Pseudoexfoliation Syndrome (Pseudoexfoliation Glaucoma) Clinical Presentation

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

History

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

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Physical

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.

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Causes

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.

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