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Ocular and Systemic Manifestations of Exfoliation Syndrome

Ritch, Robert MD

doi: 10.1097/IJG.0000000000000119
Overview
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Exfoliation syndrome is an age-related disease characterized by the production and progressive accumulation of a fibrillar extracellular material in many ocular tissues. It leads to the most common identifiable cause of open-angle glaucoma worldwide, comprising the majority of glaucoma in some countries. The material in the eye appears as white deposits on the anterior lens surface and/or pupillary border. During pupillary movement, the iris scrapes exfoliation material from the lens surface, while the material on the lens causes rupture of iris pigment epithelial cells, with concomitant pigment dispersion into the anterior chamber and its deposition on anterior chamber structures. Exfoliation material can be found in many different organs. It is an ischemic disease and is associated with elevated serum homocysteine. Systemic associations include transient ischemic attacks, hypertension, angina, myocardial infarction, cerebrovascular and cardiovascular disease, aortic aneurysm, Alzheimer disease, and hearing loss. The discovery in 2007 of nonsynonymous single nucleotide polymorphisms in the LOXL1 (lysyl oxidase-like 1) gene are expected to make a major impact not only in understanding exfoliation syndrome, but in leading to new avenues of therapy.

Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY

Disclosure: The author declares no conflict of interest.

Reprints: Robert Ritch, MD, Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, NY 10003 (e-mail: ritchmd@earthlink.net).

Received August 11, 2014

Accepted August 11, 2014

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KEY SYMPTOMS AND SIGNS

Exfoliation syndrome was first described by Lindberg in Finland in 1917.1–3 It is the most common recognizable cause of open-angle glaucoma worldwide.4 All anterior segment structures are involved in exfoliation syndrome (XFS). The diagnosis is made by finding typical white deposits of exfoliation material (XFM) on the anterior lens surface and/or pupillary border. The diagnosis should be suspected in the absence of XFM when ancillary pigment-related signs are present, which define patients as “exfoliation suspects.”5

The classic pattern consists of 3 distinct zones that become visible when the pupil is fully dilated, a central disc, an intermediate clear zone created by the iris rubbing XFM from the lens surface during its normal excursions, and a granular peripheral zone (Figs. 1, 2). XFM is often found at the pupillary border (Fig. 3).

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

Pigment loss from the pupillary ruff and iris sphincter region and its deposition on anterior chamber structures is a hallmark of XFS. As the iris scrapes XFM from the lens surface, the material on the lens causes rupture of iris pigment epithelial cells, with concomitant pigment dispersion into the anterior chamber. This leads to iris sphincter transillumination, loss of the ruff, increased trabecular pigmentation (Fig. 4), and pigment deposition on the iris surface. Pigment dispersion in the anterior chamber is common after pupillary dilation and may be profuse. Marked intraocular pressure (IOP) rises can occur after pharmacologic dilation, and IOP should be measured routinely in all patients after dilation. XFM may be detected earliest on the ciliary processes and zonules, which are often frayed and broken (Fig. 5). Spontaneous subluxation or dislocation of the lens can occur.

FIGURE 4

FIGURE 4

FIGURE 5

FIGURE 5

An increasing number of reported systemic associations include transient ischemic attacks, hypertension, angina, myocardial infarction, stroke, asymptomatic myocardial dysfunction, Alzheimer disease, and hearing loss.6–12 Some of these associations have been disputed and there is yet no clear evidence of increased mortality in patients with XFS, which one might expect with these associations, nor has there been shown a clear-cut association of XFS with a systemic disease with conclusive evidence of a functional deficit caused by the presence of XFS.

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EPIDEMIOLOGY (INCIDENCE, PREVALENCE, AGE/SEX DISPOSITION)

The prevalence of XFS increases steadily with age in all populations. The reported prevalence both with and without glaucoma has varied widely, reflecting true differences due to racial, ethnic, or other as-yet-unknown factors; the age and sex distribution of the patient cohort or population group examined; the clinical criteria used to diagnose XFS; the ability of the examiner to detect early stages and/or more subtle signs; the method and thoroughness of the examination; and the awareness of the observer.13 It comprises as much as ≥50% of the open-angle glaucoma in some countries, including Norway, Ireland, Greece, and Saudi Arabia. Previously thought rare in Africa, recent reports indicate that it comprises 25% of open-angle glaucoma in Ethiopia14 and in South African Zulus.15 In the United States, it is much more common in whites than in persons of African ancestry, comprising about 12% of glaucoma populations.16–18 There are ethnic variations within countries and geographic variations even within adjacent towns in the same area.19 In central Norway, the prevalence in 2 adjacent towns (20%) was twice that in a third, adjacent town. In Nepal, XFS was found in 12% of members of 1 ethnic group, the Gurung, and only 0.24% of non-Gurung of similar ages.20 Although common in Japan and Mongolia, it is rare in Southern China.21

The prevalence of XFS in glaucoma patients is significantly higher than in age-matched nonglaucomatous populations. Approximately 25% of XFS patients have elevated IOP and one third of these have glaucoma. This is approximately 6 times the chance of finding elevated IOP in eyes without XFS. It has been estimated (Lindberg Society) that clinically detectable XFS affects approximately 60 to 70 million people, so that there should be some 5 to 6 million persons with exfoliation glaucoma (XFG) or nearly 10% of the world’s glaucoma.

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DEVELOPMENT OF GLAUCOMA

Friction between the iris and the lens surface leads to disruption of the iris pigment epithelium at the sphincter region and concomitant dispersion of pigment into the anterior chamber. Blockage of aqueous outflow by a combination of pigment and XFM deposited in the intertrabecular spaces, and XFM in the juxtacanalicular meshwork, and beneath the endothelium of Schlemm’s canal is believed to be the major cause of elevated IOP.

Increased outflow resistance both in the trabecular meshwork and in the uveoscleral pathways,22 most probably from blockage of the outflow channels by XFM, leads to elevated IOP. Aggregates of XFM are found in the anterior portions of the ciliary muscle, on the inner surface of the trabecular meshwork, beneath the inner and outer wall of Schlemm’s canal, and in the periphery of intrascleral aqueous collector channels and aqueous veins.23 Accumulation of XFM in the meshwork may derive from both passive deposition from the aqueous on the surface of the uveal meshwork and local production by trabecular and Schlemm’s canal endothelial cells in the juxtacanalicular tissue and canal wall. Progressive accumulation of XFM in the subendothelial space leads to a marked thickening of the juxtacanalicular tissue, the site of greatest resistance to aqueous outflow. Concomitant disruption and breakdown of the normal elastic fiber network surrounding Schlemm’s canal appears to result in a progressive destabilization and disorganization of the normal tissue architecture. Collapse of aqueous veins due to perivascular accumulation of elastotic material can also occasionally be observed.

The amount of XFM within the juxtacanalicular region correlates with the presence of glaucoma, the average thickness of the juxtacanalicular tissue, and the mean cross-sectional area of Schlemm’s canal, and also with the IOP level and the axon count in the optic nerve.23,24 These findings suggest that therapeutic efforts to improve outflow need to address the alterations in the juxtacanalicular area to obtain lasting IOP reduction.

In addition to XFM and pigment obstruction of the meshwork, increased aqueous protein concentrations, and cellular dysfunction may also contribute to elevated IOP. Several members of the phospholipase A2 enzyme family, which play a major role in phospholipid metabolism and membrane homeostasis, are significantly decreased in the trabecular meshwork of XFG patients compared with normal controls or primary open-angle glaucoma (POAG) patients.25 These observations may indicate abnormal physiological functions, decreased structural stability and flexibility, and reduced protection against oxidative stress in trabecular meshwork cells of XFG eyes.

Increased trabecular pigmentation is a prominent and early sign of XFS. In patients with clinically unilateral XFG, the pigment is usually denser in the involved eye. Eyes with POAG or eyes without glaucoma tend to have less pigmentation than eyes with XFG. Glaucomatous damage is usually more advanced in the eye with greater pigmentation. Pigment dispersion and deposition in the trabecular meshwork may lead to acute pressure rises after pupillary dilation.

Although XFG is characteristically a high-pressure disease with a predominant mechanical component of optic nerve damage, pressure-independent (eg, vascular) risk factors, and structural alterations of the lamina cribrosa may further increase the individual risk for glaucomatous damage. In a prospective study, patients with clinically unilateral involvement, in whom IOP was equal throughout the follow-up period, disk changes took place only in the involved eye, suggesting that the exfoliative process itself may be a risk factor for optic disk changes.26 Marked elastosis in the connective tissue sheets of the lamina cribrosa of XFS eyes may adversely affect tissue elasticity and increase the susceptibility of optic nerve fibers toward mechanical and vascular damage.27,28 Moreover, accumulation of XFM in the walls of retrobulbar vessels increased the rigidity of their walls.29 The recently identified sequence variants in the LOXL1 gene and reduced tissue levels of LOXL1, a key enzyme in elastic fiber homeostasis, may predispose to these elastotic matrix processes characterizing XFS and possibly contribute to glaucoma development in XFS patients.

Angle closure is also associated with XFS. Ritch30 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. 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.

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PROGNOSIS

The prognosis of XFG is more severe than that of POAG. Patients with XFS are twice as likely to convert from ocular hypertension to glaucoma and when glaucoma is present, to progress.31,32 The mean IOP is greater in normotensive patients with XFS than in the general population and greater in XFG patients at presentation than in POAG patients. At any specific IOP level, eyes with XFS are more likely to have glaucomatous damage than are eyes without XFS. There is greater 24-hour IOP fluctuation, greater visual field loss and optic disc damage at the time of detection, poorer response to medications, more rapid progression, greater need for surgical intervention, and greater proportion of blindness.33

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GENETICS AND GENETIC RISK FACTORS

Several lines of evidence, including regional clustering, familial aggregation, and genetic linkage analyses, had previously supported a genetic predisposition to XFS.34 Recently, a genome-wide association study detected 2 common single nucleotide polymorphisms (SNPs) in the coding region of the lysyl oxidase-like 1 (LOXL1) gene on chromosome 15q24 were specifically associated with XFS and XFG in 2 Scandinavian populations from Iceland and Sweden, accounting for virtually all XFS cases.35 These disease-associated polymorphisms appeared to confer risk of glaucoma mainly through XFS. The combination of alleles formed by the 2 coding polymorphisms determined the risk of developing XFG, which is increased by a factor of 27 if the high-risk haplotype is present. Individuals carrying 2 copies of this high-risk haplotype would have a 700 times increased risk of developing XFG. Moreover, these genetic alterations also lead to decreased tissue expression of LOXL1 dependent on the individual haplotype. These genetic findings have been confirmed in populations of European descent in Iowa,36 New York,37 Utah,38 Boston,39 and Australia.40 One different SNP and 1 common SNP have been reported in a Japanese population.41 The LOXL1 gene variations are not associated with POAG or primary angle closure.42

LOXL1 is a member of the lysyl oxidase family of enzymes, which are essential for the formation, stabilization, maintenance, and remodeling of elastic fibers and prevent age-related loss of tissue elasticity.43 It is involved in cross-linking tropoelastin to mature elastin using elastic microfibrils as a scaffold,44 thus serving both as a cross-linking enzyme and a scaffolding element which ensures spatially defined elastin deposition.45 The functional consequences of the LOXL1 gene variants in XFS are not yet known; however, inadequate tissue levels of LOXL1 could predispose to impaired elastin homeostasis and to increased elastosis. Genetic variation in LOXL1 may be a factor in spontaneous cervical artery dissection, a cause of stroke in younger patients.46 Reduced LOXL1 levels are also found in patients with varicose veins and venous insufficiency.47 Overactivity of lysyl oxidase, with localization of the enzyme in blood vessel walls and in plaque-like structures, has been found in Alzheimer disease.48 Mice deficient in LOXL1 develop pelvic organ prolapse secondary to a generalized connective tissue defect,49 and women with prolapse have reduced mRNA for LOXL1.50 Marked elastosis with elastic fiber degeneration has been observed in the skin and connective tissue of the lamina cribrosa in XFS eyes.27 Although further studies correlating the genetic variants and tissue alterations associated with XFS are needed, these new findings already provide a basis for both genetic testing and novel treatment approaches.

Various nongenetic factors, including dietary factors, autoimmunity, infectious agents, and trauma, have also been hypothesized to be involved in the pathogenesis of XFS. Reports dealing with sunlight exposure (ultraviolet radiation) are conflicting. Eskimos are the only people reported to have no XFS, but it is common in Lapps living at the same latitude.51 Persons living at lower latitudes develop XFS at younger ages, whereas those living at higher altitudes had a greater prevalence in 2 series52,53 but not in a third.54 In 1 series, XFS was detected more frequently in eyes with blue irides versus brown irides.55 Herpes simplex virus type I was detected by polymerase chain reaction in 13.8% of iris and anterior capsule specimens of patients with XFS compared with 1.8% of controls.56 Younger patients have developed XFS after penetrating keratoplasty using buttons from elderly donors.57–60 Altogether, it appears that XFS represents a complex, multifactorial, late-onset disease, involving both genetic and nongenetic factors in its pathogenesis.

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TREATMENT OF EXFOLIATIVE GLAUCOMA

The sole focus of therapy in XFG should not be the reduction of IOP. Understanding the mechanisms leading to elevated IOP in XFS could allow us to develop new and more logical approaches to therapy.

Most ophthalmologists approach medical treatment with topical prostaglandin analogues and aqueous suppressants. In addition to lowering IOP, prostaglandin analogues may interfere with the disease process. Latanoprost treatment had a marked effect on the aqueous concentration of TGF-ß1, MMP-2, and TIMP-2 in XFG patients.61 Aqueous suppressants do not interfere with the mechanism of pigment liberation and trabecular blockage. Cholinergic agents, in contrast, not only lower IOP, but by increasing aqueous outflow, should enable the trabecular meshwork to clear more rapidly, and by limiting pupillary movement, should slow the progression of the disease. Aqueous suppressants result in decreased flow through the trabecular meshwork. Treatment with aqueous suppressants may lead to worsening of trabecular function.62 Pilocarpine 2% qhs can provide sufficient limitation of pupillary mobility without causing visual side effects. A prospective trial (International Collaborative Exfoliation Syndrome Treatment Study) comparing latanoprost and 2% pilocarpine qhs versus timolol/cosopt for patients with XFS and ocular hypertension or glaucoma has been completed and the data are currently being analyzed.

Argon laser trabeculoplasty (ALT) is particularly effective, at least early on, in eyes with XFS. Approximately 20% of patients develop sudden, late rises of IOP within 2 years of treatment.63 Continued pigment liberation may overwhelm the restored functional capacity of the trabecular meshwork, and maintenance miotic therapy (again 2% pilocarpine qhs) to minimize pupillary movement after ALT might counteract this. Selective laser trabeculoplasty needs further evaluation as an effective and safe alternative to ALT in the treatment of XFG.

Trabeculectomy results are comparable with those in POAG. Trabeculotomy is also successful.64 Jacobi et al65 described a procedure termed trabecular aspiration, designed to improve outflow facility by eliminating the trabecular blockage by pigment and XFM. Deep sclerectomy and similar procedures including a deroofing of Schlemm’s canal are becoming popular choices in some centers owing to the reduced risk profile of nonpenetrating surgery. In 1 series, XFG patients had significantly better success than POAG patients following deep sclerectomy with an implant.66 Moreover, phacoemulsification combined with penetrating and nonpenetrating procedures does not seem to adversely influence success rate.

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PATHOGENESIS OF XFS AND EXFOLIATIVE GLAUCOMA

The precise etiology and pathogenesis of XFS remain unknown. However, the pathologic process in intraocular and extraocular tissues is characterized by the progressive accumulation of an abnormal fibrillar matrix, which is either the result of an excessive production or an insufficient breakdown or both, and which is regarded as pathognomonic for the disease based on its unique light microscopic and ultrastructural criteria.

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ULTRASTRUCTURE AND COMPOSITION OF XFM

Exfoliation fibers are clearly distinguishable from any other known form of extracellular matrix. Light microscopy reveals XFM to be PAS-positive, eosinophilic, bush-like, nodular, or feathery aggregates on the surfaces of anterior segment tissues. On transmission electron microscopy, the aggregates consist of randomly arranged, fuzzy fibrils, 25 to 50 nm in diameter, frequently with 20 to 25 or 45 to 50 nm cross-banding. These composite fibers are generally associated with 8 to 10 nm microfibrils, which resemble elastic microfibrils and which aggregate laterally into mature fibers. However, a coating of electron-dense amorphous material usually hides the microfibrillar core of complex fibers.

The exact chemical composition of XFM remains unknown. Indirect histochemical and immunohistochemical evidence suggests a complex glycoprotein/proteoglycan structure composed of a protein core surrounded by abundant glycoconjugates, including various glycosaminoglycans (heparin sulfate, chondroitin sulfate, hyaluronan) indicating excessive glycosylation.67 The protein components contain epitopes of the elastic fiber system, such as elastin, tropoelastin, amyloid-P, and vitronectin.68 Components of elastic microfibrils, such as fibrillin-1, microfibril-associated glycoprotein (MAGP-1), and the latent TGF-ß binding proteins (LTBP-1 and LTBP-2), are associated with XFM deposits in intraocular and extraocular locations and colocalize with latent TGF-ß1 on exfoliation fibers.69–72

A recent direct analytical approach by using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) showed XFM to consist of the elastic microfibril components fibrillin-1, fibulin-2, and vitronectin, the proteoglycans syndecan and versican, the extracellular chaperone clusterin, the cross-linking enzyme lysyl oxidase, and some other proteins, confirming many of the previously reported immunohistochemical data.72 Together, these findings support the notion that XFM represents an elastotic material arising from abnormal aggregation of elastic microfibril components interacting with multiple ligands.

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ORIGIN OF XFM

Ocular XFM is closely associated with the nonpigmented ciliary epithelium, preequatorial lens epithelium, iris pigment epithelium, trabecular and corneal endothelia, and virtually all cell types in the iris stroma and vasculature, all showing signs of active fibrillogenesis.33,73 Passive distribution of XFM by the aqueous humor may be responsible for abnormal deposits on the central anterior lens capsule, the zonules, the anterior hyaloid surface, vitreous, and intraocular lenses. In extraocular locations, fibers are found in close proximity to connective tissue fibroblasts, vascular wall cells, smooth and striated muscle cells, and cardiomyocytes.74,75

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MOLECULAR PATHOGENESIS

Differential Gene Expression

With gene expression analyses, XFS tissues contain a number of differentially expressed genes that were mainly involved in extracellular matrix metabolism and in cellular stress.76,77 One set of genes consistently upregulated in anterior segment tissues comprised the elastic microfibril components fibrillin-1, LTBP-1, and LTBP-2, the cross-linking enzyme transglutaminase (TGase)-2, tissue inhibitor of matrix metalloproteinase (TIMP)-2, transforming growth factor (TGF)-ß1, several heat shock proteins (Hsp 27, Hsp 40, Hsp 60), proinflammatory cytokines, apolipoprotein D, and the adenosine receptor (AdoR)-A3. Genes reproducibly downregulated in XFS tissues included TIMP-1, the extracellular chaperone clusterin, the antioxidant defense enzymes glutathione-S-transferases (mGST-1, GST-T1), components of the ubiquitin-proteasome pathway (ubiquitin-conjugating enzymes E2A and E2B), several DNA repair proteins (ERCC1, hMLH1, GADD 153), the transcription factor Id-3, and serum amyloid A1.

Together, these findings provide evidence that the underlying pathophysiology of XFS is associated with an excessive production of elastic microfibril components, enzymatic cross-linking processes, overexpression of TGF-ß1, a proteolytic imbalance between MMPs and TIMPs, low-grade inflammatory processes, increased cellular and oxidative stress, and an impaired cellular stress response, as reflected by the downregulation of antioxidative enzymes, ubiquitin-conjugating enzymes, clusterin, and DNA repair proteins.

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PATHOGENETIC FACTORS AND KEY MOLECULES

Factors which might stimulate the synthesis and stable deposition of XFM include growth factors, a dysbalance of MMPs and TIMPs, and increased cellular and oxidative stress conditions.

Apart from increased concentrations of various growth factors (basic-fibroblast growth factor, hepatocyte growth factor, connective tissue growth factor, TGF-ß1) in the aqueous humor of XFS patients,78,79 TGF-ß1, a major modulator of matrix formation in many fibrotic diseases, appears to be a key mediator in the XFS process. It is significantly increased in the aqueous humor of XFS patients, both in its latent and active form, it is upregulated and actively produced by anterior segment tissues, and it regulates most of the genes differentially expressed in XFS eyes, for example, fibrillin-1, LTBP-1 and LTBP-2, tissue transglutaminase-2, and clusterin.80,81 Binding of TGF-ß1 to XFM via the TGF-ß binding proteins LTBP-1 and LTBP-2 may represent a mechanism of regulation of growth factor activity in XFS eyes. Whereas the TGF-ß3 isoform was also reported to be significantly increased in aqueous humor of XFS patients,82 levels of TGF-ß2 were significantly higher in the aqueous humor of POAG patients but not of XFS patients.

Changes in the local MMP/TIMP balance and reduced MMP activity in aqueous humor and tissues may further promote abnormal matrix accumulation in XFS. Significantly increased concentrations of MMP-2, MMP-3, TIMP-1, and TIMP-2 were detected in aqueous humor of XFS patients with and without glaucoma compared with controls.83,84 However, levels of endogenously active MMP-2, the major MMP in human aqueous humor, were significantly decreased as was the ratio of MMP-2 to TIMP-2, resulting in a molar excess of TIMP-2 over MMP-2. An imbalance of MMPs and TIMPs has been also reported in meshwork specimens from XFG patients.85

There is increasing evidence that cellular stress conditions (oxidative, ischemia/hypoxia) are involved in the pathobiology of XFS. Significantly reduced levels of antioxidants (ascorbic acid, glutathione) and increased levels of oxidative stress markers (8-isoprostaglandin-F2α, malondialdehyde) in aqueous humor, serum, and tissues indicate a faulty antioxidative defense system and increased oxidative stress in the anterior chamber of XFS eyes.86–90

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VASCULAR ABNORMALITIES IN XFS

An emerging clinical spectrum of associations with cardiovascular and cerebrovascular diseases elevates XFS to a condition of general medical importance. XFS is associated with ocular ischemia, particularly iris hypoperfusion and anterior chamber hypoxia,91 and with a reduced ocular and retrobulbar microvascular and macrovascular blood flow occurring both in patients with and without glaucoma.92 Blood flow of the lamina cribrosa and neural rim decreases with increasing glaucomatous damage.93 In clinically unilateral cases, ipsilateral pulsatile ocular blood flow and carotid blood flow are reduced.94,95 Recently, pathologic carotid artery function as well as altered parasympathetic vascular control was reported.96 In a large study, XFS was reported to be an important risk factor for coronary artery disease.97

The vasoactive peptide endothelin-1 is significantly increased in the aqueous of XFS patients,98 whereas levels of nitric oxide, a potent physiological vasodilator, were decreased in a small number of XFS patients.99 This imbalance may play a role in the obliterative vasculopathy of the iris causing local ischemia early in the disease process. Elevated homocysteine levels in the aqueous humor of patients with XFS100,101 may further contribute to ischemic alterations, such as endothelial dysfunction, oxidative stress, enhancement of platelet aggregation, reduction of nitric oxide bioavailability, and abnormal perivascular matrix metabolism. These findings have been summarized in a recent editorial.102

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Keywords:

exfoliation syndrome; glaucoma; pigment; homocysteine; LOXL1; epidemiology

© 2014 by Lippincott Williams & Wilkins.