By Christopher P. Majka, MD, and Pratap Challa, MD
Edited by Ingrid U. Scott, MD, MPH, and Sharon Fekrat, MD
Pseudoexfoliation syndrome is a systemic disorder in which a fibrillar, proteinaceous substance is produced in abnormally high concentrations within ocular tissues. It is the most common cause of secondary glaucoma worldwide, and the most frequent cause of unilateral glaucoma. In a U.S. population, the Framingham Eye Study revealed the overall prevalence of pseudoexfoliation syndrome to be 0.6 percent in 52- to 64-year-olds, rising to 5 percent in 75- to 85-year-olds. In addition, the resultant pseudoexfoliation glaucoma responds poorly to medical therapy compared with other types of glaucoma and can lead to rapid progression of optic nerve damage. Owing to pseudoexfoliation glaucoma’s prevalence and severity, ophthalmologists should examine the eye for signs of pseudoexfoliation syndrome, as it is a major risk factor for glaucoma development.
What Is Pseudoexfoliation Syndrome?
Pseudoexfoliation syndrome is a systemic disease with primarily ocular manifestations characterized by deposition of whitish-gray protein on the lens, iris, ciliary epithelium, corneal endothelium and trabecular meshwork. Although attempts at identifying the material have been unsuccessful, pathologic study has revealed that the lens epithelium, trabecular meshwork, iris, ciliary processes, conjunctiva and periocular tissue are its source. The material is insoluble and floats in the aqueous humor, where it is filtered and deposited in the trabecular meshwork. Meanwhile local production of the proteinaceous material by the trabecular endothelial cells continues. All of this accumulates in the trabecular spaces and focally collapses Schlemm’s canal. This decreases aqueous humor outflow and increases IOP.
It is important to note that not every individual with pseudoexfoliation syndrome will develop pseudoexfoliation glaucoma. Pseudoexfoliation syndrome does, however, significantly predispose those affected to the development of increased IOP, and it results in glaucoma in 15 percent to 30 percent of cases.
Pseudoexfoliation syndrome occurs in all areas of the world. Researchers have been able to identify pseudoexfoliation as the cause of more than 50 percent of the cases of open-angle glaucoma in Scandinavian countries. In addition, some studies report a higher prevalence among women than men. Another major risk factor is age, as pseudoexfoliation syndrome rarely occurs in individuals under the age of 50. Other risk factors associated with this disorder include living at higher altitudes or in northern latitudes, and disproportionately high exposure to ultraviolet light.
Signs and Symptoms
The signs of pseudoexfoliation syndrome can usually be identified on slit-lamp examination. Clinical examination using biomicroscopy has 85 percent sensitivity and 100 percent specificity.
An easily recognizable sign of pseudoexfoliation is white, flaky material on the pupillary border of the iris or on the anterior surface of the lens. The lens frequently demonstrates a “three-ring sign” on the anterior lens capsule, which consists of a central zone of visible exfoliation material measuring 1 to 3 millimeters in diameter, combined with a middle clear zone and a peripheral cloudy ring. The central zone is usually well demarcated and can have curled edges. The middle clear zone is thought to be created by the posterior surface of the iris rubbing off the pseudoexfoliative material from the lens. This also results in a loss of iris pigment, which can lead to transillumination defects.
The pigment granules can often be seen accumulating in the trabecular meshwork. The peripheral cloudy ring of the lens is usually only visible upon dilation. It is important to note that more than 20 percent of patients with pseudoexfoliation syndrome have associated narrow angles; therefore, the anterior chamber depth of these patients should be assessed before dilation in order to avoid precipitating acute angle-closure glaucoma.
Gonioscopy reveals pigment deposition on the trabecular meshwork, usually more marked inferiorly, along with pigment around Schwalbe’s line. In addition, pseudoexfoliation material has been identified on the iris surface, corneal endothelium and zonules.
Pseudoexfoliation glaucoma commonly presents unilaterally with IOP that tends to escalate faster than among patients with primary open-angle glaucoma (POAG). The higher IOP observed in pseudoexfoliation glaucoma can lead to more rapid optic nerve damage and visual field loss. When symptoms are present in one eye, the contralateral eye must be examined carefully and monitored, since pseudoexfoliation glaucoma will develop in the other eye of more than 40 percent of these patients.
Poor pupillary response to dilation is a subtle finding that is observed frequently in patients with pseudoexfoliation syndrome and resultant glaucoma. This is believed to be related to iris dilator muscle atrophy and can complicate cataract surgery. Such eyes have weak zonular attachments as well, also complicating cataract surgery.
A thorough history may reveal a family history of pseudoexfoliation syndrome. A slit-lamp exam with IOP measurement can expose many of the findings in pseudoexfoliation glaucoma. In addition, gonioscopy should be performed to assess for pigment deposition and a Sampaolesi’s line. The anterior chamber angle should also be examined in order to ensure safe dilation, followed by a dilated fundus exam with stereo disc photographs to identify any glaucomatous change. Visual field testing may be necessary to check for any characteristic peripheral visual field loss and to ascertain the potential stage of glaucoma.
Various imaging studies can also be used to detect and monitor glaucomatous changes in the retinal nerve fiber layer and optic disc. Optical coherence tomography (OCT) allows the retinal nerve fiber layer to be assessed for any changes. Heidelberg retina tomography (HRT) is another imaging study that can provide measurements of the optic disc and retinal nerve fiber layer. Both OCT and HRT can be used to aid in the diagnosis and follow-up of patients with pseudoexfoliation glaucoma.
Pigmentary glaucoma. Pigment deposition on the trabecular meshwork and anterior segment structures is also observed in pigmentary glaucoma. Pigmentary glaucoma is caused by pigment dispersion syndrome, an autosomal dominant disorder characterized by pigment liberation from the iris epithelium.
Similar to the pathophysiology of pseudoexfoliation glaucoma, material accumulates in the trabecular meshwork, leading to progressive trabecular dysfunction and increased IOP. However, pigmentary glaucoma has an earlier age of onset, with ocular hypertension usually developing in 20- to 40-year-old patients. In pigmentary glaucoma there is often a vertical pigment band on the corneal endothelium, termed a Krukenberg’s spindle or Zentmeyer line—a feature rarely found in pseudoexfoliation glaucoma. Both pigmentary and pseudoexfoliation glaucoma can have iris transillumination defects. However, in pigmentary glaucoma the defects are slitlike in a radial distribution of the midperipheral iris, whereas in pseudoexfoliation glaucoma the defects are more patchy and closer to the pupillary margin. The iris in pigmentary glaucoma tends to have a concave configuration peripherally, which is another distinguishing feature.
Primary open-angle glaucoma. POAG should be considered in the differential. As noted earlier, the IOP in POAG tends to escalate more slowly than that observed in pseudoexfoliation glaucoma.
Amyloidosis. In amyloidosis, amyloid material that resembles pseudoexfoliation material can deposit in a similar distribution and can even lead to glaucoma. However, amyloidosis is a systemic disease affecting the kidney, liver and spleen, leading also to recognizable nonocular symptoms.
Exfoliation. Also in the differential is true exfoliation (capsular delamination), which occurs after chronic exposure to intense heat, classically in a glassblower, followed by a thin membrane peeling off the anterior lens capsule. Severe uveitis can also cause a membrane to peel off.
Several treatment options exist for pseudoexfoliation glaucoma, and your management approach should be tailored to each patient. Traditional IOP-lowering medications are less effective in pseudoexfoliation glaucoma than in POAG, but they are used frequently as first-line therapy. These medications include beta blockers, selective alpha2-receptor agonists, topical and systemic carbonic anhydrase inhibitors, prostaglandin agonists and sympathomimetics. The next line of therapy is argon or selective laser trabeculoplasty (ALT or SLT). Most studies have shown good responses to ALT and SLT. Of note, once laser trabeculoplasty starts to wear off, patients with pseudoexfoliation glaucoma tend to demonstrate a more rapid IOP increase than POAG patients. If medications and laser treatment do not control IOP adequately, a guarded filtration procedure may be performed.
Pseudoexfoliation glaucoma has a worse prognosis than primary open-angle glaucoma because the IOP is high relative to POAG, and pseudoexfoliation glaucoma’s poor response to medication leads to faster optic nerve damage, and to visual field defects that progress more quickly and are more severe.
Patients with pseudoexfoliation syndrome are at increased risk of developing cataracts and are more prone to complications at the time of cataract extraction. Decreased pupillary dilation, along with weakened zonular fibers and synechiae between the iris and peripheral anterior lens capsule, make the cataract surgery technically difficult. In addition, there is an increased incidence of capsular rupture, vitreous loss and zonular dehiscence during cataract extraction in patients with pseudoexfoliation syndrome. Postoperative complications of cataract extraction are also increased in pseudoexfoliation syndrome, including inflammation, posterior capsular opacification, capsule contraction syndrome and IOL decentration.
Retinal vein occlusion has also been associated with pseudoexfoliation glaucoma, which is another factor making the prognosis of pseudoexfoliation glaucoma more guarded than POAG.
Pseudoexfoliation glaucoma tends to follow an unpredictable course, as it can be relatively benign or progress rapidly to advanced optic nerve damage. Due to the volatile nature of this condition, patients with pseudoexfoliation glaucoma who demonstrate rising IOP should be examined every one to three months. If topical therapy is initiated, the patient’s IOP should be rechecked in three to six weeks. Patients receiving laser trabeculoplasty should also be reexamined in three to six weeks.
Patients with pseudoexfoliation syndrome and no evidence of glaucoma are generally not treated, but they should be followed every six to 12 months as they have an increased risk of developing glaucoma.
Current research on pseudoexfoliation syndrome is centered on genetic factors that predispose certain populations to its development. Many pedigrees have been published that demonstrate an autosomal dominant inheritance. One pedigree has also suggested mitochondrial inheritance, similar to Leber’s Hereditary Optic Neuropathy, Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia.
Most likely, however, pseudoexfoliation syndrome is like POAG in that it is a late-onset disorder with complex inheritance.
Dr. Majka has completed a six-year accelerated BS/MD program at the Northeastern Ohio Universities College of Medicine and will be training in ophthalmology at The Kresge Eye Institute in Detroit. Dr. Challa is assistant professor of ophthalmology on the glaucoma service and residency director at the Duke University Eye Center in Durham, N.C.
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