A. HEREDITY

The above concept of the pathophysiology of PDS helps us to better understand a number of clinical aspects of the disorder. Structural abnormalities are characteristic of autosomal dominant disorders. Only occasional families with Krukenberg spindles were reported prior to the 1980s. (70,92,94,97,103,105,110) Reports in the 19801s described familial PDS, but were inconclusive regarding the mode of inheritance. (44,47,68,77) McDermott et al (72) examined relatives of 21 probands, and found involvement in 36% of parents and 50% of siblings, but none in children under the age of 21 years. This suggested a strong pattern of autosomal dominance, with phenotypic onset probably beginning in most persons in the mid-20s. That Caucasians are almost exclusively affected is also consistent with a genetic origin.

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Men and women are equally affected by PDS, women having predominated in some series (11,94) and men in others. (61,66) However, men develop glaucoma about 3 times as often as women and at a younger mean age. (6,66,74,94,106) Berger et al (9) found no difference in age at diagnosis of PDS between men and women, but men were significantly younger than women at the time of diagnosis of PG. No population based study has yet been performed. If myopia is the major determinant of phenotypic expression, then one would expect an equal incidence of men and women, since the prevalence of myopia in the United States is similar between men and women. (102) Why then do more men develop glaucoma and do women appear to develop it at a somewhat older mean age? It is possible that female hormones exert a protective effect against the development of elevated IOP. A curious and unconfirmed finding reported by Duncan (27) was the development of Krukenberg spindles in 4 black women during pregnancy; these regressed after delivery. One report relating to hormonal treatment of PG has never received further attention in the literature. (71)

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About 60-80% of patients with PDS and PG are myopes and 20% are emmetropes (-1.00 to +1.00 diopters). (94,106) In earlier series which reported about 10% of patients to be hyperopes, there appears to have been some confusion between PDS and exfoliation syndrome, particularly as the hyperopes in these series tended to be older and to be women. Eyes with PG are significantly more myopic than those with PDS and the higher the myopia, the earlier is the age of onset of glaucoma. (9)

Campbell (18,19) suggested that enlargement of the myopic eye in young patients allows the peripheral iris more space in which to bow posteriorly. Kaiser-Kupfer et al (47) mentioned that transillumination defects can precede the development of myopia and increase without any concomitant progression of significant refractive error.

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Since PDS is a bilateral disorder, asymmetric involvement requires explanation. A second disorder may make one eye worse. The most common cause in older patients appears to be the development of exfoliation syndrome in one eye in patients who had had PDS or PG glaucoma in earlier life. (58) Angle recession in one eye has also been reported. (85) It is also possible for one eye to have a second disorder which reduces the severity of PDS, such as unilateral traumatic cataract extraction in youth prior to the onset of pigment dispersion or development of unilateral cataract during the pigment dispersion phase, which decreases iridozonular contact by causing pupillary block. (90) Horner's syndrome may achieve the same effect. (54) We have also seen anisometropic patients with greater involvement in the more myopic eye (unpublished data).

In other cases, mild to marked asymmetry may exist without any other evident process. Kaiser-Kupfer et al (47) reported 4 normotensive patients with markedly asymmetric involvement and no obvious cause for asymmetry. Three had anterior chamber depths 0.2 mm greater in the affected eye. Anderson (4) remarked that there should be asymmetry in the anatomic or physiologic factors relevant to the underlying pathogenesis. Liebmann et al (63) examined four patients with markedly asymmetric PDS and no other ocular conditions to explain the asymmetry and found greater iridolenticular contact and a more posterior iris insertion in the more involved eye in all cases.

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The mean age of onset of PDS remains unknown, but is probably in the mid-20s. The youngest patients reported have been aged twelve, (47) fourteen, (9,94) and fifteen. (91) Although it seems logical that PDS might develop in the mid-teens, when myopia is commonly progressive, a screening of over 300 students at Stuyvesant High School, a school for especially intelligent children in New York City, did not reveal a single case (unpublished results). Moreover, McDermott et al (72) found no children of probands positive up to age 21. Further studies are warranted. The development of PDS later in life is unlikely because of gradual lens enlargement and loss of accommodation.

The phenotypic expression of PDS varies widely. Referral practices tend to have patients with more extensive involvement, although even in these patients, the diagnosis is often missed. More subtle manifestations may never be detected either because of a lack of suspicion on the part of the examiner, unawareness of the examiner of pathognomonic signs in patients with mild phenotypic involvement, failure to perform slit-lamp examination in patients presenting for refraction, and simply lack of an eye examination. Failure to perform gonioscopy may result in lack of diagnosis of patients with trabecular hyperpigmentation but without Krukenberg spindles, since transscleral transillumination is often the least likely test to be performed. It is not known whether the variability in phenotypic expression is hereditary, environmental, or a combination of both. For instance, the concavity due to iris position and size (genetic) could be affected by the cumulative amount of accommodation (environmental). Further studies are warranted.

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The timing of the onset of the regression phase of PDS is easier to explain. The severity of involvement of both PDS and PG decreases in middle age when pigment liberation ceases, at least in the majority of patients. Lichter and Shaffer (61) observed decreased pigment in the trabecular meshwork in 10% of 102 cases, concluding that pigment could pass out of the meshwork with age. Transillumination defects may disappear, (18,28) most likely by migration of pigment epithelial cells adjacent to the defects. The IOP may return toward normal. (28,101,113) Some patients treated with long-term miotic therapy have been able to reduce or discontinue treatment for glaucoma. (20,101) Older patients presenting with glaucoma may have only very subtle manifestations, if any, of PDS, and may be misdiagnosed as primary open-angle glaucoma or low-tension glaucoma.(84) Remission of PG has also been reported following glaucoma surgery (94) and following lens subluxation. (88)

Trabecular pigmentation is initially dense and homogeneous for 360 degrees. With age and clearance of pigment from the angle, it becomes lighter and more localized to the filtering portion of the meshwork, while it disappears from Schwalbe's line and the scleral spur. When the trabecular meshwork begins to recover, the normal pigment pattern reverses and the pigment band becomes darker superiorly than inferiorly. We have termed this the "pigment reversal sign" and, in older patients, it may be the only finding suggestive of previous PDS. Although it cannot be regarded as diagnostic, examination of the patient's offspring in such a case may be confirmatory. The pigment reversal sign may also be found in patients after long-term miotic therapy in patients with PDS/PG and also in patients with exfoliation syndrome, confirming that it occurs as a result of pigment clearing from the meshwork.

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The development of relative pupillary block secondary to an age-related increase in lens thickness and loss of accommodation with the onset of presbyopia are two processes which presumably lead to the cessation of pigment liberation in middle age. Older patients with PDS develop little or no accentuation of the iris concavity with accommodation. (81) By eliminating the iris concavity and iridozonular contact, miotic therapy may prevent progression of the disease and the development of glaucoma by immobilizing the pupil and may allow previously existing damage to reverse more readily. Since most PDS patients are young and cannot tolerate pilocarpine drops because of induced myopia and accommodative spasm, pilocarpine Ocuserts have proven to be the best available for of miotic therapy.

The success rate of argon laser trabeculoplasty (ALT) in PG is greater in younger patients than in older ones and decreases with age. (62,67,87) Pigment in younger patients is largely in the uveoscleral and corneoscleral meshworks, whereas in older patients, it if primarily localized to the juxtacanalicular meshwork and the back wall of Schlemm's canal. (87) A larger portion of patients fail within a shorter period of time compared to POAG patients. (38,67,87) Initially successful trabeculoplasty may be followed by a sudden, late rise in IOP, similar to that seen in exfoliative glaucoma. Patients in the pigment liberation stage who undergo ALT should be maintained on miotics or undergo laser iridotomy after ALT to prevent further contact between the iris and zonules. Although topical miotic drops or gel preparations are poorly tolerated by younger patients due to induced myopia and accommodative spasm, pilocarpine Ocuserts are extremely well tolerated.

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MANAGEMENT

Since the degree and stage of pigment liberation, intraocular pressure, and extent of glaucomatous optic neuropathy vary among individuals, each must be evaluated to determine the proper course of intervention. As our understanding of the pathogenesis of pigment liberation expands, consideration should also be given to gearing therapy towards eliminating acute pigment release, rather than just treating elevated IOP.

Beta-adrenergic antagonists. The mainstay of initial medical therapy for PG continues to be aqueous suppression with a topical beta-blocker, primarily because of the relatively easy dosing schedule and minimal side effects.

Parasympathomimetics. In theory, therapy directed at increasing relative pupillary block should relieve iridozonular contact and diminish pigment liberation. The relief of iridozonular contact following miotic therapy has been demonstrated with ultrasound biomicroscopy (Figure 15, 16). However, strong miotics in young individuals are rarely tolerated because of the associated spasm of accommodation and blurring of vision. Low-dose pilocarpine in the form of Ocuserts often provide enough miosis to create pupillary block, without disabling adverse effects. A careful peripheral retinal examination should be performed before and after the institution of or change in miotic therapy because of the higher incidence of retinal breaks and detachment in these patients.

Figure 20. In untreated PDS, iris is posteriorly bowed (concave) and the iris pigment epithelium is below the reference line.
Figure 21. One hour following administration of one drop of pilocarpine 2%, the pupil has become miotic, relative pupillary block has developed, and the iris has bowed anteriorly. The iris pigment epithelium is above the reference line.

Alpha-adrenergic agonists. Alpha-agonists are useful in PG, but the development of allergy in up to 50% of patients precludes their long-term use in many individuals.

Carbonic anhydrase inhibitors. Topical carbonic anhydrase inhibitors are useful agents for PG and are generally well-tolerated. Systemic agents should be reserved for particularly difficult circumstances or when the risks of surgery are unacceptably high.

Prostaglandin analogues. This new class of medications, which lower IOP by increasing uveoscleral outflow, are effective in PG and offer the advantage of once-daily administration. The iris surface color change which may occur during therapy appears to involve increased melanin production by iris melanocytes and is not known to affect the iris pigment epithelium or result in pigment dispersion.

Alpha-adrenergic antagonists. Theoretically, a drug that would constrict the pupil and make the peripheral iris taut might decrease iridozonular rubbing and eliminate pigment accumulation in the meshwork. An alpha-adrenergic blocking agent such as thymoxamine hydrochloride, which constricts the pupil but does not affect accommodation or aqueous dynamics, could be beneficial to such patients. Thymoxamine hydrochloride is not yet approved for this purpose and is unavailable for general use. In addition, in its present formulation, the ocular irritation that the drug causes makes it unlikely that patients would tolerate it.

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Laser iridectomy. Laser iridectomy eliminates the iris concavity present in PDS by permitting equalization of pressures between the anterior and posterior chambers. This causes the iris to become flat, thereby decreasing iridozonular contact (Figure 17). Anecdotal evidence suggests that this can prevent continued pigment liberation, result in a reversal of trabecular pigmentation, and subsequently, lowering of IOP. Although this approach is theoretically sound, laser iridectomy should be used with caution because there is a paucity of data regarding the long-term efficacy of this procedure.

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Figure 22. Pre-laser iridotomy scan demonstrating marked iris concavity and central iris contact with anterior lens capsule and zonules.
Figure 23. Post-laser iridotomy scan shows resolution of iris concavity and decreased length of iris contact with anterior lens capsule.
Figure 24. Repeat scan eleven days later shows recurrence of iris concavity. Slit lamp evaluation had demonstrated occlusion of the laser iridotomy by pigment.
Figure 25. Concavity resolved after reopening laser iridotomy.
Figure 26. Prior to laser iridectomy, gonioscopy demonstrates a concave iris configuration.
Figure 27. Following laser iridectomy, the iris assumes a flat configuration.

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During the formation of the secondary vitreous, a condensation of fibers extends laterally between the lens and the iris to form the marginal bundle of Druault, which extends backward between the lens periphery and the equator, attaching strongly to the internal limiting membrane of the peripheral retina to form the vitreous base. (5) It also attaches to the posterior capsule of the lens around the primary vitreous, as a ring 8-10 mm in diameter, to form the hyaloideocapsular ligament of Wiegert. Developing zonular fibers (tertiary vitreous) pass through this bundle at right angles. As the ciliary processes and the iris develop, the marginal bundle loses its connection anteriorly, but remains attached to the peripheral retina at the vitreous base. (5) A condensation of the anterior surface of the secondary vitreous finally separates the zonular fibers from the vitreous. An abnormal persistence of connections between the zonular apparatus and the marginal bundle of Druault might lead to tension on the peripheral retina.

During the 7th month, the apex of the angle moves posteriorly to become level with the middle portion of the meshwork. This is due not to cleavage, but to a differential growth rate of anterior neuroectoderm and anterior periocular mesenchyme, the latter growing more rapidly. (5) The ciliary processes move backward and become located behind the apex of the angle.

The responsible gene should also influence the size of the iris relative to the anterior segment and perhaps the susceptibility of the IPE to disruption by zonular friction. A gene affecting some aspect of the development of the middle third of the eye early in the third trimester appears reasonable at the present time.

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