Pigment dispersion syndrome (PDS) and its potential sequela, pigmentary glaucoma (PG), are characterized by disruption of the iris pigment epithelium (IPE) and subsequent deposition of the dispersed pigment throughout the anterior chamber. Once thought to be rare, PDS is now appreciated to be a very common condition. In most people, PDS can exist for long periods of time without contributing to further pathology. However, in some people the accumulation of pigment and debris liberated from the IPE is accompanied by elevated intraocular pressure (IOP) and increased risk of glaucoma. Current theories of the pathophysiology of PDS and PG are dominated by a hypothesis first postulated by Campbell that pigment dispersion is initiated by mechanical abrasion between the iris and anterior packets of lens zonules. While this hypothesis explains several clinical features of the disease and has gained wide acceptance, several gaps in knowledge still remain. This chapter reviews the current state of knowledge and draws attention to lingering questions relevant to the basic mechanisms of PDS and PG.
Key symptoms and signs
The key feature of PDS and PG is shedding of melanin pigment from the IPE with subsequent accumulation on anterior-segment structures ( Box 21.1 ). Although dispersed pigment can be widely distributed, it tends to accumulate in characteristic regions. One particularly recognizable sign of PDS is a narrow, vertical, spindle-shaped brown band of pigment deposited on the central corneal endothelium (referred to as a “Krukenberg’s spindle”; Figure 21.1 ). Dispersed pigment is also found scattered on the surface of the iris ( Figure 21.2 ), in the trabecular meshwork (especially inferiorly), and at the junction of the posterior lens capsule and zonules (referred to as a “Scheie’s stripe”). Radial, midperipheral, slit-like iris transillumination defects are typically present ( Figure 21.3 ). PDS is asymptomatic. The majority of PDS cases do not progress to PG and the prognosis is usually good.
Signs of pigment dispersion syndrome
Dispersed pigment on iris
Darkly pigmented trabecular meshwork
Dispersed pigment of anterior lens capsule
Signs of pigmentary glaucoma
Pigment dispersion syndrome
Fluctuations in intraocular pressure
Optic nerve head cupping
Visual field changes
However, in some PDS cases IOP becomes elevated and PG may ensue. The key signs of PG match those for PDS, but may also involve large fluctuations in IOP, optic nerve head cupping, and visual field changes. Like most forms of glaucoma, PG is asymptomatic for many people. Patients may present with symptoms related to episodic rises in IOP, such as colored halos around lights and blurred vision.
Current knowledge of PDS and PG began with important contributions from Krukenberg, who in 1899 reported spindle-shaped pigment deposition on the cornea, and von Hippel, who in 1901 suggested that pigment accumulations obstructing aqueous humor outflow could lead to elevated IOP. By 1949, Sugar and Barbour recognized patients sharing Krukenberg’s spindles, trabecular pigment accumulation, and open angles, naming the condition “pigmentary glaucoma.” The IPE was subsequently recognized as the source of liberated pigment, which Campbell proposed in 1979 to involve mechanical rubbing between anterior packets of lens zonules and the peripheral iris in predisposed eyes. Although originally described as rare, Ritch et al have documented that PDS is in fact a very common condition and have thus drawn attention to the need for a better understanding of factors determining whether or not PDS progresses to PG.
The epidemiology of PDS and PG suggests a multifactorial disease process. PDS is extremely common in the general population. For example, a screen conducted by Ritch et al in New York found PDS in 2.45% of people examined. In contrast, PG is less common. Studies examining the conversion rate from PDS to PG have yielded varying results, with studies of patients in glaucoma specialty practices yielding conversion rates from 35% to 50%, whereas a community-based study found a conversion rate of only 10% at 5 years and 15% at 15 years.
PG is particularly likely to affect young myopic males. PDS is most commonly observed in patients 30–50 years old. While PDS occurs in approximately equal numbers of men and women, progression to PG is more likely to occur in men. PDS and PG are both associated with myopia. However, it is unclear whether myopia contributes to the likelihood of progression from PDS to PG, with some studies finding severe myopia predictive of progression and others finding no statistically significant correlation with conversion.
PG is believed to be strongly influenced by heredity, but definitive mutations associated with the disease have not yet been identified. Several families affected by PG have been described. In some pedigrees, inheritance appears to follow an autosomal-dominant mode of inheritance. However, some pedigrees are consistent with recessive inheritance and other authors report that the majority of cases appear sporadic. Positive family histories for glaucoma among PG patients vary widely, with studies reporting a positive family history for glaucoma in 16–48% of cases. These disparate observations might be explained in several ways, including incomplete penetrance of a dominant disorder, multigenic influences, and complex gene–environment interactions, to name a few. Promising findings have reported linkage to loci at chromosomal locations 7q36 and 18q22. Mutations at these loci have not yet been identified. To date, the potential importance of these loci has neither been replicated nor refuted by other groups, leaving their potential role in most cases unclear.
Initial diagnosis of PDS is typically based entirely on slit-lamp examination. Classical features contributing to diagnosis include: (1) presence of a Krukenberg’s spindle; (2) dense trabecular pigmentation; (3) presence of Scheie’s stripe; and (4) radial, slit-like, midperipheral iris transillumination defects. However, many patients will not simultaneously exhibit all four features. Posterior bowing of the midperipheral iris, which likely contributes to mechanical abrasion between the iris and lens zonules, is often detectable ( Figure 21.4 ). The extent of pigment dispersion is an important component of diagnosis as small amounts of pigment accumulation within the trabecular meshwork are also part of the normal aging process. Because PDS tends to become quiescent with advancing age, older patients with glaucoma may have only subtle features of PDS and may be misdiagnosed with primary open-angle or normal-tension glaucoma. Diagnosis of PG involves PDS, plus signs of glaucoma. Approximately 17% of PDS cases have PG at the time of initial diagnosis, suggesting that screening for glaucoma at the initial examination is warranted.
Clinical signs of PDS and PG have been reported to show pronounced ethnic variability. For example, the slit-like midperipheral iris transillumination defects identifiable by slit-lamp exam are frequently absent in African-Americans and Chinese. Variable iris transillumination related to iris color has previously been observed in other populations, with 25% of blue irides and 68% of brown irides lacking slit-like defects. Thus, the frequent absence of iris transillumination defects in African-Americans and Chinese might partially be explained by darker iris colors. Use of sensitive infrared cameras to supplement traditional slit-lamp exams helps to detect iris transillumination defects in African-Americans with PDS, though the defects were not always the classic slit-like defects typical of PDS in Caucasians. PDS and PG have previously been thought to be quite rare in African-Americans. However, PDS might instead be underdiagnosed due to the difficulty of detecting these iris transillumination defects in African-Americans.
Differential diagnosis of PDS and PG includes exfoliation syndrome, uveitis, melanoma, iris and ciliary body cysts, trauma, postoperative conditions, and age-related changes. Exfoliation syndrome in particular involves substantial dispersion of pigment and some eyes have signs of both PDS and exfoliation syndrome. The extent of iridocorneal angle pigmentation occurring in exfoliation syndrome can correlate more strongly with presenting IOP than does the amount of exfoliative material on the anterior lens capsule, suggesting that the pigment dispersion occurring in exfoliation syndrome is also of pathologic relevance.
In the absence of elevated IOP or progressive optic nerve damage, PDS typically does not require any treatment. Regular follow-up is suggested to monitor for possible progression to PG. Treatment for PG follows the same regime as open-angle glaucoma, but with some special considerations. Miotics can decrease iridozonular contact and may prevent further progression of the disease, although use of this class of agents is limited because they can also worsen myopia and increase the risk of retinal detachment. Prostaglandin analogs such as latanoprost are effective in managing IOP in PG, although these agents often also cause increased iridial pigmentation: in the context of PDS iris disease the long-term consequences of this pigmentation are largely unknown. When treated surgically, PG patients who have trabeculectomy are more likely to have issues with hypotony maculopathy because they tend to be young and myopic.