Pseudoexfoliation Syndrome (Pseudoexfoliation Glaucoma) 

Updated: Oct 23, 2018
Author: Mauricio E Pons, MD; Chief Editor: Inci Irak Dersu, MD, MPH 



In 1917, a Finnish ophthalmologist named Lindberg first described pseudoexfoliation syndrome. This entity is characterized by flakes of granular material at the pupillary margin of the iris and throughout the inner surface of the anterior chamber. It is also associated with secondary open-angle glaucoma, known as pseudoexfoliation glaucoma, which is the most common identifiable form of secondary open-angle glaucoma worldwide. Dvorak-Thebold suggested the term pseudoexfoliation to differentiate it from true exfoliation or lamellar delamination of the lens capsule found in glassblowers. True exfoliation syndrome is due to heat or infrared-related changes in the anterior lens capsule.


Pseudoexfoliation syndrome is a common ocular manifestation of a systemic disease, known to cause disease primarily in the eye. Exact etiology of this condition remains unknown.

Pseudoexfoliation material is associated with abnormalities of the basement membrane in epithelial cells and has a wide distribution throughout the body. Pseudoexfoliative material has been found in the walls of the vortex veins and the central retinal artery. Extraocular tissues involved include lung, skin, liver, heart, kidney, gallbladder, blood vessels, extraocular muscle, connective tissue in the orbit, and meninges. In the anterior segment of the eye, it is characterized by deposition of pseudoexfoliative amyloidlike material on the anterior lens capsule, ciliary body, zonules, pupillary margin of the iris, corneal endothelium, anterior vitreous, and trabecular meshwork.

Some investigators believe that the iris pigment epithelium, the ciliary epithelium, and the peripheral anterior lens epithelium produce this pseudoexfoliative amyloidlike material, which moves into the aqueous humor and is carried to the trabecular meshwork, following the normal flow. Obstruction of the trabecular meshwork by this fibrillar material and pigment associated with degenerative changes in the Schlemm canal and the juxtacanalicular area causes elevation of the intraocular pressure (IOP) with associated glaucoma.

Zenkel et al have studied genes differentially expressed in anterior segment tissues and have postulated that pseudoexfoliation syndrome is a stress-induced elastic microfibrillopathy.[1]



United States

Roth and Epstein reported that pseudoexfoliation glaucoma was present in 12% of patients with glaucoma.[2] Kozart and Yanoff reported that glaucoma was present in 7% of 100 consecutive patients with pseudoexfoliation syndrome in Philadelphia.[3] In the Framingham study, prevalence of pseudoexfoliation syndrome was 1.8%. In a prospective study, Cashwell and Shields found that the prevalence of pseudoexfoliation syndrome in the southeastern United States was 1.6% of the total population and in 6% of an open-angle glaucoma subpopulation.[4] Prevalence of pseudoexfoliation syndrome in the glaucoma population of south Louisiana was found to be 2.7% in white patients and 0.4% in African American patients. Karger et al determined that the incidence of newly diagnosed pseudoexfoliation syndrome in residents of Olmsted County, Minnesota, was 25.9 cases per 100,000 population.[5]

Because of the increased mean age of populations, pseudoexfoliation syndrome may become more prevalent in the future.


Prevalence of pseudoexfoliation syndrome in Europe was found to be 4.7% in England, 6.3% in Norway, 4% in Germany, 1.1% in Greece, and 5.5% in France.

Bartholomew reported an 8.2% prevalence of pseudoexfoliation syndrome in the Bantu tribes of South Africa.[6] The prevalence in a Japanese population was 3.4%, 3.5% in Saudi Arabia,[7] and 3.73% in a South Indian study.[8] Hospital-based studies showed a prevalence of 6.45% in Pakistan and 7.4% in India. A prevalence rate of 0.4% was identified in China and Iran.[9]

According to the Early Manifest Glaucoma Trial, pseudoexfoliation increases the risk of progression of early glaucoma over two-fold.[10]  


In a retrospective study, Shrum et al found no association between ocular pseudoexfoliation and cardiovascular or cerebrovascular mortality.[11] Ekström and Kilander studied the association of pseudoexfoliation and Alzheimer disease and did not find an increased risk.[12]  

Serum levels of uric acid, alanine aminotransferase, and hemoglobin and red blood cell counts are similar in subjects with and without pseudoexfoliation.[13] However, other authors have found that pseudoexfoliation is linked with Alzheimer disease, senile dementia, cerebral atrophy, chronic cerebral ischemia, stroke, transient ischemic attacks, heart disease, and hearing loss.[14] Vessani et al found that homocysteine levels were higher among patients with pseudoexfoliation syndrome and pseudoexfoliative glaucoma compared with controls.[15] Roedl et al reported increased homocysteine concentrations in tear fluid and plasma of patients with pseudoexfoliation glaucoma.[16] Elevated plasma homocysteine levels have been described as a risk factor for cardiovascular disease. 

Erectile dysfunction may be associated owing to accumulation in vessel walls.[17]


Although it occurs in virtually every area of the world, a considerable racial variation exists in the incidence of pseudoexfoliation glaucoma.

In Scandinavian countries, more than 50% of cases of open-angle glaucoma are caused by pseudoexfoliation syndrome.

Pseudoexfoliation syndrome is relatively rare among African Americans and Eskimos. It was not observed at all in the Inuit who live throughout the Canadian Arctic.

Prevalence is high in the Sami people who are indigenous of northern Europe.

Among the Bantu tribes of South Africa, exfoliation was found in 19% of patients in a glaucoma clinic.

There is a high prevalence of pseudoexfoliation syndrome in Arabic populations. In Saudi Arabia, Summanen and Tonjum reported a prevalence of pseudoexfoliation syndrome of 13%.[18] It has been found to be the cause of half the cases of glaucoma in Oman.[19]

Prevalence of pseudoexfoliation syndrome in Spanish Americans in New Mexico was estimated to be 3-6%.


Pseudoexfoliation syndrome is more common in females than in males. In a series by Kozart and Yanoff, pseudoexfoliation syndrome was 3 times more common in women than in men.[3]


Pseudoexfoliation syndrome is rarely seen before age 50 years, and its incidence increases steadily with age.

In Norway, Aasved reported that the prevalence of pseudoexfoliation was 0.4% in individuals aged 50-59 years and 7.9% in individuals aged 80-89 years.[20] The reported mean age of pseudoexfoliation syndrome ranges from 69-75 years.

Jonasson et al reported a 10% annual increase for both open-angle glaucoma and pseudoexfoliation in persons aged 50 years and older in Iceland.[21]

Intraocular pressure increases slightly with age in patients with pseudoexfoliation.[22]


Most investigators agree that the prognosis for pseudoexfoliation glaucoma is worse than that for primary open-angle glaucoma because of higher IOP levels, rapid progression, and more severe optic nerve damage and visual field defects.

Brinchmann-Hansen et al reported that the response to pilocarpine treatment was less effective in controlling the IOP in patients with pseudoexfoliation glaucoma than in patients with open-angle glaucoma.

Pseudoexfoliation glaucoma patients are more likely to require laser trabeculoplasty or filtering procedures.

Patient Education

For excellent patient education resources, visit eMedicineHealth's Eye and Vision Center. Also, see eMedicineHealth's patient education articles Glaucoma Overview, Glaucoma Medications, and Glaucoma FAQs.




Patients may be asymptomatic, or they may complain of decreased visual acuity secondary to cataract or glaucomatous visual field changes.


Pseudoexfoliation syndrome is diagnosed clinically by slit lamp examination with an 85% sensitivity rate and a 100% specificity rate.

Pseudoexfoliative material can be seen on the pupillary border of the iris without dilation. Pseudoexfoliative material is seen in the image below.

Pseudoexfoliative material can be seen in this eye Pseudoexfoliative material can be seen in this eye with pseudoexfoliation glaucoma. Courtesy of S. Fabian Lerner, MD.

The most commonly recognized feature is the 3-ring sign on the anterior lens capsule, formed by a central disk, a peripheral ring, and a clear zone, which separates the two. The clear zone varies in diameter and may exhibit curled edges.

The central disc measures 1-2.5 mm in diameter and has well-demarcated borders.

The peripheral ring typically is seen after pupillary dilation. Its size is variable, and its inner border has many radial striations.

The translucent zone most likely is created by the physiologic rubbing of the posterior surface of the iris against the lens. It scrapes the pseudoexfoliative material from the surface of the lens. This scraping results in a secondary pigmentary dispersion syndrome, with a loss of melanin from the iris pigment epithelium at the pupillary margin adopting a sawtooth-like morphology. Accumulation of melanin granules in the trabecular meshwork ensues. Peripupillary iris atrophy is a common and distinctive finding. It is best visualized using infrared transillumination.

Gonioscopy shows a discontinuous pigmentation of the trabecular meshwork, usually less dense than seen in pigmentary glaucoma. Also, pigment characteristically is deposited on the Schwalbe line or anterior to the Schwalbe line (the Sampaolesi line). A high incidence of narrow, or occludable, angles in eyes with pseudoexfoliation has been reported.

Elevated IOP leads to glaucoma development in about 50% of patients. Puska et al reported that the conversion rate from pseudoexfoliation syndrome to pseudoexfoliation glaucoma was 3.2% per year.[23] Jeng et al found that, in patients with pseudoexfoliation, the probability of developing glaucoma was 44% after 15 years, and, in a study by Grodum et al, 55.1% of patients developed glaucoma after a mean of 8.7 years.[24, 25]

When glaucoma develops, it is frequently referred to as capsular glaucoma. Patients with pseudoexfoliation syndrome have higher IOP than patients with primary open-angle glaucoma. Because of these higher IOPs, visual field loss and optic nerve damage are more pronounced.

Other signs of pseudoexfoliation syndrome are insufficient mydriasis, posterior synechiae, pigment deposition on the iris surface, deposition of pigment and pseudoexfoliation material on the corneal endothelium, pigment liberation after pupillary dilation, and pseudoexfoliation material covering the ciliary processes and the zonules. Phacodonesis, lens subluxation, and corneal endothelial decompensation can be present. An associated nuclear cataract is a common finding.

Pseudoexfoliation syndrome typically presents unilaterally. Why this occurs remains unknown. The fellow eye develops signs of pseudoexfoliation in more than 40% of cases, but pseudoexfoliation material can almost always be demonstrated in fellow eyes on electron microscopy and conjunctival biopsy.

Pseudoexfoliation syndrome is associated with reduced ocular blood flow, iris hypoperfusion, and anterior chamber hypoxia. It might be a significant risk factor for the development of central retinal vein occlusion secondary to a decrease in retrobulbar circulation.[26]

Oxidative damage and free radicals may play a role in the disease. A decrease in ascorbic acid concentrations, increased 8-iso-prostaglandinF2a concentrations,[27] and increased malondialdehyde concentrations[28] have been reported.


Whether pseudoexfoliation syndrome occurs as part of a genetic process or in association with other diseases is not clear. Familial aggregation supports the notion that it may be inherited as an autosomal dominant trait with incomplete penetrance and late onset. Its frequency increases with age; however, it is not part of normal aging. Possible predisposing factors include ultraviolet light, northern latitudes, and altitude. Climate factors may not play a definitive role in the pathogenesis of the disease.

The exact nature of pseudoexfoliation material remains unknown, although its close association with zonular fibers supports the idea of pseudoexfoliation syndrome as a type of elastosis, affecting elastic microfibrils. It seems to arise from abnormal aggregation of elastin microfibrillar components.

Since 2007, a significant association between common single nucleotide polymorphisms (SNPs) 1 intronic (rs2165241) and 2 nonsynonymous (SNPs) (rs1048661, R141L; rs3825942, G153D) in exon 1 of the lysyl oxidase-like protein 1 gene (LOXL1) have been found. They represent a major susceptibility variant for pseudoexfoliation syndrome and support the idea that the variant confers risk of glaucoma by causing pseudoexfoliation syndrome. These findings have been corroborated by multiple studies in different countries.[29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42] By fluorescence in situ hybridization, Kenyon et al mapped the human LOXL gene to 15q24-q25.[43]

The risk of pseudoexfoliation glaucoma is 700 times in individuals homozygous for the high-risk haplotypes. The 2 nonsynonymous changes are highly associated with pseudoexfoliation syndrome and account for more than 99% of all pseudoexfoliation glaucoma cases from Iceland and Sweden and 88% of cases in Iowa. Fan et al found a strong association between nonsynonymous single-nucleotide polymorphisms G153D, but not R141L, and pseudoexfoliation in a clinic-based population from the Northeastern United States. Similar findings were observed in a Greek population.[42]

The LOXL1 gene has been associated with the lysyl oxidase family of proteins that has important roles in elastogenesis. LOXL1 pro-peptide binds to both tropoelastin and fibulin-5 and alterations of the gene could affect the catalytic activity of the protein producing modifications in the elastin fibers, a major pathophysiological component of the syndrome. LOXL1 serves as a crosslinking enzyme and to ensure proper spatial deposition of elastin.

The high-risk haplotype of LOXL1 alleles is very common in Caucasians with a frequency of approximately 50% in the general population, 25% being homozygous for the haplotype. This indicates that, even though LOXL1 represents a significant risk factor for pseudoexfoliation, most persons with high-risk LOXL1 alleles do not have the condition. Therefore, other factors that remain to be identified must be involved, possibly including genetic variants or environmental factors. There is evidence that oxidative stress, hypoxia, and low-grade chronic inflammatory processes may be involved in its pathogenesis.[44]

Trantow et al showed that Lyst mutant mice carrying the beige allele exhibit multiple features of pseudoexfoliation syndrome, but not glaucoma. LYST has been shown to result in altered function of some lysosomal proteins, including elastase.

Glaucoma is a secondary event. Blockage of the trabecular spaces by pseudoexfoliation material promotes accumulation of pigment and cellular debris, which causes obstruction of the aqueous channels and limits access to the Schlemm canal. Accumulation of pseudoexfoliation material in the juxtacanicular tissue adjacent to the Schlemm canal leads to narrowing of the canal lumen, collapse of its walls, disruption of its endothelium, and partial obliteration. These changes appear to be the causative factors for chronic IOP elevation and pseudoexfoliation glaucoma.

Zonular laxity allows forward movement of the lens, causing decreased anterior chamber depth and pupillary or angle closure glaucoma.

Pseudoexfoliation syndrome itself does not produce optic nerve damage.





Imaging Studies

Various imaging technologies are being used to document and monitor changes due to glaucomatous damage in the optic disc and the retinal nerve fiber layer.

Optical coherence tomography (OCT) is a valuable tool in the evaluation of glaucoma. OCT provides a cross-sectional view of the scanned retinal area that allows differentiation between the retinal layers. The thickness of the retinal nerve fiber layer can be measured using this technique.

The confocal scanning laser ophthalmoscope (Heidelberg retina tomograph [HRT]) provides topographical measures of the optic disc as well as indirect measurements of the retinal nerve fiber layer thickness.

OCT and HRT have been used to help in the diagnosis and follow-up of patients with glaucoma. Both OCT and HRT have shown a high correlation between the retinal nerve fiber layer thickness and the visual field mean defect during achromatic perimetry.

The GDx Nerve Fiber Analyzer has been reported to be a valuable tool in helping the clinician to discriminate between healthy eyes and glaucomatous eyes.

Other Tests

Gonioscopy and visual field testing

Histologic Findings

Gottanka et al found marked differences in the optic nerve between primary open-angle glaucoma and pseudoexfoliation glaucoma.[45] Eyes with primary open-angle glaucoma were found to have axon loss associated with more connective tissue in the septa and surrounding the central retinal vessels and a decrease in the density of capillaries as compared with eyes with pseudoexfoliation glaucoma where the capillary density did not change with axon loss.



Medical Care

Patients with pseudoexfoliation syndrome should have annual eye examinations for early detection of glaucoma. Glaucoma in pseudoexfoliation is more resistant to medical therapy and has a poorer prognosis than primary open-angle glaucoma.

The treatment of pseudoexfoliation glaucoma is the same as that of primary open-angle glaucoma; however, topical medications tend to be less effective. Miotics lower IOP, but they aggravate the blood-aqueous barrier dysfunction and decrease iris mobility, thereby increasing the risk of posterior synechiae and cataract formation.

Surgical Care

Argon laser trabeculoplasty is frequently used with excellent initial success. Its hypotensive effect may be facilitated by enhanced heat absorption because of increased trabecular pigmentation.

According to a published study, selective laser trabeculoplasty (SLT) has been shown to be equivalent to argon laser trabeculoplasty in terms of lowering IOP at 1 year. The theoretical advantage of SLT is that SLT is a repeatable procedure because it does not seem to produce thermal damage to the trabecular meshwork.

If medical therapy and laser therapy are unsuccessful to control the glaucoma, trabeculectomy can be performed with similar success rates to that of primary open-angle glaucoma. Because patients with pseudoexfoliation glaucoma have higher IOP, they tend to undergo glaucoma filtering surgery more frequently than patients with primary open-angle glaucoma.

Cataracts occur more commonly in patients with pseudoexfoliation syndrome. The Blue Mountains Eye Study suggest that the presence of pseudoexfoliation syndrome is associated with an increased risk of nuclear cataract and cataract surgery.[46] Weakness of the zonular fibers, spontaneous lens subluxation, and phacodonesis also can be present. Therefore, in these patients, cataract surgery alone or combined cataract surgery and glaucoma filtering surgery in the presence of pseudoexfoliation is associated with a higher incidence of intraoperative complications, most notably zonular dialysis, vitreous loss, and lens dislocation.

The increased intraoperative posterior capsule complication rate appears to correlate with the level of cataract maturity. Modern surgical techniques involving the use of capsulorrhexis, small-incision surgery, and better viscoelastics have improved the surgical outcome. Capsular tension rings have been used to decrease surgical stress on the zonules.

Postoperative cataract surgery complications can occur after uneventful operations due to continued destabilization of the zonules and capsular contraction.

Jacobi et al described a nonfiltering surgical technique consisting of trabecular aspiration with or without cataract removal with encouraging results.[47] The operation attempts to increase the outflow facility along the trabecular meshwork by removing pretrabecular and trabecular debris using an externally applied suction device. Trabecular aspiration can be performed with modern tools such as trabectome as a minimally invasive surgery.


The use of supplements with vitamin B-12 and folic acid to decrease hyperhomocysteinemia in patients at risk has been suggested. A randomized clinical trial is needed to prove its benefit.



Medication Summary

Medical therapy is aimed at lowering IOP.

Beta-adrenergic receptor blocking agents

Class Summary

Topical beta-blockers that reduce elevated and normal IOP, with or without glaucoma.

Timolol ophthalmic (Timoptic, Betimol, Istalol)

First-line treatment. Precise mechanism by which timolol decreases IOP is not well established, although believed to be through reduction of aqueous formation.

Betaxolol ophthalmic (Betoptic, Betoptic S)

Cardioselective beta1-adrenergic receptor blocking agent with minimal effect on pulmonary and cardiovascular parameters. Precise mechanism by which betaxolol decreases IOP is believed to be through reduction of aqueous formation.

Carteolol ophthalmic (Cartrol, Ocupress)

Nonselective beta-adrenergic receptor blocking with intrinsic sympathomimetic activity. Precise mechanism by which carteolol decreases IOP is believed to be through reduction of aqueous formation.

Levobunolol (AKBeta, Betagan)

Noncardioselective beta-adrenergic receptor blocking agent. Precise mechanism by which levobunolol decreases IOP is believed to be through reduction of aqueous formation.

Metipranolol (OptiPranolol)

Nonselective beta-adrenergic receptor blocking agent. Precise mechanism by which metipranolol decreases IOP is believed to be through reduction of aqueous formation.

Cholinergic parasympathomimetic agents

Class Summary

Pilocarpine is a miotic agent. It reduces IOP, decreases pupillary movement, and increases aqueous outflow. Pilocarpine 2% qhs has been recommended as a first-line agent.[48]

Pilocarpine ophthalmic (Isopto)

Produces miosis through direct stimulation of muscarinic neuroreceptors. Also produces contraction of iris sphincter, causing opening of trabecular meshwork spaces to facilitate outflow of aqueous humor.


Class Summary

May decrease IOP by increasing outflow of aqueous humor.

Latanoprost (Xalatan, Xelpros)

Prostaglandin F2-alpha agonist. Decreases IOP by increasing uveoscleral outflow.

Travoprost ophthalmic solution (Travatan, Travatan Z)

Prostaglandin F2-alpha analog and selective FP prostanoid receptor agonist. Exact mechanism of action unknown but believed to reduce IOP by increasing uveoscleral outflow.

Bimatoprost (Lumigan)

Prostaglandin agonist that selectively mimics effects of naturally occurring substances, prostamides. Exact mechanism of action unknown but believed to reduce IOP by increasing outflow of aqueous humor through trabecular meshwork and uveoscleral routes. Used to reduce IOP in open-angle glaucoma or ocular hypertension.

Unoprostone isopropyl (Rescula)

Prostaglandin F2-alpha analog and selective FP prostanoid receptor agonist. Exact mechanism of action unknown but believed to reduce IOP by increasing uveoscleral outflow.


Class Summary

Decrease aqueous production and increase outflow facility.

Dipivefrin hydrochloride (AKPro, Propine)

Converted to epinephrine in eye by enzymatic hydrolysis. Appears to act by decreasing aqueous production and enhancing outflow facility. Has same therapeutic effect as epinephrine with fewer local and systemic adverse effects. May be used as an initial therapy or as an adjunct with other antiglaucoma agents for the control of IOP.

Epinephrine (Glaucon)

Lower IOP by increasing outflow and reducing production of aqueous humor. Used as adjunct to miotic or beta-blocker therapy. Combination of miotic and sympathomimetic has additive effects in lowering IOP.

Alpha2-adrenergic receptor antagonists

Class Summary

Reduce IOP.

Apraclonidine (Iopidine)

Decreases IOP by reducing aqueous humor production. Generally used in short-term therapy.

Alpha-adrenergic receptor agonists

Class Summary

Brimonidine tartrate is an alpha-adrenergic receptor agonist that reduces IOP.

Brimonidine (Alphagan P)

Reduces aqueous humor production and may have a small effect on increasing uveoscleral outflow.

Carbonic anhydrase inhibitors

Class Summary

Brinzolamide is a sulfonamide that reduces IOP.

Brinzolamide (Azopt)

Inhibits the enzyme CA in the ciliary process, decreasing aqueous humor secretion.

Dorzolamide (Trusopt)

Sulfonamide that reduces IOP. Inhibits enzyme CA in the ciliary process, decreasing aqueous humor secretion.