22

Pigment Dispersion and Pigmentary Glaucoma

Ian Conner, MD, PhD; Kimberly V. Miller, MD; Joel S. Schuman, MD, FACS; and David L. Epstein, MD, MMM

DIAGNOSIS

Pigment dispersion syndrome (PDS) is characterized by loss of pigment from the posterior surface of the iris in the mid-periphery in both eyes and an attendant deposition of pigment on intraocular structures, such as the back of the cornea, the trabecular meshwork (TM), the iris, and the lens. PDS can occur with or without the pigmentary glaucoma (PG) that was first described as an entity by Sugar and Barbour.^1,2

We have observed the full dispersion syndrome without glaucoma in routine eye examinations, at least as frequently as actual PG. Many PDS patients who have been observed for years do not develop elevated intraocular pressure (IOP).

PDS typically occurs in people between the ages of 20 and 45 years, but it has been found in rare instances in teenagers and older adults. It is more common in men than women. Women seem to develop PG at a slightly older age than men. A family history of PG is seldom obtained, but PG has been reported in brothers,³ and we have found it in young female twins and in a father and daughter. Sometimes, there is a family history of primary open-angle glaucoma.

The onset of PG in some cases appears to be rapid, with elevated IOP, fine corneal edema, and symptoms of blurring of vision or haloes around points of light. These symptoms usually make the patient aware that there is a problem, though in most instances there is no pain. In most cases, the diagnosis can be made before there has been much damage to the optic nerve head. Unfortunately, the circumstances of onset are not always as benign. We have certainly seen some young men with this type of glaucoma who developed severe cupping and atrophy of their optic discs and loss of visual field before they became aware of any problem, as in the following case.

Case 22-1

A 30-year-old White man presented with a 1-year history of intermittent haloes. A diagnosis of PG had been made in Argentina. He was 6 D myopic in both eyes. He had fine pigment deposition on the corneal endothelium and extensive, mid-peripheral iris transillumination. Both lenses showed fine pigment dusting on the anterior capsule and pigmentation of the posterior surface peripherally. Gonioscopy revealed dense pigment bands covering the TM, with fine uveal meshwork (“iris processes”) from iris to ciliary body band and scleral spur. IOPs were 30 mm Hg OD and OS. There was marked glaucomatous cupping of both discs extending superiorly to the rim with extensive inferior field loss in both eyes.

Treatment was rapidly advanced to maximal tolerated medical therapy. There was evidence of worsening field loss in the right eye. On this basis, a filtering operation was performed on this eye. Although the bleb seemed to fail, with resumption of medical therapy, including use of pilocarpine Ocusert (Alza Pharmaceuticals; no longer clinically available at the time of this writing), and later timolol, IOPs were well controlled in the operated eye. The patient has refused operation on the left eye, but fortunately the IOP in this eye has been sufficiently controlled by topical medications, and the field has remained stable.

Unfortunately, it is not uncommon for patients with PG to present with reduced vision in one eye,4 which may have been attributed to optic neuritis in the past. We have wondered, in such patients, whether the commonly observed fluctuating IOP may have caused a previous acute optic nerve vascular insult.

Most patients with PDS have deep anterior chambers and are usually, but not always, myopic. The first clue to the disease may be found during slit-lamp examination when pigment is seen on the posterior surface of the cornea forming a Krukenberg spindle, but this is not seen in every case (Figure 22-1). Some have little or no pigment on the back of the cornea. The reason for the variable pigment deposition on the corneal endothelium is unclear. Aqueous convection currents deposit the pigment on the posterior surface of the corneal endothelium. Curiously, the pigment does not typically cause corneal endothelial decompensation.⁵ Most commonly, one can observe a sprinkling of pigment on the anterior surface of the iris stroma and on the back of the cornea.

The PDS (with or without PG) is not associated with any external or internal sign of intraocular inflammation, such as synechiae or inflammatory cells in the aqueous humor or on the back of the cornea, but we have seen cases in which pigment particles circulating in the aqueous humor have been mistaken for inflammatory cells and misdiagnosed as uveitis (eg, glaucomatocyclitic crisis). Attention to the darker color of the particles helps prevent this mistake.

GONIOSCOPY

Gonioscopy in PDS (with or without PG) typically demonstrates in each eye a deep anterior chamber, with a flat and slightly tremulous iris. A concave (posterior) iris contour is frequently observed (Figure 22-2).^6,7 (This sometimes is more readily apparent on direct Koeppe gonioscopy than on mirrored slit-lamp gonioscopy.) The iris stroma appears normal, except for pigment that may be deposited on its anterior surface. The angle is wide and open in all quadrants. The ciliary band is often broad. The most essential feature in the angle is a band of dark brown or even black, homogeneous, velvety pigment that may strikingly delineate the posterior filtration portion of the TM in the whole circumference (Figure 22-3). The pigment sometimes covers the whole width of the TM, including Schwalbe’s line (where it can form a Sampaolesi’s line, similar to pseudoexfoliation syndrome). Pigment may also be deposited on the ciliary body band. During gonioscopy, if one looks through the pupil toward the equator of the crystalline lens, one can also see an accumulation of pigment at the posterior surface of the lens (Scheie stripe or Zentmayer line) at the insertion of zonular fibers onto Wieger’s ligament. In cases with heavy pigment dispersion, there may be pigment deposition on the anterior lens surface as well.

Although a dark, dense, wide band of pigment filling the TM is the rule in PDS and PG, we have occasionally seen the density of the pigment band diminish with age, as described by Lichter and Shaffer.⁸ We are not convinced that this is necessarily accompanied by an improvement in IOP control. This same phenomenon of decreasing trabecular pigment band density was demonstrated in an experimental monkey model of PDS.⁹

In other cases, we have seen patients at a single stage with a typical transillumination pattern of the iris, but with a pigment band in the angle of only moderate density. In such cases, when the typical iris transillumination pattern has been present, we have postulated that some of the trabecular pigment may have washed out through the outflow channels or been carried away by phagocytes. The latter has also been implicated in the experimentally produced model.9

IRIS TRANSILLUMINATION

The presence of a typical iris transillumination defect (Figure 22-4) is considered essential to the diagnosis of PDS. When the examiner has dark adapted for several minutes and employs a fiber-optic transilluminator in a darkened room, one sees the typical, mid-peripheral iris transillumination pattern that is initially radial and slit or wedge-like, but later may become confluent. In advanced conditions, these abnormal iris transillumination defects can extend into the central third of the iris.

To test for loss of pigment from the posterior layer of the iris, transillumination of the iris is performed by holding a shielded fiber-optic transilluminator against the lower lid temporally or against the sclera temporally, in such a way that light passing through the sclera glows bright and pink from the pupil when one looks directly at the eye. This must be done in a darkened room. In normal eyes, the light does not shine through the iris in the manner characteristic of PDS, but in genuine cases of the syndrome, the iris trans-illuminates in a striking patchy ring in the mid-periphery. This is due to loss of pigment from this portion of the posterior pigment layer. Elsewhere, either near the pupil (except at advanced stages) or in the periphery adjacent to the ciliary body band, the pigment layer appears to remain intact. The selective loss of pigment in the mid-portion of the iris can be even better appreciated if one performs the transillumination while viewing the iris through the Koeppe gonioscopy prism. More commonly, at the slit lamp, the beam may be narrowed and placed coaxial to the observer in the patient’s pupil, in order to search for transillumination defects. This maneuver should be a routine part of one’s slit-lamp examination.

It is difficult to make a definitive diagnosis of PDS in the absence of a characteristic iris transillumination pattern, although there are rare patients (usually with dark irides) who demonstrate all other aspects of the syndrome but in whom the iris does not transilluminate and who have no known source for pigment dissemination other than the iris (ie, exfoliation, iris or ciliary body cysts, and melanoma^10–12 were ruled out). Dr. Grant saw one patient in whom a typical transillumination pattern disappeared, as though from new pigment formation; this patient also had gradual disappearance of a pigment band from the angle several years after successful filtration surgery.

Case 22-2

A 29-year-old man was aware of some aching around his left eye. His ophthalmologist found IOPs of 40 mm Hg in both eyes, with pathologic cupping of both discs, worse on the left, with a Bjerrum scotoma OS. When seen here, without treatment, the IOP was 60 mm Hg with tonographic C values of 0.05 in each eye. Both discs had deep broad cups with central vessels displaced far nasally, a thin layer of tissue preserved within the rim in most of the circumference of the right disc, but excavation to the rim lower temporally in the left. The anterior chambers were deep. By gonioscopy, the irides appeared concave, attaching just posterior to the scleral spur in the whole circumference. A dense black pigment band covered the filtration portion of the TM in the whole circumference in both eyes. Transillumination showed a striking moth-eaten defect of the posterior pigment layer of each iris in a ring peripherally, characteristic of PG in both eyes. Response to treatment with pilocarpine and epinephrine was inadequate. A filtration operation was performed on the left eye, and 3 months later on the right. A better bleb was obtained on the right eye than the left. For several months, the IOP was close to 7 mm Hg in the right and in the mid-20s in the left. Frequent digital pressure on the left globe was employed to try to improve the function of the bleb. A little more than a year after the operation, both eyes had excellent blebs and IOPs of 9 mm Hg without treatment other than periodic digital pressure. The degree of cupping became notably less in each eye than when first seen, and by 8 years after the bilateral operation, the degree of cupping of both discs had decreased remarkably, though the principal vessels remained far to the nasal side of the right disc and the left was still as pale as it had been at the first observation. By that time, the amount of pigment in the angles appeared to be decreasing, and the transillumination of the irides also appeared less than when the patient was first seen. At nearly 10 years after the operation, the blebs were not quite as pronounced as formerly. IOPs reached the high teens, and epinephrine drops were started in each eye.

There is still clinical uncertainty in PG, mainly due to important clinical observations made by observant clinicians. Karickhoff13,14 and Campbell¹⁵ observed that the normally concave iris contour present in PG reverts to a planar configuration after laser iridotomy. This has been confirmed by ultrasound.^6,16 Previously, Campbell had hypothesized that rubbing of the posterior iris surface against the zonule was responsible for the pigment dispersion from the posterior iris surface.¹⁷ Some have proposed sudden bursts of aqueous humor flow through the pupil with reverse pupillary block temporarily ensuing—a ball valve effect of the lens and iris.^7,13,15 Thus, laser iridotomy, by preventing this rubbing and eliminating the valve effect, might have applicability in the treatment of patients with PG.

Nevertheless, it is not yet appropriate¹⁸ to apply laser iridotomy as a potential cure for PG for the following reasons. Clinical studies to date have not shown laser iridotomy to have a clinical benefit in PG.¹⁹ The fundamental question in this disease, whether the pigment loss from the posterior iris surface represents a primary iris pigment epithelial degeneration or abiotrophy (a kind of presenile tissue degeneration that may be genetically predetermined)^18,20 or is, in fact, a mechanical disease due to zonular rubbing¹⁷ has still not been totally resolved.²¹ The concept of zonular rubbing is ingenious and intriguing but has not, despite its ready popularity, been unequivocally established. The hypothesis was based on studies of enucleated eyes that were fixed in a usual postmortem hypotonous state in which it is difficult to orient zonular packets with the posterior iris defects as they might appear in a normal living eye. Further, in advanced PG, the iris transillumination defects may extend well into the central third of the iris where the zonule does not typically extend.

Even more importantly, there are patients who have the full PDS including iris concavity, typical transillumination defects, and angle pigmentation who do not have elevated IOP or any abnormality in outflow dynamics. There is a strong clinical impression with some limited data that such patients will never, in fact, develop PG. Except for the normal IOP and absence of glaucomatous optic nerve changes, such PDS patients cannot be distinguished from those with PG. In such patients, the same mechanical factors that lead to loss of iris pigment in PG must also be present, and yet there is no glaucoma. There must then be more to PG than pigment dispersion alone. In fact, experimental studies in living monkeys have confirmed that one cannot, in previously normal monkeys, cause PG despite instilling vast quantities of pigment into the anterior chamber and producing TM pigment bands.^9,22 That is, experimentally, one can produce PDS but not PG.

Most likely, there is some trabecular abnormality that is required in addition to the pigment dispersion for glaucoma to occur.⁹ It could be argued that the pigment release is a stressor to the TM in such individuals and that, by diminishing this stress (eg, with laser iridotomy), it might improve the clinical condition. A retrospective study did not show benefit with this approach¹⁹; however, a prospective randomized trial did indicate less risk of elevated IOP after laser iridotomy in PDS.²³ Of note, a recent Cochrane review of the existing literature did not find evidence of benefit from laser iridotomy in patients with PDS or PG, although the quality of existing evidence reviewed was generally rated as poor.²⁴

Certainly, the time is appropriate for a randomized prospective clinical trial. It would not seem outside the spectrum of acceptable practice, as a last attempt to control PG prior to incisional surgery, to offer a laser iridotomy to one eye after a full discussion of the benefits and risks with the affected patient. However, the clinician must keep the limits of our understanding firmly in mind as he or she seeks to determine whether the course of the glaucoma is truly altered, or simply the iris concavity.

PATHOGENESIS OF THE TRABECULAR GLAUCOMA

The pathogenesis of the chronic impairment in outflow function in PG is still not entirely settled. There is both clinical²⁵ and laboratory^9,26 evidence that iris pigment can acutely obstruct outflow of aqueous humor. This seems a reasonable explanation but fails to account for other patients with similar pigment in their angles but without obstruction of outflow, either by IOP measurement or tonography. Perhaps the trabecular endothelial cells respond differently to the pigment in different individuals. Richardson et al reported electron micrographic evidence of trabecular sclerosis in PG,27 but this is likely a late phenomenon. Alvarado’s group has reported abnormalities in the cell-lined outflow pathway in PG.^28,29 Further electron microscopic examination of PDS without glaucoma, as reported by Fine et al,¹⁸ is needed. Pigment alone does not appear sufficient to fully explain the obstruction in chronic PG.²⁹

We produced a model of PDS in living monkeys that has provided some insight to this condition.⁹ Homologous uveal pigment was perfused into the anterior chamber of these monkeys. Acutely, there was a substantial lowering of outflow facility, and experimental glaucoma resulted. However, rapid recovery followed in these otherwise normal monkeys, and outflow facility returned to normal despite repetitive perfusions of pigment. The monkeys developed trabecular pigment bands, which decreased in density with time. Morphologic examination indicated that the structure of the TM remained normal despite pigment phagocytosis and possible migration of trabecular endothelial cells. A few animals were observed for several additional years, with recovery of normal aqueous humor dynamics and TM morphology and cellularity.²² We concluded that iris pigment release alone is not sufficient as the sole mechanism of chronic PG; rather, there must also be some predisposition of the TM.

Some observers have suggested that PG arises secondary to a congenital mesodermal angle anomaly, or simply as a variant of primary open-angle glaucoma. We do observe prominent uveal meshwork (so-called iris processes) in patients with PDS, both with and without glaucoma, but we doubt that this anatomy is more common in PDS than in similarly myopic eyes without PDS.

DIFFERENTIAL DIAGNOSIS

The first entity to be differentiated from PG is pseudoexfoliation (see Chapter 21), in which a smaller amount of pigment is usually seen in the TM and transillumination shows no loss of pigment from the portion of the iris affected in “pigmentary” glaucoma, rather only a loss near the pupil. Rarely, a pigment ring in the angle is seen in amyloidosis with glaucoma (see Chapter 49). Pigment in various amounts is commonly found in the angle in older people with or without primary open-angle glaucoma, and some pigment may be found in the angle in association with uveitis (see Chapter 43), with cysts of the iris and ciliary body (see Chapter 35), and after surgery, traumatic angle recession, or attacks of primary angle-closure glaucoma. However, the pigment in these conditions rarely forms a uniform band in the entire circumference. Pigment is seen in the entire circumference in pseudoexfoliation, but it is usually narrower, coarser, and less dense than in PG. In none of these conditions does the pigment layer of the iris transilluminate abnormally in the mid-periphery as it does in PG. The clinician should always seek to explain the presence of abnormal pigmentation observed on gonioscopy.

PDS nearly always affects both eyes of an individual, although its severity may be asymmetric. In rare instances, it occurs only in one eye, but before accepting such a diagnosis, one should be able to identify the iris transillumination pattern and rule out other causes of monocular pigment dissemination, especially melanoma¹² of the anterior uveal tract (see Chapter 42) causing melanomalytic glaucoma.^10,11

PIGMENT DISPERSION SYNDROME WITHOUT GLAUCOMA

Pigment dispersion with consistently normal IOPs can easily escape recognition because transillumination (and gonioscopy!) is not often routinely performed, and a Krukenberg spindle may be over looked or may not be present. We commonly discover cases of PDS without glaucoma by doing a screening transillumination during routine slit-lamp examination by narrowing the slit beam to fit into the pupil, making the beam coaxial with the microscope, and observing the iris for transillumination with low magnification. The following case is an example.

Case 22-3

A 60-year-old man presented to the emergency department with a corneal abrasion. Bilateral Krukenberg spindles were noted. The past eye history was negative except for conjunctivitis. The family history was negative for glaucoma.

Several areas of abnormal iris transillumination in the mid-periphery were noted, and gonioscopy revealed a heavy trabecular pigment band in both eyes. The discs were normal, and the fields were full. Applanation IOPs were 16 mm Hg OU, and tonographic C values were 0.23 right and 0.25 left. No exfoliation was seen. During 10 years of follow-up, the IOPs remained in the teens.

This man with PDS without glaucoma is being followed as a PG suspect, but at his age and with his good outflow facility, it is unlikely that he will ever develop PG.

Recognizing that PDS without glaucoma is a real and not-so-rare entity raises the important question of whether these patients will eventually develop PG. It has been observed that the risk of conversion from PDS to PG is 10% in 5 years and 15% in 15 years.³⁰ Clearly, this means that a large portion of patients will never convert, or that it may take many years. Sugar has observed the onset of glaucoma 12 to 20 years after pigment dispersion was first detected.² In our longest follow-up, we can say that a patient with PDS can go for 20 years without developing glaucoma. This occurred in the following case.

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