Pigment dispersion syndrome

Pigment dispersion syndrome (PDS) is a condition characterised by the liberation of pigment from the iris pigment epithelium secondary to iridozonular friction and its deposition in a number of locations within the eye. These include the trabecular meshwork, which can restrict aqueous outflow and lead to severe glaucoma.
It is considerably more common than was once thought, yet it may not be diagnosed unless it leads to pigmentary glaucoma (PG). PDS shows the characteristics of autosomal-dominant inheritance,1 and around 2.5 per cent of Caucasians have it,2 so in an average week an optometrist might expect to see one or two cases.
The condition was at one time thought to be restricted to Caucasians. This is now known to be untrue, though in African-Americans exhibiting PDS, Caucasian genetic heritage may be an important predisposing factor.3
About 10 per cent of PDS subjects develop glaucoma, though estimates as high as 50 per cent appear based on previous under-estimations of the prevalence of PDS.
Men and women are equally likely to show PDS, yet males are about three times as likely to develop PG than females,4-6 and develop it at a younger age.7 Female hormones may have a protective effect against a rise in intraocular pressure.
Myopia is an important clinical correlate. Of those patients found to have PDS, 60-80 per cent are myopes, and 20 per cent emmetropic or less than a dioptre hyperopic.4,8
Furthermore, those that go on to develop PG are significantly more myopic than those who do not and the more myopic develop PG earlier.7
PDS and PG are usually bilateral and symmetrical, but assymetric cases do occur. Some appear to be associated with anisometropia, with the more myopic eye being worst affected, but most asymmetric cases occur when a unilateral anomaly is superimposed on the bilateral one. The most common in older patients is exfoliation syndrome.9
Some conditions may actually limit the effect of PDS in an eye. Early extraction of a traumatic cataract, or the development of unilateral cataract which causes pupillary block, thus reducing iridozonular contact, may limit pigment loss from the iris.10
Horner's syndrome may also have the same effect.11 Leibmann12 described four cases of asymmetric PDS where the only correlate appeared to be greater iridolenticular contact in the more affected eye.

CLINICAL FINDINGS
It is highly unlikely that PDS will be detected unless a slit-lamp examination is performed, since the classic triad of signs are unlikely to be seen otherwise. Conceivably, transillumination defects might be picked up with an ophthalmoscope, and a deep anterior chamber with a pentorch or focused ophthalmoscope beam, but either is a long shot.
Initially, the things to look for are Krukenberg's spindle, iris transillumination and a deep anterior chamber.

Krukenberg's spindle
This is likely to be the first sign detected in a routine eye examination, provided a slit lamp is used to examine the anterior chamber of the eye.
First described in 1889, it consists of pigment deposited on the back surface of the cornea. These deposits may be in the eponymous spindle shape or in a triangular formation with the apex pointing upward.
In either case, the lower half of the cornea is favoured. The distribution is a consequence of the convection currents in the aqueous humour. The significance of such a finding is often not realised. PDS has been termed a 'masquerade syndrome' in that it may imitate, and be mistaken for, anterior uveitis. Any patient with a Krukenberg's spindle and no diagnosis should be referred even if the eye is otherwise unremarkable, since the diagnosis is likely to be either PDS or chronic anterior uveitis, which in view of its association with granulomatous disease, may have long-term health implications for the patient. Not all PDS patients show a Krukenberg's spindle.

Iris transillumination (Figure 1)
Of course, the pigment has to come from somewhere, and its origin may be eloquently demonstrated by transillumination of the iris. The illumination and observation systems are aligned and placed in the straight-ahead position. A small circular or square beam of light is directed through the pupil, which should be undilated wherever possible.
The light reflected by the fundus will retro-illuminate the iris and lens. The iris pigment would normally prevent the passage of this light but in PDS the loss of iris pigment allows transillumination defects. These appear as radial, slit-like, bright lines in the mid-periphery of the iris in the area overlying the zonular fibres of the lens. Occasionally, the lines may extend more peripherally, though this is unusual.

Anterior chamber depth (Figure 2)
Patients with PDS tend to have unusually deep anterior chambers. This is often not a subtle effect. In van Herick terms, we are talking grade 8 or so. The iris insertion appears further back than normal and the iris may show a concave shape in the mid-periphery, resulting in a pie-dish appearance (Figure 3). Most normal eyes only show this effect during accommodation, and the effect is made more obvious in PDS eyes during accommodation. Some myopes without PDS also show iris concavity without accommodation.
In addition to this triad, a number of other observations may be made on some patients with the slit lamp.

Iris pigmentation (Figure 4)
Pigment may deposit on the iris, usually accumulating in the furrows, sometimes in concentric rings. More diffuse deposition may cause the whole iris to deepen in colour, and where the condition is asymmetric, heterochromia may result, with the darker eye being the more affected.

Lens pigmentation
Some pigment may find its way on to the anterior lens surface, but pigment may also accumulate on the zonular apparatus and at Weigert's ligament, which is the region of contact between the anterior hyaloid face and the posterior lens capsule. This may be seen as an arc or complete ring of pigmentation with a dilated pupil, though gonioscopy may also be required. Pigmentation of Weigert's ligament is pathognomic for PDS.
Pupil anomalies
Anisocoria may be associated with asymmetric PDS, the larger pupil corresponding to the eye with greater pigment loss from the iris.13 A distorted pupil may be seen, with the pupil diameter greatest in the direction of maximal transillumination.14

Trabecular pigmentation
Gonioscopy will reveal increased trabecular pigmentation. It tends to be dense and homogenous in appearance, unlike the more variegated pigmentation found with exfoliation, uveitis or angle-closure glaucoma.
In some individuals only the posterior trabecular meshwork is involved, but in others, the pigmentation may extend to the anterior meshwork, Schwalbe's line or even the peripheral cornea. In older patients who have passed through the regression stage, 'the pigment reversal sign' may be evident. This occurs when the pigment has cleared from all but the filtering portion of the network, and may be the only sign of previous pigment deposition in an old patient.
Retinal abnormalities
Retinal detachment is relatively common in PDS patients, with a 6-8 per cent lifetime chance.
Lattice degeneration and retinal breaks are thought to be about twice as common in PDS than in age- and refraction-matched controls. The degree of myopia, and the use of miotics, do not seem to be factors. That pigment epithelia of the iris and retina share a common embryological origin suggests that patients with PDS and PG show abnormal electro-oculographic results.15,16

PATHOPHYSIOLOGY
So what is actually happening in the eye? Evidence for the disease process has until recently come mostly from post-mortem histological studies on human subjects and ultrasound biomicroscopy.

Histological studies
The iris pigment epithelium (IPE) has come under scrutiny, and there appears to be not only a loss of pigment cells but hyperplasia and hypertrophy of the dilator fibres of the inner IPE, along with a degenerated sympathetic nerve supply. Kupfer et al17 felt that the primary defect in PDS lay in the inner IPE, and might be either a developmental anomaly or the result of the interruption of sympathetic innervation.
The degenerated nerve supply may tie in with comments that epinephrine compounds appear to be more effective in PG than in patients with primary open-angle glaucoma (POAG).4,18 The distribution of the iris transillumination defects corresponds in position and number to the zonular bundles. Campbell19,20 put forward the hypothesis that the posterior bowing of the iris brings it into contact with the underlying zonules, and the resulting friction disrupts the IPE, causing the release of liberated pigment into the posterior chamber.
Ultrasound biomicroscopic findings appear to support this theory.

Ultrasound Biomicroscopy
Modern ultrasound biomicroscopy imaging allows the shape of the iris and the degree of contact between the iris and underlying structures to be studied and measured both in 'still' and 'video' formats.
In PDS, the iris appears to be over-large, and its root further back from the trabecular meshwork,21 which would tend to promote iridozonular contact. Iridociliary contact also occurs and while it appears to be less of a factor, transillumination defects occasionally extend to the periphery of the iris, suggesting that friction may damage the epithelium of both the iris and ciliary body.
In individuals with PDS, the iris appears concave, but if blinking is prevented, the iris eventually flattens, and may become convex.22 Resumption of blinking returns the iris to its previous concave configuration. Campbell proposed that blinking deforms the cornea, causing a transient increase in IOP and pushes the iris back towards the lens. In normal eyes, this in turn pushes some aqueous humour through the pupil into the anterior chamber, equalising the pressure on both sides of the iris.
In PDS, excessive iridolenticular contact prevents this equilibration. This has been termed the 'reverse pupillary block'.23,24 If further blinking is prevented, aqueous outflow via the trabecular meshwork eventually reduces the pressure in the anterior chamber and the iris flattens, but with normal blinking there is insufficient time for trabecular outflow to achieve iris flattening, particularly if this outflow is compromised by pigment deposition on the trabecular meshwork.
Interestingly, there seems to be a correlation between the degree of myopia and increasing iridolenticular contact22 which is independent of PDS, and this may explain why myopia is such a factor in both PDS and PG.
Accommodation in normal eyes causes iris concavity similar to that found in PDS patients, and in PDS patients the concavity is enhanced.22,25 Ultrasound biomicroscopy of eyes with PDS shows iridozonular contact at the lens margin, corresponding to the location of iris transillumination defects.26 Accommodation causes anterior movement of the lens and increased iridolenticular contact. Furthermore, it is accompanied by the near pupil reflex and the miosis linked to accommodative effort. The mydriasis that comes with relaxation of the ciliary muscle may contribute to the friction which liberates pigment from the iris. Some PDS patients are known to develop sudden rises in IOP after shedding pigment following pupil dilation27-30 and provocative tests have been designed on that basis. Bouncing-type exercises, such as jogging or basketball, can also result in sudden release of pigment.31

Recently published work
So far the evidence has all pointed towards a purely mechanical model for PDS, with an over-large and posteriorly-rooted iris rubbing against the zonules. At least one gene responsible for this has been mapped.32
However, Jun-Song Mo et al recently reported findings which could have profound implications for PDS patients.33 There exists a strain of mice with pigment dispersion glaucoma and it has been used to study immune responses in the eye.
Normally the eye is 'immune privileged'. In other words, it can respond to invasion without permitting the full gamut of immune responses which occur in other tissues of the body. In a delicate and precise organ such as the eye, full-blown inflammation could destroy vision. Those white blood cells which would cause inflammation (T-cells) are suppressed. In the model mice, bone-marrow-derived white blood cells programmed for inflammation were found in the iris tissue, even before the pigment dispersion itself became manifest. The authors suggest that the first thing that the genes responsible for PDS do is to break down the immune privilege, leaving the eye vulnerable to inflammation.
The theory was further tested by replacing the bone marrow of the PG mice with that of normal mice. Immune privilege was maintained and pigment dispersion did not occur. The mice are being followed to see whether they go on to develop glaucoma. Should this also be prevented, and provided the results translate to human subjects, the implications for the prevention and treatment of PG are huge, and there may be a similar impact on other blinding eye diseases.
Active and regression phases
The onset of PDS appears to be typically in the mid-20s, though younger patients have been reported.4,7,34 The precise clinical signs vary widely, and the exact reason for this could be hereditary or environmental, or both.
However, it appears that the liberation of pigment reduces or ceases in the majority of cases in middle age. This may be related to the loss of accommodation and to the development of a relative pupil block which accompanies the age-related increase in thickness of the lens. Phagocytosis of existing pigment deposits may occur, and Krukenberg's spindles may fade.
Trabecular pigmentation may become more localised to the filtering portion of the meshwork, giving rise to the 'pigment reversal sign'. Lichter and Schaffer35 reported decreased pigment in the meshwork with age in 10 per cent of cases studied. Transillumination defects may disappear19,36 and the IOP may fall,36-38 allowing some patients to discontinue miotic treatment.37,39 As a result, some older patients may be misdiagnosed as either POAG or even normotensive glaucoma.

MANAGEMENT
The management of PG and PDS depends on the degree and stage of pigment liberation, IOP and glaucomatous damage, which can vary widely.
Beta-adrenergic antagonists (beta-blockers) such as Betagan reduce aqueous production, thus lowering IOP. These are the mainstay of initial treatment for PG.
Parasympathomimetics enhance relative pupil block by causing miosis, and the concavity of the iris is reduced or eliminated. Zonular friction is also reduced and the pupil is immobilised. This will reduce pigment liberation during the active phase of PDS and guard against sudden surges after exercise.
The drawback with strong parasympathomimetics is that they also cause ciliary spasm in pre-presbyopes, and most active PDS falls into this category. Pilocarpine Ocuserts have become a popular option for younger patients. The lower dose will reduce concavity of the iris without causing marked spasm, though some patients still find the variability of their refractive error irritating. With all miotic therapy, careful examination of the peripheral retina is needed, in view of the increased risk of retinal detachment in PDS.
Alpha-adrenergic agonists (sympathomimetics) such as Alphagan also reduce aqueous production and may increase uveoscleral outflow. Unfortunately, about half of their users develop allergy with long-term use.
Carbonic anhydrase inhibitors like Trusopt are used topically and, in particularly difficult cases, systemic agents may be used, if surgery is too risky.
Prostaglandin analogues increase uveoscleral outflow and have the advantage that they only need to be administered once a day at bedtime. All of them cause an increase in iris pigmentation due to increased melanocyte activity, but this appears not to result in pigment dispersion.
They are also contra-indicated where inflammation is present, though how this will relate to the recent study33 by Jun-Song Mo et al is not clear.

SURGICAL MANAGEMENT
Argon laser trabeculoplasty (ALT)
Argon laser trabeculoplasty may be offered in cases of uncontrolled PG and the initial result is often good. Long-term control is less good than in POAG40-42 and the IOP may occur rapidly, in a similar way to that seen in exfoliation syndrome.
The success rate of ALT decreases with age, probably because the distribution of pigment changes.
In young patients, deposition is primarily found in the uveoscleral and corneoscleral meshworks, while older patients show pigmentation mainly in the back wall of Schlemm's canal and the juxtacanalicular meshwork.42
Patients who undergo ALT while in the active pigment liberation stage should receive medication (Ocuserts) or surgery (iridotomy) to prevent further iridozonular contact.

Filtering surgery
This is used in the same way as in patients with uncontrolled POAG, with the aim being to reduce IOP.
Laser iridotomy
Essentially this involves punching a hole through the iris, which allows aqueous to move from the posterior chamber into the anterior, and relieving the 'reverse pupil block'.
It will usually relieve iris concavity, but not always.43 Iridolenticular contact reduces,44 and the number of pigment granules found in the aqueous may be brought down by as much as 65 per cent.46 However, the increase in iris concavity induced by accommodation is not eliminated.47 Exercise-induced shedding of pigment can also be reduced but not eliminated,48,49 whereas pilocarpine may do so completely.48-50

CONCLUSION
If you are in full-time optometric practice, there are probably one or two people with pigment dispersion consulting you in an average week. They need to be identified before the unlucky ones progress to pigmentary glaucoma, as in older patients the signs of pigment dispersion may be subtle and they may be mistaken for primary open-angle glaucoma. Detection may be tricky. Pigment dispersion is an inherited condition, but most of those with it are likely to be unaware.
There is no guarantee that the offspring of those who do not progress to glaucoma will themselves be free of it. Consequently, we cannot identify an 'at-risk' group from symptoms and history alone. The best chance of detection would seem to be to perform slit-lamp examination of the corneal endothelium and anterior chamber on every patient over 20 at intervals, if not every time they are tested.
Myopes tend to be those most at risk of pigmentary glaucoma. Most of them will have an eye examination every now and then, but those with smaller prescriptions could slip through the net until presbyopia sets in.
Any patient in whom glaucoma is suspected should be carefully examined for signs of pigment dispersion. Those found to have pigment dispersion but no glaucoma should still be routinely referred for monitoring by the HES and possible preventative treatment.

Acknowledgements
Figures 1, 3, 4 and 5 were taken by Ngaire Franklin. Thanks to James Wolffsohn for Figure 2.

References
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Andrew Franklin is professional programme tutor at Boots Opticians and a visiting clinician at Cardiff University