous eyes in Denmark Acta Ophthalmol 44:1-4, 1966.

 

40.        Ball SF: Exfoliation prevalence in the glaucoma population of South Louisiana Acta Ophthalmol 66(Suppl 184):93-98, 1988.

 

41.        Ball SF, Graham S, Thompson H: The racial prevalence and biomicroscopic signs of exfoliative syndrome in the glaucoma population of southern Louisiana Glaucoma 11:169-175, 1989.

 

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44.        Barbujani G, Jacquez GM, Ligi L: Diversity of some gene frequencies in European and Asian populations. V. Steep multilocus clines Am J Hum Genet 54:867-875, 1990.

 

45.        Barbujani G, Oden NL, Sokal RR: Detecting regions of abrupt change in maps of biological variables Syst Zool 38:376-389, 1989.

 

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49.        Bartholomew RS: Phakodonesis: a sign of incipient lens displacement Br J Ophthalmol 54:663-668, 1970.

 

50.        Bartholomew RS: Pseudocapsular exfoliation in the Bantu of South Africa. I. Early or pregranular clinical stage Br J Ophthalmol 55:693-699, 1971.

 

51.        Bartholomew RS: Pseudocapsular exfoliation in the Bantu of South Africa.  II. Occurrence and prevalence Br J Ophthalmol 57:41-45, 1973.

 

52.        Bartholomew RS: Spheroidal degeneration of the cornea Doc Ophthalmol 43:325-340, 1977.

 

53.        Bartholomew RS: Effect of cataract extraction on the intraocular pressure in eyes with pseudoexfoliation of the lens Trans Ophthalmol Soc UK 99:312-313, 1979.

 

54.        Bartholomew RS: Incidence of pseudoexfoliation in South African Negroes and Scots Trans Ophthalmol Soc UK 99:299-301, 1979.

 

55.        Bartholomew RS: Anterior chamber depths in eyes with pseudoexfoliation Br J Ophthalmol 64:322-323, 1980.

 

56.        Bartholomew RS: Pseudoexfoliation and angle-closure glaucoma Glaucoma 3:213-216, 1981.

 

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58.        Becker B: Does hyposecretion of aqueous humor damage the trabecular meshwork? (editorial)  J Glaucoma 4:303-305, 1995.

 

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60.        Benedikt O, Roll P: The trabecular meshwork of a non-glaucomatous eye with the exfoliation syndrome, Virch Arch 384:347-355, 1979.

 

61.        Bergeå B: Some factors affecting the intraocular pressure reduction after argon laser trabeculoplasty in open-angle glaucoma Acta Ophthalmol 62:696-704, 1984.

 

62.        Bergeå B, Bodin L, Svedbergh B: Primary ALT vs pilocarpine.  II.  Long-term effects on intraocular pressure and facility of outflow. Study design and additional therapy Acta Ophthalmol 72:145-154, 1994.

 

63.        Bergeå B, Bodin L, Svedbergh B: Primary ALT vs pilocarpine Acta Ophthalmol 73:216-221, 1995.

 

64.        Bergeå B, Bodin L, Svedbergh B: Primary ALT vs pilocarpine. III. Long-term effects on visual fields Acta Ophthalmol 73:207-215, 1995.

 

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