Chapter 224 – Pigmentary Glaucoma
STUART F. BALL
• A form of open-angle glaucoma characterized by disruption of the iris pigment epithelium with deposition of pigment throughout the anterior segment.
• The classic triad consists of corneal pigmentation (Krukenberg’s spindle); slit-like, radial, midperipheral iris transillumination defects; and heavy accumulation of pigment in the trabecular meshwork.
• 25–50% of patients with pigment dispersion syndrome develop pigmentary glaucoma.
• Typically young, myopic men.
• Predominantly Caucasian.
• “Reverse” pupillary block mechanism.
• Autosomal dominant inheritance.
The pigment dispersion syndrome once was thought to be responsible for a form of rare, secondary, open-angle glaucoma but is now recognized as a common primary condition. It is associated with an autosomal dominant inherited form of glaucoma that affects an estimated 0.5–5% of the glaucoma population of the United States.
The term pigmentary glaucoma was first used in 1949 by Sugar and Barbour to describe a single patient who had signs of pigment dispersion syndrome and glaucoma. By 1966, they had collected 147 cases that suffered loss of pigment from the iris and pigment deposition throughout the anterior segment, which characterizes this disease. In 1979, Campbell presented evidence that the pigmentation resulted from friction of the zonular packets that rubbed on the neuroepithelium of the iris and, in 1993, Karickhoff postulated the mechanism of reverse pupillary block. The classic physical triad remains—Krukenberg’s spindle; radial, midperipheral iris transillumination defects of the iris; and heavy pigmentation of the trabecular meshwork. As more becomes known of the physical characteristics of the affected eyes, the mechanism of disease development, and the genetics behind it, new strategies of both management and prevention may become possible.
EPIDEMIOLOGY AND PATHOGENESIS
Surveys of glaucoma practices estimate the prevalence of pigment dispersion syndrome to be in the range of 25,000–220,000 affected individuals in the United States. Because the phenotypic expressions of the disease may be mild and the disease may be overlooked or misdiagnosed, the true prevalence might be underestimated grossly. Of 934 New York office workers screened using a slit lamp, 2.5% of the Caucasians had pigment dispersion syndrome, which suggests much higher prevalences. The pigment dispersion syndrome is rare in African–Americans and Asians. Approximately 25–50% of individuals with pigment dispersion syndrome eventually go on to manifest pigmentary glaucoma.
As expected from its likely autosomal dominant inheritance, pigment dispersion syndrome is found in roughly equal numbers of men and women. However, the phenotypic expression often is more pronounced in men; a 3:1 male-to-female predominance of pigmentary glaucoma exists, and a younger mean age of pigmentary glaucoma development occurs in men (35 years) than in females (46 years). 
Several features of eyes that have pigment dispersion syndrome may be important in its pathogenesis. Compared with control eyes, those with pigment dispersion syndrome are more likely to be myopic,   have a larger iris, have a midperipheral iris back-bow that increases with accommodation, have a posterior iris insertion, have a relative “reverse pupillary block” of increased lens-to-iris touch that is created by eyelid blinking, and have an increased incidence of lattice degeneration. It is believed that the particular combination of anatomical features in the eyes of these patients achieves a relative reverse pupillary block of contact between the midiris and the lens. In this “ball–valve” mechanism, each eyelid blink causes aqueous to squirt from the posterior chamber into the anterior chamber; equilibration by return flow is prevented by the peripupillary iris, which presses against the lens like a closed valve. The anterior chamber pressure gradient forces the susceptible iris to bow back against the zonules of the lens. The resultant friction during normal iris movement rubs off the pigment from the posterior surface of the iris, where it has been bowed back in contact with the zonular packets. Exercise, particularly jarring activities like jumping, in which inordinate friction might be expected, has been associated with episodes of abundant pigment liberation and sudden IOP rises, pain, and haloes. These episodes of symptomatic pigment showers are quite infrequent—normal jogging actually lowers IOP. African–Americans and Asians only rarely manifest the disease, perhaps because the iris stroma is thicker and more dense in their eyes, which renders it insufficiently flexible either to create a ball–valve mechanism or to bow posteriorly against the zonular packets. Men have a larger iris size than women and, correspondingly, may be more susceptible to the disease.
The liberated pigment deposits throughout the anterior segment, particularly in the trabecular meshwork. The pigment is felt to be responsible directly for the rare, acute, episodic IOP rises and is likely to be an essential element of the damage to the trabecular meshwork that results over time.   A positive correlation exists between duration of pigment shedding, degree of pigment shedding, and production of pigmentary glaucoma.
In the natural course of the disease, active pigment dispersion generally ceases when the patient reaches 45–50 years of age, presumably coincident with the development of presbyopia and relative pupillary block. This suggests that if the active pigment dispersion stage of the disease in these eyes could be temporarily or permanently retarded, the entire cascade of pigmentary glaucoma might be prevented. Just such a pharmacological or surgical manipulation of the iris configuration is, indeed, now
possible (see below under Treatment ). The results of such interventions are being studied.
The gene or genes that code for most cases of pigment dispersion syndrome are about to be isolated and have been mapped to chromosome 7q35–q36.  With the ability to screen genetically for pigment dispersion syndrome and with the relative ease the slit-lamp examination to identify the phenotype or phenocopies of the disease, preventive strategies could be employed easily if they are proved effective. Individuals who have the gene or the phenotype are at highest risk for glaucoma—particularly young Caucasian myopic males who have a susceptible iris stroma—theoretically could be offered prevention. A large-scale, prospective clinical trial is required to evaluate the effectiveness of these strategies.
Pigmentary glaucoma is a bilateral disorder characterized by loss of pigment from the pigment epithelium of the iris, usually in the midperipheral region. It often is revealed on transillumination
Figure 224-1 Transillumination defects (arrowheads). The radial, midperipheral, spoke-like iris transillumination defects typical of patients with pigmentary glaucoma correspond anatomically with zonular packets.
Figure 224-2 Unusually dense Krukenberg’s spindle (arrowhead). The pattern represents pigment deposited on the corneal endothelium in a vertical spindle pattern and is probably the result of the action of aqueous convection currents.
as radial, slit-like defects ( Fig. 224-1 ). Transillumination defects often are seen inferiorly first but may not be detectable early in the disease, or at all, in patients who have thick iris stroma.
The liberated pigment granules disperse with aqueous convection currents through the posterior and anterior chambers and collect in characteristic regions. Generally, the pigment assumes a narrow, vertical, spindle-shaped, brown band on the back of the central cornea, 1–2?mm in width and 3–6?mm in height, termed a Krukenberg’s spindle ( Fig. 224-2 ). With the slit lamp, the pigment often is seen widely scattered on the surface of the iris also; when viewed by gonioscopy through a dilated pupil, pigment collections also may be seen on the zonules, peripheral lens capsule, and anterior vitreous face ( Fig. 224-3 ). Typically, a homogeneous collection of pigment occurs in the trabecular meshwork, which initially is confined to the pigmented meshwork and is more dense inferiorly. With increasing dispersion, the pigment collection extends onto the nonpigmented meshwork and anterior to Schwalbe’s line (Sampaoelesi’s line; Fig. 224-4 ). The pigment may disappear substantially and is much faded by the sixth and seventh decade of life in most patients, the result of a cessation of active pigment dispersion coupled with the eyes’ natural phagocytic and clearing mechanisms. However, in later life, pigment dispersion syndrome may overlap with exfoliation syndrome in the same patient, creating confusion in the natural course of pigment signs, and likely manifesting as a comorbid condition.
Compared with normal eyes, those affected by pigment dispersion syndrome have a deeper anterior chamber, larger iris, a more posterior iris insertion, and often a posterior concavity of the iris associated with increased midiridolenticular touch. Pigment dispersion syndrome is only rarely seen in African–Americans and Asians. The generally thicker, more rigid, and less crypted iris stroma of African–Americans’ and Asians’ eyes may inhibit the
Figure 224-3 Gonioscopic view of pigmentary glaucoma. The patient’s dilated pupil shows dense pigment accumulation on anterior (arrowhead) and posterior (double arrowheads) zonular packets.
Figure 224-4 Gonioscopic view of pigmentary glaucoma. The patient has a wide, open anterior chamber angle, which shows a back-bowed peripheral iris (dotted lines) and dense band of pigment on trabecular meshwork (arrowhead) and Schwalbe’s line (Sampaoelesi’s line) (double arrowheads).
development of pigment dispersion syndrome. It may be that an inherently flaccid iris is a prerequisite. The back-bowed iris, seen best as a posterior concavity on gonioscopic examination, is likely pathogenic of the pigment dispersion and, if so, should be the first observable clinical trait. The posterior concavity is eliminated after iridectomy, is reduced by prolonged nonblinking, can be altered by either miotic or cycloplegic drugs, and disappears spontaneously in patients by 45 or so years of age.
With prolonged pressure elevation, optic nerve head and visual field changes are produced. The pattern of glaucomatous damage is typical of primary open-angle glaucoma. Optic nerve cupping and visual field damage proceed progressively with uncontrolled intraocular pressure (IOP) and have been reported to occur in the absence of elevated IOP in a pattern akin to normal-tension glaucoma in patients of 60–80 years of age.
DIAGNOSIS AND ANCILLARY TESTING
Identification of patients who have pigment dispersion syndrome consists of examination for, and detection of, the clinical signs. The Krukenberg’s spindle is best seen with indirect slit-lamp illumination and specular scatter. Its density usually correlates with the intensity of pigment in the meshwork but is sometimes only faintly perceptible and may disappear late in the disease.   The trabecular pigmentation is identified easily using routine gonioscopy, and the uniform distribution and homogeneous pattern helps differentiate it from other conditions that produce pigment, like pseudoexfoliation and uveitis, which are associated more commonly with patchy trabecular pigmentation and clumps of cells and debris. The heavy trabecular pigmentation is the most consistent and reliable finding of the disease and the one most heavily relied on for the diagnosis. Pigment accumulation on the ocular surfaces, such as the iris, zonules, ciliary body, and anterior vitreous, is less common, and when present always is accompanied by very dense pigment in the trabecular meshwork.
Iris transillumination defects in a midperipheral, radial, spoke-like configuration is characteristic of pigment dispersion syndrome, but it often is difficult to demonstrate and is not always present. The defects are best seen at the slit lamp by a sufficiently dark-adapted observer using retroillumination through a 3–4?mm pupil, or by using a fiberoptic light source for transscleral illumination. The research technique of infrared videography has demonstrated even greater sensitivity. It may be impossible to transilluminate eyes of patients who have dense iris stroma, even with considerable iris pigment epithelial loss, so demonstration of transillumination is supportive of but not required for the diagnosis. The posterior concavity of the iris, when present, is an extremely supportive finding, because it is the likely precursor to all subsequent events in the pigment dispersion cascade.
Several glaucomatous conditions are associated with excessive liberation and dispersion of pigment. Pseudoexfoliation (see Chapter 223 ) usually is differentiated by older age group, the presence of exfoliation material on the lens, lack of the spoke-like, midperipheral iris transillumination defects (defects in pseudoexfoliation usually are confined to the pupillary border), and generally more patchy distribution of trabecular pigment. Glaucoma secondary to iris chaffing from malpositioned posterior chamber intraocular lens haptics is differentiated by the history and pattern of iris transillumination that corresponds to the intraocular lens configuration. Uveitis (see Chapter 226 ) produces signs of inflammation such as anterior chamber cells, keratic precipitates on the cornea, and synechiae that are not present with pigmentary glaucoma. Melanosis and melanoma (see Chapter 230 ) are differentiated easily. A form of primary open-angle glaucoma associated with pigment liberation has been described in predominantly older,
Figure 224-5 Gross and scanning electron microscopic views. A, Gross specimen from patient with pigment dispersion syndrome. B, A scanning electron microscopy view of the posterior surface of the iris. D, defects of pigment epithelium in iris; C, ciliary processes; A, area devoid of pigment epithelium; P, posterior surface of iris. (From Yanoff M, Fine BS. Ocular pathology, ed 5. St. Louis, Mosby; 2002.)
hyperopic African–American women, but lacks iris transillumination and the iris back-bowing, and is not confused easily with pigmentary glaucoma.
The manifestations of pigment dispersion syndrome and pigmentary glaucoma generally are considered to be exclusively ocular, with no well-accepted systemic associations. It has been suggested recently that patients who have pigment dispersion syndrome are more likely to have systemic adrenergic hypersensitivity and a higher mean intelligence, as well as to be more prone to cardiovascular disease, more goal oriented, and more prone to stress than control patients. An increased incidence of pigment dispersion syndrome has been documented in patients who test positive for the ability to taste phenylthiocarbamide, a genetic marker.  This genetic link increases the possibility that the above associations, and perhaps others yet uncovered, may be linked with pigment dispersion syndrome and pigmentary glaucoma.
The reverse pupillary block of pigment dispersion syndrome creates a friction between the posterior iris surface and the anterior zonular packets of the lens. Scanning electron microscopy clearly reveals the congruity of the radial defects of posterior iris neuroepithelium that overlies the zonular bundles, and ruptured epithelial cells, which contain individual pigment granules ( Fig. 224-5 ). The free pigment granules line spaces of the uveal meshwork and the inner portion of the corneoscleral trabecular meshwork. Intracellular pigment accumulation is seen in the deeper portions of uveal and trabecular meshwork cells
Figure 224-6 Pigment dispersion syndrome. Melanin pigment (P) is present within the endothelial cells lining the beams of the trabecular meshwork (T). S, Stroma; SC, Schlemm’s canal. (Courtesy of Dr. BS Fine.)
( Fig. 224-6 ). The collapse of trabecular beams and increased loss of cells that line the beams mirror the pathology seen in specimens from primary open-angle glaucoma.   However, pigment accumulation on and within corneal endothelial cells in pigment dispersion syndrome seems to create no change in cellular morphology or function.
The major goal of management of pigmentary glaucoma is to lower IOP to prevent optic nerve damage. All ocular hypotensive medications for open-angle glaucoma also are effective in pigmentary glaucoma and, thus, may be employed, although the miotic agents are tolerated less well in the age group affected. Patients respond well initially to laser trabeculoplasty, probably because the pigment facilitates the effect of the argon laser, but the effect may be short lived, perhaps because of continued dispersion of the pigment and progressive trabecular damage. When these modalities fail, filtration surgery is indicated; a higher percentage of patients with pigmentary glaucoma go on to filtration surgery compared with those who have primary open-angle glaucoma. The success rate of filtration surgery is good. Pigmentary glaucoma responded better than chronic open-angle glaucoma to trabecular aspiration surgery, implying that removal of free and accumulated melanin granules is beneficial to IOP control in pigmentary glaucoma.
If the assumption of the mechanism of disease in both pigment dispersion syndrome and pigmentary glaucoma is correct, then theoretically it should be possible to prevent the progression from pigment dispersion syndrome into pigmentary glaucoma and the progression from early pigmentary glaucoma into more advanced pigmentary glaucoma by prevention of the pigment dispersion process itself. Indeed, the posterior bowing of the iris seen in cases of pigment dispersion syndrome and pigmentary glaucoma may be reversed, a reversal easily achieved using laser iridectomy. The rush of pigment from the anterior chamber to the posterior chamber witnessed at the laser slit lamp after iridectomy dramatically confirms that the reverse pupillary block has been eliminated. Iridectomy in patients with pigmentary glaucoma results in a significant (65%) reduction in aqueous melanin granules. Unfortunately, this intervention as a prophylactic management in pigment dispersion syndrome or as a palliative management in pigmentary glaucoma has not yielded measurable benefit in the 10 years since its introduction. Similarly, management with miotic agents, delivered as drops, ointments, or sustained release inserts, may tighten the iris and flatten its contour, and perhaps reduce the iridolenticular contact and zonular friction. Long-term use of miotic drugs may result in a reduced volume of dispersed pigment, progressively fewer iris transillumination defects, and easier pressure control. However, these drugs are tolerated poorly by young patients because of induced myopia, and a greater risk of detachment exists in the presence of myopia and lattice degeneration.
COURSE AND OUTCOMES
The natural history of pigment dispersion syndrome and pigmentary glaucoma is well charted. The onset of clinically manifest disease usually occurs at about 25 years of age. Active pigment dispersion seemingly accelerates during the following decade until it tapers off at about 40–50 years of age, presumably because of the development of relative pupillary block and the loss of accommodative ability. Signs of pigment dispersion syndrome and pigmentary glaucoma may regress—pigment deposition in the trabecular meshwork, the corneal endothelium, and surface of the iris may clear substantially or even disappear ; iris transillumination defects may fill in. Clinical expression of pigment dispersion syndrome, consequently, is much less common in those 60–80 years of age.
Although many patients with pigment dispersion syndrome may “burn out” in later years, this is rare among patients with pigmentary glaucoma followed prospectively over long periods. Conversely, pigmentary glaucoma generally exhibits a more aggressive character and patients come to filtration surgery earlier compared with those who have primary open-angle glaucoma.   Because pigmentary glaucoma often has a very aggressive nature and because no proof exists that the transition from pigment dispersion syndrome to pigmentary glaucoma can be aborted using therapeutic interventions (such as prophylactic iridectomies), patients who have pigment dispersion syndrome must be followed at least yearly with pressure checks and optic nerve examinations.
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