Pigment dispersion syndrome (PDS) is a unique and fascinating entity. Far more prevalent than previously suspected, (89) it is the first common disease leading to glaucoma for which we are on the verge of a coherent overall explanation of pathogenesis and pathophysiology. This paper is an attempt to tie together many interesting and sometimes disparate and/or apparently anomalous findings in order to synthesize a coherent portrait of the disease.

This is the beginning of a Living Document on PDS and pigmentary glaucoma (PG). The concept of a living document is to create a summary and databank of all the world's knowledge on this particular subject. It will grow and develop over time. Ideally, in the future, newly discovered facts may be peer reviewed and inserted directly into the Document. This Document is intended to serve as a source of information both for professionals and patients. As such, it may be highly technical to some readers. A glossary is being developed and will be posted when completed. Nevertheless, with the extensive illustrations, the gist of the material should be largely intelligible to the interested reader.

PDS and pigmentary glaucoma (PG) are characterized by disruption of the iris pigment epithelium (IPE) and deposition of the dispersed pigment granules throughout the anterior segment. The classic diagnostic triad consists of corneal pigmentation (Krukenberg spindle; slit-like, radial, mid-peripheral iris transillumination defects, and dense trabecular pigmentation. The iris insertion is typically posterior and the peripheral iris tends to have a concave configuration. The basic abnormality in this hereditary disorder remains unknown.

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In 1899, Krukenberg (56) described spindle-shaped pigment deposition on the cornea. In 1901, von Hippel (111) suggested that pigment obstructing the aqueous outflow system could lead to elevated intraocular pressure (IOP). Levinsohn (59) first suggested that pigment in the anterior chamber angle of patients with glaucoma originated from the IPE. A cause-and-effect relationship between pigment and glaucoma found both support (46,51) and opposition (12,30,110).

In 1949, Sugar and Barbour (107) described two young, myopic men with Krukenberg spindles, trabecular hyperpigmentation and open angles, whose IOP increased with mydriasis and decreased with pilocarpine. They identified the disorder as a rare, distinct form of glaucoma, which they termed pigmentary glaucoma. More patients were subsequently reported, and in 1966 Sugar (106) reviewed 147 cases in the world literature, mentioning several additional features, including bilaterality, frequent association with myopia, greater incidence in men than in women, and a relatively young age of onset. These features were confirmed by Scheie and Cameron. (94)

In the 1950s, the discovery of iris transillumination defects led to the concept that the trabecular pigment originated from the IPE and perhaps the ciliary body. (10,95) Congenital atrophy or degeneration of the IPE was suggested as a cause of loss of iris pigment.(14,91)

In 1979, Campbell (18) proposed the pathogenesis to involve mechanical damage to the IPE during rubbing of the posterior iris against the anterior zonular bundles during physiologic pupillary movement. Subsequently, the autosomal dominant inheritance, natural history, reversibility, and more precise therapeutic approaches have become increasingly delineated. Ultrasound biomicroscopic studies are presently revealing new insights into the pathophysiology of PDS.

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A. ANTERIOR SEGMENT

Loss of iris pigment appears clinically as a midperipheral, radial, slit-like pattern of transillumination defects seen most commonly inferonasally and more easily in blue eyes than in brown ones. Although the defects can sometimes be seen by retroillumination, they are more easily detected by a dark adapted examiner using a fiberoptic transilluminator in a darkened room. Infrared videography provides the most sensitive method of detection.(3) Pigment particles deposited on the iris surface tend to aggregate in the furrows.(76,106) Rarely, this pigment can be dense enough to darken the iris or to cause heterochromia when involvement is asymmetric.(60,106) Iris vascular hypoperfusion on fluorescein angiography has been reported,(36) a finding which awaits verification.

Anisocoria may occur with asymmetric involvement, the larger pupil corresponding to the eye with greater pigment loss from the iris.(2,31,32) Alward and Haynes (2) suggested the presence of an efferent defect in the eye with the larger pupil. The pupil may be distorted in the direction of maximal iris transillumination.(31,32,42) This would be consistent with the presence of hyperplasia of the iris dilator muscle (see below).(40)

Corneal endothelial pigment generally appears as a central, vertical, brown band (Krukenberg spindle), the shape being attributed to aqueous convection currents. The pigment is phagocytosed by endothelial cells,(43,52) but endothelial cell density and corneal thickness remain unchanged compared to controls.(76) Coincident PDS and megalocornea has been reported,(17,91,94,100) as have subluxated lenses.(88,94)

The anterior chamber is deeper both centrally and peripherally than can be accounted for by sex, age, and refractive error. Davidson (et al. 25) compared the central and peripheral anterior chamber depths of patients with PDS to statistical controls. The anterior chamber was significantly deeper and the anterior chamber volume was significantly greater in the PDS group, the difference being greatest inferiorly.

The angle is characteristically widely open, with a homogeneous, dense hyperpigmented band on the trabecular meshwork. Pigment may also be deposited on Schwalbe's line. The iris insertion is posterior and the peripheral iris approach is often concave. The iris is most concave in the midperiphery. In younger patients, the scleral spur may be poorly demarcated, blending with the ciliary face due to pigment deposition on these structures. Pigment may be deposited on the zonules (60,95,114) and on the posterior capsule of the lens, where it is apposed to the anterior hyaloid face at the insertion of the posterior zonular fibers.(8,50,95,114)

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Figure 1. Krukenberg spindle. Liberated pigment granules are borne by aqueous currents and deposited on the structures of the anterior segment. The vertical accumulation of thesepigment granules along the corneal endothelium is known as Krukenberg's spindle). The spindle tends to be slightly decentered inferiorly and wider at its base than its apex
Figure 2. Ultrasound biomicroscopy in PDS. The iris concavity in PDS has been investigated using high frequency, high resolution ultrasound biomicroscopy. Ultrasound biomicroscopy is an innovative diagnostic tool which employs high frequency ultrasound to permit high resolution in vivo imaging of the anterior segment. It has been particularly useful in the evaluation of the structures surrounding the posterior chamber. The iris (I) is bowed posteriorly, towards the zonules and posterior chamber (PC). The ciliary body (CB), cornea (C), anterior chamber (AC), and lens capsule (LC) are visible. Although most young individuals with undisputed PDS (young age, zonular pigment dispersion, increased meshwork pigmentation, myopia) have a demonstrable iris concavity which can be measured during ultrasound biomicroscopy, the prevalence of iris concavity at the time of initial diagnosis has not been evaluated in a large study.
Figure 3. Iris transillumination. Movement of the posteriorly bowed, concave iris along the anterior zonular bundles causes a disruption of the iris pigment epithelium along the radial orientation of the zonular fibers which results in characteristic mid-peripheral, iris transillumination defects seen during slit-lamp examination. This finding is pathognomonic for zonular pigment dispersion and differentiates PDS from other glaucomas related to accumulation of pigment in the trabecular meshwork. The width, length, and frequency of these defects varies among individuals and a high index of suspicion on the part of the examiner is often needed to make the diagnosis. It is best to search for iris transillumination defects prior to pupillary dilation by using a small slit beam in a darkened room. However, those patients who do not appear to have transillumination defects on retroillumination but have increased trabecular pigmentation, Krukenberg spindle, myopia or juvenile open angle glaucoma should be examined with scleral transillumination using a fiberoptic scleral transilluminator in a darkened room to facilitate detection. Pupillary dilation may prevent the detection of transillumination defects because of the compaction of the peripheral iris stroma.
Figure 4. Infrared video pupillography. The number of iris transillumination defects often corresponds clinically to the degree of anterior segment pigment liberation and elevated IOP, although this is not always the case. In eyes with asymmetric disease, the eye with the higher pressure is invariably the one with the greater pigment liberation.Some physicians have advocated the documentation of the numbers of transillumination defects as a means of the following the progression of the disease. Individuals in the pigment liberation phase of the disease typically have an increasing number of transillumination defects, whereas those individuals who are no longer actively liberating pigment may have defects which shrink in size or disappear. Although standard slit-lamp photography can be used to document the number of defects, infrared video pupillography may provide more accurate visualization
Figure 5. Iris surface pigmentation. Pigment accumulation on the anterior surface of the iris often appears as concentric rings within the iris furrows. More diffuse pigmentation can cause a diffuse darkening of iris color, which is more apparent in lightly pigmented irides because of the degree of color change. Asymmetry of pigment liberation may result in iris heterochromia, with the darker iris being the more affected side.
Figure 6. Trabecular pigmentation. Increased trabecular pigmentation occurs in a wide variety of glaucomas. In PDS, the trabecular pigmentation is typically homogeneous in its distribution, unlike the variegated appearance associated with exfoliation syndrome, uveitis, or angle-closure glaucoma. The degree of pigmentation ranges from moderate to dense and is often quite striking. In some individuals the increased pigmentation may be limited to the posterior trabecular meshwork, while in others the anterior meshwork, Schwalbe's line, or peripheral cornea may be covered with dense pigmentation.
Figure 7. Lens pigmentation. Pigment deposition on the zonular apparatus may allow visualization of the radial anterior zonules as they traverse the posterior chamber to the anterior lens surface. Since liberated pigment floats freely within the aqueous, some of the pigment granules may also move posteriorly behind the lens equator, where they accumulate at Weigert's ligament, the region of contact between the anterior hyaloid face and the posterior lens capsule. Visualization of this circular ring or arc of pigmentation requires pupillary dilation and upon occasion, gonioscopy, and is considered pathognomonic for PDS, since it has not been identified in other disorders associated with pigment liberation in the anterior segment.