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Pseudoexfoliation Syndrome and Open-Angle Glaucoma

Pratap Challa, MD, MS and David L. Epstein, MD, MMM

Once thought to be an unusual form of open-angle glaucoma primarily associated with Scandinavian ancestry, we now know that exfoliation (or pseudoexfoliation) glaucoma constitutes a significant portion of most glaucoma practices in the world. This is an age-related systemic disorder that was initially described by Lindberg in 1917¹ when he observed small flecks of bluish-gray material on the pupillary border of many patients with chronic glaucoma. In 1925, Vogt² further characterized this disorder and felt that the particles were produced by the lens and was a form of capsular glaucoma. Dvorak-Theobald³ introduced the nomenclature of pseudoexfoliation of the lens to differentiate this disorder from the rare true exfoliation that occurs from infrared damage in glassblowers (and in recent times, in some welders who do not wear eye protection). Therefore, both pseudoexfoliation and exfoliation usually refer to the same disorder. The presence of glaucoma distinguishes pseudoexfoliation glaucoma from pseudoexfoliation syndrome. In many locations, initial reports indicated that pseudoexfoliation was rare, but then, with more focused detection methods, a higher prevalence was subsequently observed. Several points are worth emphasizing: pseudoexfoliation open-angle glaucoma mimics primary open-angle glaucoma (POAG) in most, but not all, features and therefore may be underdetected or misdiagnosed. Recognition involves meticulous observation that includes the following (see Chapter 5):

• Careful attention to the crystalline lens on dilated slit-lamp examination
  
• The need to explain increased pigmentation observed on gonioscopy
  
• The observation of white flecks in the angle, on the lens, or on the zonules or ciliary processes (when visualized)
  
• The need to explain peripupillary iris transillumination defects

This is an important disorder that is the most common form of secondary open-angle glaucoma worldwide, accounting for 20% to 25% of open-angle glaucoma.⁴

DISEASE PREVALENCE

Pseudoexfoliation syndrome is a systemic disorder in which a poorly characterized, fibrillar substance is produced in abnormally high concentrations within ocular tissues. The incidence of pseudoexfoliation varies among ethnic groups,⁵ with incidences of 20% to 25% in the Scandinavian countries of Iceland and Finland⁶ to no reported cases among Greenland Eskimos.⁷ The Framingham Eye Study (United States)⁸ revealed an age-related increase among nonglaucoma individuals of 0.6% in individuals aged 52 to 64 years that rose to 5.0% for individuals aged 75 to 85 years. A relatively high incidence of pseudoexfoliation has been reported among Navajo Indians attending an eye clinic in New Mexico where 38% of older individuals had manifestations of pseudoexfoliation.^9,10 White individuals older than 60 years in the United States have a prevalence of pseudoexfoliation between 1.6% and 3%, and Black individuals are lower at approximately 0.4%.^11,12

Both Lindberg¹ and Vogt² noted pseudoexfoliation’s association with glaucoma and increasing age. Pseudoexfoliation is associated with 20% to 60% of open-angle glaucoma in various regions of the world including the Scandinavian countries, Greece, Russia, Iran, Nepal, Ethiopia, and South Africa.5,13,14 High incidences are reported from Ireland¹⁵ and Sweden¹⁶ where pseudoexfoliation glaucoma is present in up to two-thirds of individuals with open-angle glaucoma. Reported prevalence ranges from 0.4% to 28% of open-angle glaucoma in the United States.^12,17–19 All prevalence rates are complicated by high variability between examiners. This may be due to the difficulty with diagnosing typical deposits on the lens surface or other intraocular tissues due to both a missed diagnosis and that the deposits can become manifest over time after an initial diagnosis of POAG or ocular hypertension.^19,20 Moreover, typical deposits are hard to see unless a postdilation examination of the anterior lens surface is performed. Some individuals have been shown on conjunctival biopsy specimens to have pseudoexfoliation syndrome before the typical slit-lamp findings were present.²¹ The authors have observed that some patients who were initially diagnosed with POAG were later found to develop the typical fibrillar deposits on the lens (visible after dilation) and/or pupillary border and hence convert to a diagnosis of pseudoexfoliation glaucoma.

Pseudoexfoliation is a disease of basement membranes of the eye and other systemic tissues.^22,23 As discussed in Chapter 2, the base of the nonpigmented ciliary epithelial cell (head-to-head with the sclerad pigmented ciliary epithelial cell) faces the posterior chamber as does the base of the posterior iris pigment epithelial cell and the base of the lens epithelial cell, which constitutes the lens capsule. The base of all 3 of these cells, which line the posterior chamber, extrude pseudoexfoliation material onto their surface where presumably the material can enter the aqueous humor as well as lead to lens instability by weakening and disinserting zonular attachments.^24–27 Pseudoexfoliation has also been reported to develop locally separate from this, within the trabecular meshwork (TM), around Schlemm’s canal,²⁸ and also in other intraocular sites, such as the corneal endothelium.²⁹ Pseudoexfoliation has also been reported to develop locally in the palpebral conjunctiva^28,30,31 and at systemic sites^23,32 and is believed to be a systemic abnormality,^23,32 although it is curious that it seems to cause clinical disease only within the eye.

The origin of pseudoexfoliation from multiple basement membrane sites within the eye is also believed to explain certain clinical features, such as the development of glaucoma and weakness of the zonules and/or lens capsule at the time of extracapsular cataract surgery.^33,34 Transmission electron microscopy of the outflow system in patients with pseudoexfoliation glaucoma reveals the presence of an abundance of pseudoexfoliation particles within the juxtacanalicular (JXT) layer with minimal to no material in the uveoscleral and corneoscleral layers of the TM. This favors the concept of local production of the material with possible secondary accumulation of material produced elsewhere in the eye (ie, material produced elsewhere may be floating into the aqueous humor and due to normal aqueous flow it reaches the TM). The accumulation of the pseudoexfoliation material in the JXT leads to compression and even focal collapse of Schlemm’s canal (Figure 21-1). This disruption of normal Schlemm’s canal architecture then leads to elevated intraocular pressures (IOPs) with associated optic nerve damage³⁵ and makes this form of glaucoma relatively more resistant to medical therapy. This also has implications for surgical techniques focused on Schlemm’s canal, such as canaloplasty and trabectome surgery. The authors have found it more difficult to perform these procedures in pseudoexfoliation compared to POAG patients presumably due to focal collapse of Schlemm’s canal.

Local production of the material by the lens epithelium and presumably by the ciliary epithelium can lead to zonular weakness and even disinsertion at their attachments to their respective structures. Electron microscopy studies of affected lens tissue demonstrates that the pseudoexfoliation material can aggregate into clumps that appear to work their way through the lens capsule onto the surface of the lens. If they come through the capsule at regions of zonular attachments, they can weaken or even disrupt the zonular insertions.^27,36,37 This process likely accounts for the increased rate of both intraoperative surgical complications and later-onset pseudophakic lens dislocations.³⁸ Another clinical feature is the loss of pigment from the posterior iris epithelium.^39–41 This appears as transillumination defects in the iris sphincter region and may be due to mechanical rubbing of the iris against the lens surface. Furthermore, pseudoexfoliation patients frequently demonstrate poor pupillary dilation. Histology demonstrates that the pseudoexfoliation material is also produced by the iris vascular endothelium.^42–44 However, iris angiography studies have not established iris ischemia as the causative mechanism for pigment loss and poor pupillary dilation.⁴⁵ This may be due to a limitation of this investigative technique, and the authors suspect that a low-grade and progressive iris ischemia may play a partial role in both pigment release and poor dilation.

Until recently, considerable discussion occurred over whether pseudoexfoliation might be only an incidental finding and whether affected patients with glaucoma might actually have simply POAG instead. Current thinking and genetic studies would not support such a tenet. Although it is true that patients can have pseudoexfoliation with no elevation of IOP (and totally normal outflow facility by tonography), there have been important studies, many from Scandinavia, that have documented the increasing risk of development of glaucoma in such patients with time.46–51 As with pigmentary dispersion syndrome, there may be patients with the distinct syndrome who do not have, and perhaps may never develop, trabecular dysfunction. These diseases may require some trabecular abnormality in addition to either the pseudoexfoliation material or pigment, but it is naive to assume that this is the same trabecular defect that is present in POAG. For example, the latter may not require an insult such as deposited debris or pigment. However, POAG, itself, likely has more than one pathophysiological mechanism and constitutes more than one entity. It appears that the presumed basement membrane abnormality (and accumulation of typical material) within the TM and Schlemm’s canal, itself, in pseudoexfoliation is the key to the presence or absence of abnormal outflow function.

There are also sometimes subtle but important clinical differences between pseudoexfoliation and POAG: the frequent substantial asymmetry or unilaterality,⁵¹ the potential for rapid escalation of IOP and refractoriness to anti glaucoma therapy,⁵² the more favorable early response to argon laser trabeculoplasty (LTP),^53,54 and the lesser incidence of “corticosteroid responsiveness” in pseudoexfoliation.^30,55

Finally, important histopathological differences occur in the outflow pathway in pseudoexfoliation glaucoma compared with POAG. In the latter, the specific pathological finding is not unequivocal (see Chapter 19), but increased extracellular “plaque material,”⁵⁶ decreased cellularity,⁵⁷ and a disorganized trabecular beam structure have been observed. In contrast, in pseudoexfoliation glaucoma, the cellularity of the outflow pathway appears generally “normal,” except for the presence of the extracellular pseudoexfoliation material.^24,58 However, in more advanced cases, changes in Schlemm’s canal architecture can be seen. Thus, we believe that pseudoexfoliation is a secondary open-angle glaucoma due to the locally produced pseudo-exfoliation material in the TM.

What contributed in the past to this uncertain discrimination between pseudoexfoliation and POAG was the common occurrence of cases of apparent unilateral pseudoexfoliation but bilateral glaucoma. However, we now know from the work of Mizuno and Muroi⁵⁹ that most such cases have occult pseudoexfoliation in the seemingly unaffected fellow eye. We have learned that one of the earliest sites for pseudoexfoliation to be observed is on the ciliary processes rather than the more easily viewed anterior crystalline lens surface.⁵⁹ (Of course, a current critical question is: Are we missing detecting even earlier sites because of the limitations of our observation techniques?)

The potential for multiple ocular and systemic sites of production of pseudoexfoliation material raises another consideration that was mentioned in Chapter 20 and may be stated as follows: there is a strong clinical sense that patients with pseudoexfoliation glaucoma who have had high IOP in the past may demonstrate optic nerves that are still susceptible to further damage despite normalization of the IOP that has been stabilized by medications and/or LTP. Could local production of pseudoexfoliation or some related fundamental cellular abnormality within the optic nerve and especially its connective tissues explain this susceptibility? Of note, pseudoexfoliation deposits are present within the optic nerve sheath but what role they play in the pathogenesis of glaucoma is unclear. Pseudoexfoliation has also been associated with retinal vein occlusions suggesting a role for vascular compromise in the disorder. However, the role of pressure fluctuations vs the role of pseudoexfoliation material is unclear.⁶⁰ We do not have answers to these questions, but they deserve attention not only from the clinical management point of view but also because it might lend insight into other causes for low-tension glaucoma–like optic nerve susceptibility. Regardless, the clinical point is that, in patients with pseudoexfoliation open-angle glaucoma, the clinician must pay special attention to the possibility of a low-tension glaucoma equivalent condition (see Chapter 20).

GENETIC STUDIES

Pseudoexfoliation syndrome is a late-onset inherited condition in which pedigrees have demonstrated autosomal dominant, autosomal recessive, and maternal inheritance patterns. A genome association study by Thorleifsson and colleagues⁶¹ has demonstrated 3 single nucleotide polymorphisms (SNPs) of the lysyl oxidase-like 1 (LOXL1) gene as strong genetic risk factors for pseudoexfoliation and pseudoexfoliation glaucoma in Icelandic and Swedish populations. LOXL1 is located on chromosome 15q24.1 and is part of a family of 5 lysyl oxidase enzymes (LOX, LOXL1, LOXL2, LOXL3, and LOXL4) that collectively play a key role in cross-linking between collagen and elastin in connective tissues.⁶² Individually, LOXL1 catalyzes tropoelastin cross-linking and regulates elastin fiber formation and remodeling.⁶³ Therefore, perturbations in the function of LOXL1 may be another cause of the zonular instability seen with this disorder. Moreover, a growing body of molecular and biochemical evidence indicates that pseudoexfoliation arises from a stress-induced elastic microfibrillopathy. Although the exact pathogenesis of pseudoexfoliation syndrome remains unknown, it is believed to involve inadequate breakdown and/or excessive production of elastic fiber components.64,65

Studies performed in the United States,^66–70 Australia,⁷¹ and Europe⁷² have confirmed that 2 nonsynonymous coding SNPs (rs3825942 and rs1048661) and 1 intronic SNP (rs2165241) from the LOXL1 gene are strong genetic susceptibility factors for pseudoexfoliation and pseudoexfoliation glaucoma. In Indian,⁷³ Japanese,^74–79 and Chinese^80,81 cohorts, the association with rs3825942 confirmed that this is the strongest risk allele across different ethnicities and is present in 94% to 100% of affected individuals. However, the causative nature of these SNPs is unclear because other studies have shown inverse relationships for the reported risk alleles of rs3825942 (G), rs1048661 (G), and rs2165241 (T). The rs3825942 has an inverse relationship among individuals from South Africa,⁸² while rs1048661 and rs2165241 are inversely related among Japanese^74–79 and Chinese⁸¹ cohorts. This inverse relationship implies that the allele that is associated with the disease in most populations is actually the protective allele in these populations. Furthermore, there is early evidence that the expression of LOXL1 decreases in patients with pseudoexfoliation glaucoma.⁸³ However, the functional significance of the LOXL1 gene in the pathogenesis of pseudoexfoliation syndrome is unclear at present. Moreover, the disease SNPs are present in a large proportion of the control (unaffected) group—anywhere from 50% to 92% of these individuals—and despite extensive sequencing, the exact gene mutation has not been identified. Therefore, the presence of the LOXL1 SNPs cannot be the only cause of the development of pseudoexfoliation syndrome or glaucoma, and there must be other genes or environmental factors that play a role. Current and future studies may eventually elucidate the exact mechanisms that lead to this disorder.

Further association studies have revealed other genes and loci associated with pseudoexfoliation syndrome but none as strong as LOXL1.^84,85 The CACNA1A gene polymorphism rs4926244 was initially identified in a genome wide association study of Japanese patients and subsequently replicated in patients from 17 countries. The risk allele was consistent across all the individuals studied and displayed an allele frequency from 10% to 40% in affected individuals. The risk allele increased pseudoexfoliation risk by 1.16-fold compared to a 10- to 18-fold increased risk for LOXL1.^61,84,85 Therefore, multiple genes are associated with pseudoexfoliation syndrome, and despite the inverse association in some populations, LOXL1 has the strongest disease association to date.

One interesting question regards what environmental factors play a role in pseudoexfoliation syndrome. There are several environmental factors associated with increased pseudoexfoliation prevalence such as geography (more northern latitudes), increased ultraviolet light exposure, cooler temperatures, and increased coffee consumption.^86–88 The mechanism by which environmental factors alter a disease course are unclear but can involve direct actions on affected tissues or alterations in the epigenetic regulation of genes. The first intron/exon boundary of LOXL1 carries a very large concentration of CpG islands and the LOXL1 gene may be epigenetically regulated in other disorders such as cutis laxa.⁸⁹ To date, an epigenetic mechanism for pseudoexfoliation syndrome has not been definitively shown.

CLINICAL FINDINGS

Although in many respects this type of glaucoma closely resembles POAG, there are some important differences. In addition, in open-angle glaucoma associated with pseudoexfoliation, we have found in most cases an abnormal accumulation of pigment in the filtration portion of the corneoscleral TM, usually involving the whole circumference, and distinctly more than is found in normal eyes of patients of the same age or in patients who have POAG. Pseudoexfoliation often presents monocularly, and the associated excessive pigmentation of the TM and the open-angle glaucoma are also commonly limited to the eye showing the pseudoexfoliation. However, sometimes in patients with bilateral pseudoexfoliation glaucoma, the severity of the glaucoma may actually be worse in the eye with lesser trabecular pigmentation. (More commonly, however, the more heavily pigmented angle is associated with the more severe glaucoma.)

POAG differs in that it almost always affects both eyes, although one eye may be affected more severely than the other, and in that the primary form of open-angle glaucoma usually is not associated with excessive pigmentation of the TM. As mentioned, there is a widely held opinion, which we share, that glaucoma associated with pseudoexfoliation tends to be less responsive to medical treatment than POAG.^30,48,52

Pseudoexfoliation material is most commonly detected during slit-lamp examination when the pupillary border and face of the lens are examined (Figures 21-2 and 21-3). Fine light gray amorphous flakes resembling dandruff may be noted at the pupillary margin or a matte gray membrane with curled edges on the anterior surface of the lens. If the pupil is small, the pseudoexfoliation material may be hidden behind the pupillary margin and may be detected only when, using gonioscopy, one looks just under the pupillary margin. If the pupil is dilated, one may see on the anterior surface of the crystalline lens an area of lusterless gray that is smooth and homogeneous in the pupillary area, but ends in a series of scallops peripherally (see Figure 21-2), with the most peripheral portion of the lens capsule appearing uncoated and normally lustrous. The edges of the coating on the lens sometimes appear rolled as though a portion of the anterior capsule were being exfoliated. If there is a coloboma of the iris, one may see that the amorphous coating on the lens extends further peripherally than in the areas where the iris is intact. Examination through the gonioscope lens and examination of enucleated eyes have established that material having the same gray amorphous appearance is also present on the zonules of the lens, on the ciliary processes, and on the posterior surface of the iris. It may also be occasionally deposited on the corneal endothelium.

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