Chapter 223 – Pseudoexfoliative Glaucoma
WILLIAM J. LAHNERS
THOMAS W. SAMUELSON
• A common, potentially aggressive form of secondary open-angle glaucoma characterized by the deposition of whitish, fibrillar material within the structures of the anterior segment and angle.
• Characteristic whitish, fibrillar material on the anterior lens capsule and related structures.
• Most commonly open angle with increased trabecular meshwork pigmentation; less commonly narrow or closed angle.
• Variable intraocular pressure that ranges from normal to markedly elevated.
• Iris transillumination defects in peripupillary region.
• Reduced pharmacological dilatation.
• Weakened zonular attachments with lens instability and variable chamber depth.
• Reduced integrity of blood–aqueous barrier.
Pseudoexfoliation (PEX) syndrome is an important ocular manifestation of a systemic disorder. It has been described as the most identifiable cause of open-angle glaucoma. Glaucoma secondary to PEX syndrome often is far advanced when diagnosed and may be difficult to control medically. Markedly elevated intraocular pressure (IOP), despite an open angle, is not uncommon. However, not all patients who have PEX syndrome develop glaucoma. Despite extensive research, the pathogenesis of PEX glaucoma remains obscure, and it is difficult to predict which patients with PEX will develop visual loss.
EPIDEMIOLOGY AND PATHOGENESIS
The first report of PEX glaucoma was in Finland by Lindberg in 1917. PEX syndrome reportedly is most common in patients of Scandinavian heritage and relatively uncommon among African–Americans. However, the syndrome has been documented in most populations. PEX syndrome is more common in women, although this observation may occur as a result of bias because of the longer life span of women. A syndrome of the elderly, it is unusual for it to be diagnosed before the age of 50 years. The prevalence of PEX syndrome increases markedly with age. For example, the prevalence of PEX syndrome in the United States was found to be 0.6% for those in the age range 52–64 years and 5% in the age range 75–85 years. Although the condition may occur bilaterally, almost one half of the cases appear to be unilateral at the time of diagnosis. However, PEX material has been detected by electron microscopy in the conjunctiva of fellow eyes which have no apparent PEX based on biomicroscopic examination. In addition, ultrastructural studies have shown changes in the iris and ciliary body epithelia, iris dilator muscle, iris stromal vessels, and juxtacanalicular trabecular meshwork. As such, presumed unilateral cases most likely represent asymmetrical, bilateral cases. Indeed, 25% of patients who have unilateral PEX syndrome develop the disease in the fellow eye within 10 years.
Of patients who have PEX syndrome, 20% have glaucoma and elevated IOP at the time of diagnosis. Patients who have PEX syndrome but not glaucoma should be considered vulnerable to glaucoma, because 15% of such patients develop increased IOP within 10 years. This underscores the need for careful follow-up in patients who have PEX syndrome. PEX syndrome accounts for 15–20% of cases of open-angle glaucoma. There is some evidence to support a genetic basis for PEX including transmission in two-generation families, twin studies, an increased risk of PEX in relatives of affected patients, and human lymphocyte antigen studies. Nearly all pedigrees reported in the literature suggest maternal transmission, raising the possibilities of mitochondrial inheritance, X-linked inheritance, and autosomal inheritance with genomic imprinting. Because of geographical variabilities, it has also been suggested that there may be a combination of genetic and non-genetic factors at work.
PEX syndrome is a systemic disorder, although its clinical relevance, based on current knowledge, is limited primarily to its ocular manifestations. PEX material has been identified in many visceral organs, as well as in the eye. 
Many theories exist as to the pathogenesis of glaucoma associated with PEX syndrome. Most research now indicates that the glaucoma is a secondary process distinct from primary open-angle glaucoma. PEX glaucoma may result from blockage of the trabecular spaces by the PEX material and pigment—PEX material contributes to the accumulation of pigment and debris within the aqueous outflow channels. Many patients who have PEX syndrome do not develop increased IOP, perhaps because of individual variations in the metabolic activity of the trabecular meshwork. In some individuals, long-term exposure to PEX material and pigment overwhelms the system and results in increased resistance to aqueous outflow, damage to the juxtacanalicular region and Schlemm’s canal, and subsequent increased IOP. Orbital blood flow velocities by Doppler imaging have shown a significant reduction in peak systolic and diastolic velocities in the short posterior ciliary arteries, central retinal artery, and the ophthalmic artery, as well as increased mean resistance in patients with PEX glaucoma.
Although generally associated with open angles, PEX glaucoma is associated with a greater frequency of angle closure. This is likely related to the phenomenon of zonular instability and anterior displacement of the lens iris diaphragm. Moreover, posterior synechiae and iris rigidity may increase pupillary block. Miotic medications may exacerbate the pupillary block and must be used with caution in patients who have PEX syndrome with narrow angles. 
Patients who have PEX syndrome most often have no symptoms—PEX material is noted as an incidental finding on examination. The PEX material may be apparent in one or both eyes, but it is commonly asymmetrical or unilateral. Although the fellow eye frequently appears uninvolved, as noted earlier, the “uninvolved” eye most likely has subclinical PEX syndrome.  As such, asymmetrical may be a better term than unilateral.
Occasionally, patients who have PEX syndrome seek treatment in a dramatic fashion. The IOP may be elevated markedly despite an open angle. Frequently, in such cases the patient has far-advanced optic disc and visual field changes. The IOP may be 50–60?mmHg (6.7–8.0?kPa) or higher. Most often, patients are not symptomatic of the elevated pressure, which indicates chronicity of the pressure elevation. Patients often seek medical attention
Figure 223-1 Initial appearance of pseudoexfoliative glaucoma. A, Advanced optic disc damage. (Reproduced with permission from Samuelson TW. Management of coincident glaucoma and cataract. Curr Opin Ophthalmol. 1995;1:14–21.) B, Visual field loss.
when they become aware of visual loss and subsequently are found to have far-advanced optic nerve and concomitant visual field damage ( Fig. 223-1 ). Less often, patients experience corneal edema, pain, and markedly elevated pressure, a clinical picture that must be differentiated from primary angle-closure glaucoma. Occasionally, patients who have PEX syndrome have a subluxed or completely dislocated lens ( Fig. 223-2 ).
Figure 223-2 Subluxed crystalline lens. Exfoliative material (of the same patient as shown in Fig. 223-1 ) can be seen along the equator of the lens and within the zonules. In addition, peripupillary atrophy is evident. (Reproduced with permission from Samuelson TW. Management of coincident glaucoma and cataract. Curr Opin Ophthalmol. 1995;1:14–21.)
Figure 223-3 Exfoliative material at the pupillary margin.
Figure 223-4 Scrolling of exfoliative material at the periphery of the anterior lens capsule.
On examination, the hallmark of the PEX syndrome is the characteristic pattern of whitish PEX material on the anterior lens capsule ( Figs. 223-3 and 223-4 ). Classically three zones are seen :
• A central disc of homogeneous appearance
• A relatively clear intermediate zone around the central disc
• An outer peripheral zone of PEX material
The intermediate clear zone results from the physiological movement of the iris, which clears the PEX material from this region of the lens. The peripheral zone may have various appearances but is always present. In contrast, the central disc may be absent in 10–20% of cases. One early sign of PEX syndrome is the development of radial, nongranular striae in the middle third of the anterior lens capsule, behind the iris. Other early signs of PEX syndrome include increased pigmentation of the trabecular meshwork and a ground-glass appearance of the anterior lens capsule. Dilatation of the pupil helps in the identification of PEX material—the syndrome may be overlooked if the pupils are not dilated. PEX material also accumulates on the ciliary body and zonules and frequently is seen in the anterior chamber angle, corneal endothelium, and anterior vitreous face. The condition also may be diagnosed in pseudophakic or aphakic patients by the identification of PEX material on an intraocular lens or within anterior vitreous fibrils.
Patients who have PEX syndrome tend to have increased pigmentation of the anterior chamber angle. Pigment may also be present on the corneal endothelium. PEX syndrome has been associated with non-guttate endothelial loss and subsequent corneal decompensation.  The trabecular pigment is often patchy and unevenly distributed, in contrast to the pigment dispersion syndrome (PDS) in which a homogeneous pattern of trabecular pigmentation generally is found. Dilatation of the pupils may liberate additional pigment and postdilatation pressure spikes are not uncommon, despite a persistently open angle. As such, postdilatation pressure readings are frequently useful.
DIAGNOSIS AND ANCILLARY TESTING
The diagnosis of PEX syndrome is made on the basis of observation of the characteristic whitish PEX material on the surface of the anterior lens capsule. Additional suggestive signs include atrophy and transillumination of the iris sphincter, pupillary ruff defects, poor dilatation of the iris, a ground-glass appearance of the anterior lens capsule, and commonly a Sampaolesi line is noted in the inferior angle on gonioscopy. Traditionally, the term PEX glaucoma has been reserved for those cases which have pressure-related optic nerve and visual field abnormalities. The diagnoses of PEX syndrome and PEX glaucoma are primarily clinical. All patients who have PEX syndrome must be followed as glaucoma suspects. Patients who have PEX glaucoma are followed in much the same manner as patients who have primary open-angle glaucoma with periodic tonometric, optic disc, nerve fiber layer, and visual field examinations. The frequency of such testing depends on the severity of the disease in individual patients.
Several conditions may mimic the PEX syndrome. These include PDS, capsular delamination or true exfoliation, and primary amyloidosis. As mentioned previously, PEX syndrome has several features which distinguish it from PDS, which appears primarily in myopic men in the third and fourth decades (whereas PEX syndrome is a condition of the elderly). In contrast to PEX syndrome, PDS is usually a bilateral disease at time of diagnosis. The trabecular pigmentation is homogeneous, rather than patchy as in PEX syndrome. Another important differentiating feature between PEX and PDS is that the transillumination defects generally occur at the pupillary margin in the former, while in the latter they are located in the midstroma of the iris. Capsular delamination or true exfoliation occurs secondary to heat, trauma, irradiation, or inflammation. A split in the anterior lens capsule occurs without deposition of PEX material and the characteristic frosty appearance of the lens capsule. Another rare condition that may produce fibrillar material on the lens surface is primary familial amyloidosis. Evaluation of this material has shown it to be distinctly different from PEX material. Most often, PEX glaucoma is misdiagnosed as primary open-angle or primary angle-closure glaucoma because of the failure to recognize the characteristic PEX material. Finally, PEX syndrome may be confused with iritis when the deposition of the PEX substance on the corneal endothelium results in the appearance of a pseudokeratic precipitate ( Box 223-1 ).
Ultrastructural studies performed on eyes during autopsy suggest that PEX syndrome is a systemic disorder. PEX material has been found in a number of organs, which include skin, lung, gallbladder, liver, myocardium, kidney, bladder, and meninges.  The staining of the material in these organs is positive for elastin and human amyloid P protein, which is similar to the staining pattern characteristic of the material found in the eye. These findings provide evidence for the systemic nature of PEX syndrome, which involves an aberrant connective tissue metabolism throughout the body.
Although the systemic associations of PEX syndrome have been considered of primarily academic interest, some new reports have challenged this opinion. One study has shown a higher incidence of PEX syndrome in patients with abdominal aortic aneurysms compared with age-matched controls with vascular disease. Another study has demonstrated an increased risk cardiovascular disease in patients with PEX syndrome. However, at least one study has failed to show an association of PEX syndrome with increased cardiovascular or cerebrovascular mortality. No systemic evaluation is needed or recommended in the routine evaluation and management of PEX glaucoma.
Histologically, PEX material is homogeneous, eosinophilic material positive for periodic acid–Schiff analysis and rich in polysaccharides ( Fig. 223-5 ). It is composed of randomly arranged fibrils and filaments, which are thought to be derived from elastin and basement membrane material. PEX material has origins in both intraocular and extraocular sites. Pre-equatorial epithelium of the crystalline lens produces the substance, which then traverses the lens capsule and appears on the surface of the anterior capsule—the posterior capsule and the central epithelium are not involved in the production of this material. By using a modified method of gonioscopy known as cycloscopy, PEX material has been seen to coat the ciliary processes and zonules, and it also accumulates at the insertion of the zonules into the ciliary body. In addition, the PEX material affects the zonular attachments to the lens capsule, which leads to instability of the zonular apparatus because of fragmentation. PEX material within the trabecular meshwork results from both deposition from the aqueous and local production by the endothelial cells
Differential Diagnosis of Pseudoexfoliative Glaucoma
Primary open-angle glaucoma
Primary angle-closure glaucoma
True exfoliation/capsular delamination
Figure 223-5 Pseudoexfoliative syndrome. A, In the central disc area, the material is deposited as small slivers that line up parallel to each other and perpendicular to the lens capsule. B, In the peripheral area, the material is abundant and has a thick, dendritic appearance. (A–B, From Yanoff M, Fine BS. Ocular pathology, ed 5. St. Louis: Mosby; 2002.)
in the outer trabecular meshwork. This material may contribute to the disorganization of the trabecular cells and fusion of the trabecular beams. The iris is involved extensively in PEX glaucoma, because the material accumulates on the iris pigment epithelium, anterior stroma, and iris vasculature, which results in atrophy of the iris pigment epithelium. Involvement of the iris vessels produces obliteration of the vascular lumen and eventual iris atrophy. The corneal endothelium also has been identified as a source of pseudoexfoliative material. Extraocular sites of pseudoexfoliative material include bulbar and palpebral conjunctiva, along with periocular skin.
Medical management of PEX glaucoma is similar to that for primary open-angle glaucoma and includes the use of aqueous suppressants, prostaglandin analogs, and miotic agents. PEX glaucoma is frequently more resistant to medical management and has a higher failure rate compared with primary open-angle glaucoma.  If miotics are used to manage elevated IOP, careful follow-up for posterior synechiae and angle closure is recommended. Although miotic medications may have significant local side effects, they may be particularly useful in PEX glaucoma via the inhibition of pupillary activity and may subsequently decrease the amount of pigment and PEX material liberated into the anterior chamber. Despite this potential benefit of miotic agents, aqueous suppressants are generally the initial step in the management of PEX glaucoma.
If medical management with one or more agents is unsuccessful, argon laser trabeculoplasty may be considered; it is reported to have a higher success rate with PEX syndrome than for primary open-angle glaucoma. As such, argon laser trabeculoplasty is often used earlier in the management regimen than for other forms of open-angle glaucoma. If pressure is not controlled with medical or laser treatment, surgical trabeculectomy is considered. The results of trabeculectomy are favorable, with no significant difference in the postoperative complication rate compared with filtration surgery in primary open-angle glaucoma. However, patients who have PEX syndrome are more prone to an increased postoperative inflammatory response because of the alteration of the blood–aqueous barrier in this condition. Trabecular aspiration has been used with success as another surgical alternative;   however, long-term follow-up is lacking.
In many instances, trabeculectomy is combined with cataract surgery in patients affected by PEX syndrome. Several important considerations exist for surgeons who perform combined cataract and glaucoma surgery in patients who have PEX syndrome. First, the zonular attachments in PEX syndrome may be weakened by the accumulation of PEX material. This may result in a higher incidence of the lens subluxation, zonular dialysis, and vitreous loss. The rate for these complications has been estimated to be 5–10 times higher than in patients who do not have PEX syndrome.    Another factor which may complicate surgery is the reduced response to pharmacological dilatation in patients who have PEX syndrome. Poor dilatation is the single most important risk factor for vitreous loss in cataract surgery among these patients. The use of pupillary stretch techniques or iris retractors has enhanced greatly the safety of cataract surgery in patients who have PEX syndrome. Other techniques which can be useful include the use of capsular tension rings to reduce capsular instability and improve implant centration. In some cases it may be necessary to place the lens into the ciliary sulcus or fixate the lens with sutures. Other observations made in eyes affected by PEX syndrome include a greater risk for perioperative pressure spikes, posterior synechia formation, and cellular precipitates on intraocular lenses. Preoperatively, all patients must be examined predilatation and postdilatation, with careful observation for phacodonesis and iridodonesis, which may help tailor the surgical approach. This is best performed with the aid of a gonioscope. If the lens is unstable, it may be best to perform supracapsular phacoemulsification by aggressive hydrodissection of the lens from the capsular bag. If it is not possible to remove the lens anteriorly, a pars plana approach may be necessary. With a gentle and methodical surgical technique, the results of combined cataract and glaucoma surgery in patients who display PEX may be quite good.
In patients with PEX glaucoma and controlled IOP on medication without advanced visual field loss, clear cornea cataract surgery alone can offer improved pressure control without the additional technical difficulties and risks of combined cataract and trabeculectomy surgery. A trabeculectomy can then be offered as a second procedure, if necessary, at a later time, with potentially greater likelihood of success. This option of a staged approach to management of coincident cataract and PEX glaucoma can usually be considered only in patients with reasonable pre-operative IOP control and without advanced visual field loss, because IOP spikes can occur after even uncomplicated cataract surgery in patients with PEX.
COURSE AND OUTCOMES
PEX syndrome is a common cause of glaucomatous visual loss. About 10% of patients who have PEX syndrome eventually develop glaucoma. Despite medical or surgical management, one study noted that 25% of patients affected by PEX glaucoma are blind in at least one eye and 7% are blind in both eyes  (but there may be bias because of the referral nature of the study group). These data underscore the potentially aggressive nature of glaucoma associated with the PEX syndrome. With careful and meticulous follow-up, most patients have a favorable outcome. Understanding of the nature of the PEX material and its role in the pathogenesis of glaucoma will pave the way for new approaches in management, control, and prevention.
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