A UNIFICATION HYPOTHESIS OF PIGMENT DISPERSION
BY Robert Ritch, MD
Purpose: To synthesize recent findings regarding pigment dispersion syn-
drome in order to arrive at a hypothesis concerning the nature of an
underlying genetic predisposition.
Methods: The literature on the subject was reviewed and analyzed.
Results: Eyes with pigment dispersion syndrome differ from normal in that
theyhave a larger iris, a midperipheral posterior iris concavity that increas-
es with accommodation, a more posterior iris insertion, increased irido-
lenticular contact that is reversed by inhibition of blinking, possibly an
inherent weakness of the iris pigment epithelium, and an increased inci-
dence of lattice degeneration of the retina.
Conclusion: A gene affecting some aspect ofthe development ofthe mid-
dle third ofthe eye early in the third trimester appears at the present time
to be the most likely cause.
Pigment dispersion syndrome (PDS) is a unique and fascinating entity. Far
more prevalent than previously suspected,' it is the first common disease
leading to glaucoma for which we are on the verge of a coherent overall
explanation ofpathogenesis and pathophysiology. This paper is an attempt
to tie together many interesting and sometimes disparate and/or appar-
ently anomalous findings in order to synthesize a coherent portrait of the
PDS and pigmentary glaucoma (PG) are characterized by disruption
of the iris pigment epithelium (IPE) and deposition of the dispersed pig-
ment granules throughout the anterior segment. The classic diagnostic
'From the Departments ofOphthalmology, NewYork Eye and Ear Infirmary, NewYork, and
New York Medical College, Valhalla. Supported by the New York Glaucoma Research
Institute and an unrestricted grant from Allergan.
TR. AM. OPHTH. SOC. VOL. XCIV, 1996
triad consists of corneal pigmentation (Krukenberg spindle); slitlike, radi-
al, midperipheral iris transillumination defects, and dense trabecular pig-
mentation. 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.
In 1899, Krukenberg' described spindle-shaped pigment deposition on
the cornea. In 1901, von Hippel3 suggested that pigment obstructing the
aqueous outflow system could lead to elevated intraocular pressure (IOP).
Levinsohn4 first suggested that pigment in the anterior chamber angle of
patients with glaucoma originated from the IPE. A cause-and-effect rela-
tionship between pigment and glaucoma found both support56 and oppo-
In 1949, Sugar and Barbour"° described 2 young, myopic men with
Krukenberg spindles, trabecular hyperpigmentation, and open angles,
whose IOP increased with mydriasis and decreased with pilocarpine. The
investigators identified the disorder as a rare, distinct form of glaucoma,
which they termed pigmentary glaucoma. More patients were subse-
quently reported, and in 1966 Sugar" reviewed 147 cases in the world lit-
erature, mentioning several additional features, including bilaterality, fre-
quent association with myopia, greater incidence in men than in women,
and a relatively young age at onset. These features were confirmed by
Scheie and Cameron."
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.'3"4 Congenital atrophy or degeneration of the IPE was
suggested as a cause of loss of iris pigment."5"6
In 1979, Campbell'7 proposed the pathogenesis to involve mechanical
damage to the IPE during rubbing ofthe posterior iris against the anteri-
or zonular bundles during physiologic pupillary movement. Subsequently,
the autosomal dominant inheritance, natural history, reversibility, and
more precise therapeutic approaches have become increasingly delineat-
ed. Ultrasound biomicroscopic studies are presently revealing new insights
into the pathophysiology ofPDS.
Loss of iris pigment appears clinically as a midperipheral, radial, slitlike
pattern oftransillumination defects seen most commonly inferonasally and
Pigment Dispersion Syndrome
more easily in blue eyes than in brown ones (Fig 1). Although the defects
can sometimes be seen by retroillumination, they are more easily detect-
ed by a dark-adapted examiner using a fiberoptic transilluminator in a
darkened room. Infrared videography provides the most sensitive method
of detection.'8 Pigment particles deposited on the iris surface tend to
aggregate in the furrows.""9 Rarely, this pigment can be dense enough to
darken the iris or to cause heterochromia when involvement is asymmet-
ric."'20 Iris vascular hypoperfusion on fluorescein angiography has been
reported,2' a finding which awaits verification.
Iris transillumination defects. Typical defect is midperipheral, radial, and slit-like. Some
defects, especially inferiorly, have peripheral clublike endings, giving them the appearance of
an exclamation point. These peripheral transillumination dots might result from iridociliary
Anisocoria may occur with asymmetric involvement, the larger pupil
corresponding to the eye with greater pigment loss from the iriS.22-24
Alward and Haynes22 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.'5 This would be consistent with the pres-
ence of hyperplasia of the iris dilator muscle (see below).26
Corneal endothelial pigment generally appears as a central, vertical,
brown band (Krukenberg spindle), the shape being attributed to aqueous
convection currents (Fig 2). The pigment is phagocytosed by endothelial
cells,27,28 but endothelial cell density and corneal thickness remain
unchanged compared with controls.'9 Coincident PDS and megalocornea
have been reported,12162930as have subluxated lenses.'2'3'
The anterior chamber is deeper both centrally and peripherally than
can be accounted for by sex, age, and refractive error. Davidson and asso-
ciates32 compared the central and peripheral anterior chamber depths of
patients with PDS to statistical controls. The anterior chamber was signif-
icantly 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 (Fig 3). 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
Pigment Dispersion Syndrome
Pigment reversal sign in 48-year-old man. A. Inferior angle. B. Superior angle. Pigment is
denser in superior angle. Note that pigment band has sharp anterior and posterior margins
and appears smooth, indicating that pigment was deposited in past and is now localized to
region of filtering portion oftrabecular meshwork. Iris is inserted posteriorly.
demarcated, blending with the ciliary face owing to pigment deposition on
these structures. Pigment may be deposited on the zonules','20' and on the
posterior capsule of the lens, where it is apposed to the anterior hyaloid
face at the insertion ofthe posterior zonular fibers.'4'3
PDS is associated with a high incidence of retinal detachment.'2'3637 Most
detachments occur in phakic men who are not highly myopic.'2 Miotics
have been incriminated in precipitating these.?840 It is significant that the
incidence of retinal detachment in PDS is 6% to 8% independent of
miotic treatment, and when detachment is associated temporally with
miotics, a preexisting lesion was most likely present. Lattice degeneration
is commonly found in myopes4142 and may be hereditary.4344 Its incidence
appears to be higher for all degrees ofmyopia in patients with PDS45 than
in the general population.46 Despite the fact that comparable prevalences
of lattice degeneration in blacks and whites have been demonstrated at
autopsy,47 PDS and retinal detachment are both uncommon in blacks. It
may be preceded or caused by chronic, localized vitreoretinal traction,48
which is exaggerated around the margins of the lesion.411 The reason for
the prominence ofthe vitreoretinal traction has not been explained.
In a small series of 5 patients with glaucoma and optic nerve head
drusen, 4 had PG.5l Additional such patients have not been reported, and
the significance of this observation remains unknown.
In 1958, Scheie and Fleischauer'4 described iris transillumination defects
associated with PDS and attributed them to IPE atrophy. With no real evi-
dence except a "somewhat waxy or pale" appearance ofthe ciliary body in
a few patients, they extended the hypothesis of congenital atrophy to
include this structure.
Fine and colleagues52 examined the eyes ofa 55-year-old man who had
been found to have PDS without glaucoma at age 43. In the iris midpe-
riphery, there was an abrupt transition from normal to abnormal IPE. In
this region, IPE loss was accompanied by hyperplasia of the iris dilator
muscle, and there was marked hyperplasia ofthe muscle spur ofGrunert at
the iris root. Pigment epithelial cells appeared to be migrating anteriorly
and differentiating into smooth-muscle-containing cells. Rodrigues and
coworkers,"' on the other hand, reported a focally thickened dilator muscle
with thinning in the areas of epithelial atrophy. They found an increased
number of immature melanosomes in the IPE and suggested that a delay
in melanogenesis occurred as part of a developmental defect.
Pigment Dispersion Syndrome
Kupfer and coinvestigators53 considered the primary lesion in PDS to
be an epithelial abnormality. The dilator fibers ofthe inner IPE appeared
to be hypertrophic and hyperplastic, resembling the sphincter muscle, and
were associated with degenerated neural elements. They felt that the pri-
mary defect lay in the inner IPE and could represent a congenital or devel-
opmental abnormality, but could also be the result ofinterruption of sym-
The relevance of dilator muscle hyperplasia and nerve fiber degener-
ation to the disease process remain unknown. The possibility of an adren-
ergic hypersensitivity in patients with PDS and PG might explain com-
ments made in passing that epinephrine compounds, alone or in combi-
nation with other agents, seem to be more effective in patients with PG
than in those with POAG.12,5
Campbell"7,- proposed that posterior bowing of the iris brings it into
contact with the anterior zonular bundles. The location and number ofthe
transillumination defects correlated with the position and number of the
underlying zonular bundles. He noted that hyperplasia of the iris dilator
muscle was localized to areas of iridozonular contact and hypothesized
that iridozonular friction during pupillary movement disrupts the IPE,
releasing pigment into the posterior chamber. Scanning electron micro-
scopic observations supported this hypothesis.5657
ULTRASOUND BIOMICROSCOPIC FINDINGS
The advent of high-frequency, high-resolution, anterior-segment ultra-
sound biomicroscopy has enabled us to elucidate a number offacets ofthe
pathophysiology of PDS.584 One overall impression obtained from imag-
ing studies is that the size of the iris is overly large relative to that of the
anterior segment (Fig 4). This may be the basic anatomic cause ofthe mid-
peripheral iris concavity and predispose to iridozonular contact. Sokol and
associates65 compared patients with PDS to age-, sex-, and refraction-
matched controls and found a greater mean iris-trabecular meshwork dis-
tance in the PDS group. Thus, iridozonular contact appears to be facilitat-
ed by a congenitally more posterior iris insertion.
Both iridozonular and iridociliary contact have been imaged (Fig 5).
Although iridociliary contact does not appear to be much ofa factor in pig-
ment liberation, the occasional extension of transillumination defects into
the periphery of the iris, creating an appearance similar to that of an
exclamation point, suggests that contact between the 2 surfaces may dam-
age the pigment epithelium of both and may account retrospectively for
the observation of Scheie and Fleischauer14 regarding the "pale and waxy"
appearance of some ciliary processes (Fig 1).
Ultrasound biomicrograph ofnormal eye (A) and, eye with pigment dispersion syndrome (B).
Iris is large relative to size of anterior segment, and midperipheral concavity is prominent.
There is extensive iridolenticular contact.
Pigment Dispersion Syndrome
Anterior ciliary processes appear to be in contact with iris pigment epithehum. (Reproduced,
with permission, from Potash SD, Tello C, Liebmann J, et al: Ultrasound biomicroscopy in
pigment dispersion syndrome Ophthalmology 1994; 101:332-339.)
Lid blinking may be important in determining iris configuration.
Campbell67 noted and Liebmann and colleagues62 confirmed that when
blinking is prevented in PDS patients, aqueous humor builds up in the
posterior chamber and the iris assumes a planar and even a convex con-
figuration. As the volume of the posterior chamber increases relative to
that ofthe anterior chamber, the iris gradually flattens, iridolenticular con-
tact diminishes, and iridozonular and iridociliary process distances
increase. In the most pronounced cases, iridolenticular contact disappears,
the iris sphincter lifting completely offthe surface of the lens without the
posterior chamber losing its expanded volume (Fig 6). Eyes with PDS take
longer to reach a steady-state position because their initial iris concavity is
greater than that of control eyes.62
The mechanism by which blinking affects the anatomy ofthe anterior
segment appears to be a mechanical one. Campbell67 proposed that a blink
initially deforms the cornea, transiently increasing IOP and pushing the
iris posteriorly against the lens. When PDS patients are permitted to blink
and rescanned, the concave iris configuration returns in all eyes.62 Chew
and coworkers68 demonstrated that during blinking ofthe nictitating mem-
Inhibition ofblinkidngfor several minutes results inexpansionofposterior chamber, a convex
irisconfiguration, and loss of iridolenticular contact in thiseyeofpafientwithpigmentdis-
persion syndrome. Despite lack of iridolenticular contact, aqueous pressure in posterior
chamber is sufficient to maintain iris in convexposition. (Reproduced,withpermission,from
LiebmannJM,Tello C, ChewSJ,et al: Prevention ofblinkingalters irisconfigurationinpig-
mentdispersion syndromeand in normaleyes. Ophthalmology 1995; 102:446-455.)
brane in the chickeye,the cornea indents in a wave from theperipheryto
the center and that anterior chamberdepth similarlydecreases(Fig 7).
Extrapolatingthis to humans, wehypothesize thatblinkingacts as a
mechanicalpumptopush aliquotsofaqueous humor from theposterior
chamber to the anterior chamber. Apressurewave is created, pushingthe
irisposteriorlytoward the zonules. This wavebeginsat the irisperiphery
and movescentrally, pushing aqueousbefore it into the anterior chamber
contact ineyeswith PDSprevents equilibration ofaqueous between the
anterior andposterior chambers, a situation that has been termed reverse
pupillaryblock.67'69At the same time, the iris reassumes its concaveconfig-
uration. The now increased volume ofaqueous in the anterior chamber
helps to maintain the midperipheraliris concavity, althoughwhether or
not there is apressure gradient accentuatingtheconcavityremains to be
shown. As aqueous leaves the eye through the meshwork and enters via
ciliary secretion, the anterior chamber volume decreases and theposteri-
or chamber volume increases, until the next blink starts thecycleall over
'' r; t1! :ti
.: rifIIIiWi'i ; p
A. Chick cornea prior to blinking of nictitating membrane. B. During blink, the cornea
indents. (From reference 68)
Pigment Dispersion Syndrome
again. Interestingly, increasing myopia is also a predictor ofincreasing iri-
dolenticular contact, independent of the presence of PDS.6' This may
explain why myopia enhances the phenotypic expression of the genetic
abnormality underlying PDS. It also raises the question as to whether
decreased trabecular function and reduction ofthe aqueous outflow coef-
ficient might serve to accentuate the iris concavity.
Accommodation in normal, young individuals and PDS patients may also
affect iris contour (Fig 8).6270 Accommodation in normal eyes causes an iris
concavity indistinguishable from that in PDS. Contraction of the ciliary
ring allows shallowing of the anterior chamber, anterior lens movement,
and increased iridolenticular contact. Aqueous in the anterior chamber is
forced into the angle recess, and the peripheral iris becomes more con-
cave. As accommodation is relaxed, the iris resumes its initial configura-
Accommodation might enhance pigment liberation in 2 ways. In addi-
tion to posterior iris bowing during accommodation, the pupil constricts.
Relaxation of accommodation accompanied by pupillary dilation might
result in additional iridozonular friction. Ultrasound biomicroscopy during
accommodation in eyes with PDS shows iridozonular contact at the lens
margin, consistent with the usual position of iris transillumination
EFFECT OF MIOTICS AND LASER IRIDOTOMY
Scanning following administration of pilocarpine shows resolution of the
iris concavity and iridozonular contact in all eyes (Fig 9). Pilocarpine pro-
duces a convex rather than a planar configuration. Laser iridotomy relieves
reverse pupillary block by allowing aqueous to flow from the anterior to
the posterior chamber and produces a planar iris configuration (Fig 10).
Some eyes undergoing iridotomy may still retain a concave iris configura-
tion.72 Iridotomy does appear to prevent the accentuation of the iris con-
cavity that accompanies accommodation.7' In some PDS patients, rises in
IOP may occur after shedding pigment with exercise orwith pupillary dila-
tion.73-79 The exercise-induced release ofpigment and elevation ofIOP can
be blocked by pilocarpine.788L Whereas pilocarpine completely inhibits
exercise-induced pigment release and IOP elevation, iridotomy does so
Pigment Dispersion Syndrome
A. Normal myopic eye prior to accommodation. B. Accommodation produces midperipher-
al iris concavity mimicking that seen in pigment dispersion syndrome. (Reproduced with per-
mission, from Liebmann JM, Tello C, Chew SJ, et al: Prevention of blinking alters iris con-
figuration in pigment dispersion syndrome and in normal eyes. Ophthalmology 1995;
One drop of2% pilocarpine produces convex iris configuration mimicking that produced by
inhibition ofblinking. (Reproduced, with permission, from Haynes WL, Alward WLM, Tello
C, et al: Incomplete elimination ofexercise-induced pigment dispersion by laser iridotomy in
pigment dispersion syndrome. Ophthalmic Surg Lasers 1995; 26:484-486).
Laser iridotomy produces planar iris configuration, since aqueous can freely redistribute
through iridotomy site.
Pigment Dispersion Syndrome
The above concept of the pathophysiology of PDS helps us to better
understand a number of clinical aspects ofthe disorder. Structural abnor-
malities are characteristic of autosomal dominant disorders. Only occa-
sional families with Krukenberg spindles were reported prior to the
1980s. 9,2,82-86 Reports in the 1980s described familial PDS but were incon-
clusive regarding the mode ofinheritance."7- McDermott and colleagues9'
examined relatives of 21 probands and found involvement in 36% of par-
ents and 50% of siblings, but none in children under the age of 21 years.
This suggested a strong pattern ofautosomal 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.
Men and women are equally affected by PDS, women having predomi-
nated in some series'292 and men in others.9394However, men develop glau-
coma about 3 times as often as women and at a younger mean age.",2'94-96
Berger and associates97 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. Ifmyopia is the major determinant ofphenotypic expres-
sion, then one would expect an equal incidence of men and women, since
the prevalence ofmyopia in the United States is similar between men and
women.99 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 ele-
vated IOP. A curious and unconfirmed finding reported by Duncan99 was
the development of Krukenberg spindles in 4 black women during preg-
nancy; these regressed after delivery. One report relating to hormonal
treatment ofPG has never received further attention in the literature."'0
About 60% to 80% of patients with PDS and PG are myopes and 20% are
emmetropes (-1.00 to +1.00 diopters).1112 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 the age at onset of glaucoma.97
Campbell'7'55 suggested that enlargement of the myopic eye in young
patients allows the peripheral iris more space in which to bow posteriorly.
Kaiser-Kupfer and coinvestigators8' mentioned that transillumination
defects can precede the development ofmyopia and increase without any
concomitant progression of significant refractive error.
Since PDS is a bilateral disorder, asymmetric involvement requires expla-
nation. A second disorder may make 1 eye worse. The most common cause
in older patients appears to be the development ofexfoliation syndrome in
1 eye in patients who had PDS or PG in earlier life.10' Angle recession in 1
eye has also been reported.'0' It is also possible for one eye to have a sec-
ond disorder that reduces the severity ofPDS, such as unilateral traumat-
ic cataract extraction in youth prior to the onset ofpigment dispersion or
development of unilateral cataract during the pigment dispersion phase,
which decreases iridozonular contact by causing pupillary block.'03
Homer's syndrome may achieve the same effect."' We have also seen ani-
sometropic patients with greater involvement in the more myopic eye
In other cases, mild to marked asymmetry may exist without any other
evident process. Kaiser-Kupfer and coinvestigators88 reported 4 normoten-
sive 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'05 remarked that there should be asymmetry in the
anatomic or physiologic factors relevant to the underlying pathogenesis.
Liebmann and associatesf4 examined 4 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.
The mean age at onset of PDS remains unknown but is probably in the
mid 20s. The youngest patients reported have been aged 12,' 14,"12
15.16 Although it seems logical that PDS might develop in the mid teens,
when myopia is commonly progressive, a screening ofover 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 and colleagues9l found no children ofprobands 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 accommo-
Pigment Dispersion Syndrome
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 ofan eye
examination. Failure to perform gonioscopy may result in lack of diagno-
sis ofpatients 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.
The timing ofthe onset ofthe regression phase ofPDS is easier to explain.
The severity ofinvolvement ofboth PDS and PG decreases in middle age,
when pigment liberation ceases, at least in the majority ofpatients. Lichter
and Shaffer93 observed decreased pigment in the trabecular meshwork in
10% of 102 cases, concluding that pigment could pass out ofthe meshwork
with age. Transillumination defects may disappear,",", most likely by
migration ofpigment epithelial cells adjacent to the defects. The IOP may
return toward normal."''08 Some patients treated with long-term miotic
therapy have been able to reduce or discontinue treatment for glauco-
ma.80",07 Older patients presenting with glaucoma may have only very sub-
tle manifestations of PDS, if any, and may be misdiagnosed as having pri-
mary open-angle glaucoma or low-tension glaucoma."'9 Remission of PG
has also been reported following glaucoma surgery'2 and following lens
Trabecular pigmentation is initially dense and homogeneous for 3600.
With age and clearance ofpigment from the angle, it becomes lighter and
more localized to the filtering portion ofthe 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 (Fig 3). 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 or PG and also in
patients with exfoliation syndrome, confirming that it occurs as a result of
pigment clearing from the meshwork.
LOGIC OF TREATMENT
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 2 processes that presumably lead to the cessation of pig-
ment liberation in middle age. Older patients with PDS develop little or
no accentuation ofthe iris concavity with accommodation.7' By eliminating
the iris concavity and iridozonular contact, miotic therapy may prevent
progression of the disease and the development of glaucoma by immobi-
lizing the pupil and may allow previously existing damage to reverse more
readily. Since most PDS patients are young and cannot tolerate pilo-
carpine drops because ofinduced myopia and accommodative spasm, pilo-
carpine Ocuserts have proved to be the best available for of miotic thera-
The success rate of argon laser trabeculoplasty (ALT) in PG is greater
in younger patients than in older ones and decreases with age."10-"12
Pigment in younger patients is largely in the uveoscleral and corneoscler-
al meshworks, whereas in older patients, it is primarily localized to the jux-
tacanalicular meshwork and the back wall of Schlemm's canal."'1 A larger
portion of patients fail within a shorter period of time compared with
POAG patients."o0"""'3 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 owing
to induced myopia and accommodative spasm, pilocarpine Ocuserts are
extremely well tolerated.
THE BASIC LEGION
Any hypothesis concerning the basic defect in PDS must take into account
the various anatomic findings noted above. Most difficult is explaining the
relationship to lattice degeneration. A structural abnormality of the mid-
dle third of the eye causing an abnormally concave peripheral iris and the
vitreous base/anterior retina to be drawn anteriorly could be consistent
with previously proposed mechanisms.
During the formation of the secondary vitreous, a condensation of
Pigment Dispersion Syndrome
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."' It also attaches to the
posterior capsule ofthe lens around the primary vitreous, as a ring 8 to 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 periph-
eral retina at the vitreous base."4 A condensation ofthe anterior surface of
the secondary vitreous finally separates the zonular fibers from the vitre-
ous. An abnormal persistence ofconnections between the zonular appara-
tus and the marginal bundle of Druault might lead to tension on the
During the seventh month, the apex ofthe angle moves posteriorly to
become level with the middle portion ofthe 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.'14 The
ciliary processes move backward and become located behind the apex of
The responsible gene should also influence the size ofthe iris relative
to the anterior segment and perhaps the susceptibility of the IPE to dis-
ruption by zonular friction. A gene affecting some aspect of the develop-
ment of the middle third of the eye early in the third trimester appears
reasonable at the present time.
PDS is an inherited disorder ofabnormal iridozonular contact that is exag-
gerated byphysiologic pupillary movement and accommodation. This con-
tact results in disruption ofthe IPE cells and liberation ofpigment, which
is deposited on structures throughout the anterior segment. Pigment lib-
eration can be triggered by exercise and by pupillary dilation Myopia pre-
disposes to the phenotypic expression of the disorder, which affects men
and women equally, but men develop glaucoma 2 to 3 times as often as
women and at an earlier age. Pigment dispersion begins in the teens or 20s
and continues until about the mid 40s in most people, at which time a
combination of relative pupillary block and presbyopia leads to gradual
cessation ofpigment liberation. After this, the visible signs ofpigment loss
can reverse, and IOP control can improve. Older patients presenting for
the first time with glaucomatous damage and normal IOP may be misdi-
agnosed as having normal-tension glaucoma.
Anatomically, the iris seems excessively large for the eye and is poste-
riorly inserted, resulting in a characteristic concave midperipheral config-
uration, iridozonular contact, and abnormally extensive iridolenticular
contact. When blinking is inhibited, the iris assumes a convex configura-
tion that is immediately reversed upon blinking, suggesting that the act of
blinking acts as a mechanical pump to push aqueous humor from the pos-
terior to the anterior chamber. Once in the anterior chamber, aqueous
backflow is prevented by the abnormal iridolenticular contact, which pro-
duces a reverse pupillary block, further enhancing the iris concavity.
Treatment should begin early in order to prevent the development of
glaucomatous damage and should be designed to prevent progression of
the disease rather than merely lower IOP. Miotic treatment produces a
convex iris configuration, completely inhibiting pigment liberation, while
laser iridotomy produces a planar configuration and may not completely
inhibit pigment liberation. Aqueous suppressants theoretically may nega-
tively impact the course of the disease. Argon laser trabeculoplasty pro-
duces better results in younger patients than older ones because of the
location ofthe pigment in the trabecular meshwork.
Persons with pigment dispersion also have an abnormally high inci-
dence of lattice degeneration of the retina and retinal detachment. Any
hypothesis regarding the origin ofthis disease must take this into account.
It must also provide.a reason why many myopes without PDS have an iris
concavity that also increases with accommodation. An abnormal persis-
tence of the marginal bundle of Druault might lead to an abnormality of
zonular position. The responsible gene should also affect the size ofthe iris
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DR MYRON YANOFF. Dr Ritch has presented a thoughtful analysis that tries
to tie together the disparate findings in the pigment dispersion syndrome
(PDS) into a unifying, genetic hypothesis. Many theories have been cham-
pioned to explain the findings in PDS. Most of these theories, however,
are less than satisfying because they explain findings after the fact without
predictive value. Why does one myopic young man develop PDS and
another does not? In fact, why are not all of the PDS patients myopic?
Where does the glaucoma fit into the picture? From Krukenberg's origi-
nal description in 1899 up until the present, many investigators have pon-
dered the multitude of questions that Dr Ritch raises.
present analysis of PDS has elevated our understanding of this condition
to a new level.
The ability to view in vivo a cross section of the peripheral irido-cil-
iary-zonular-lens structures by high-frequency, high-resolution, anterior-
segment ultrasound biomicroscopy certainly has provided new informa-
tion. The eyes with PDS have a more posterior insertion of the iris and a
greater iridolenticular contact than normal eyes. Even in the 2 eyes ofthe
same patient, 1 eye may be less involved than the other eye, leading to
asymmetric findings. Simplistically, the iris appears to be too big for the
eye. To explain this iris abnormality, Dr Ritch has postulated a genetic
basis. As Dr Ritch points out in his paper, PDS families with an autoso-
mal dominant inheritance pattern have been reported. Other investiga-
tors'-4 have suggested a congenital origin to the iris abnormality, an abnor-
mality that resides in the most posterior layer of the iris, namely, the iris
pigment epithelium (IPE).
In 1974, my colleagues and 12 described the light and electron micro-
scopic changes in 2 autopsy eyes removed from a patient who had clini-
cally documented PDS. One unexpected finding dealt with the IPE. We
found, in the region ofthe posterior IPE defect, dysplastic changes in the
I believe that his
IPE. These changes consisted of transformation of the normally partially
pigmented and partially smooth-muscularized anterior pigment epitheli-
um into a complete smooth muscle cell, often in a hyperplastic form, and
anteriorly migrated into the iris stroma. We felt that this type of dysplas-
tic change could not have occurred secondarily but had to be a primary
congenital abnormality ofthe iris. This finding of a congenital iris abnor-
mality certainly fits in with Dr Ritch's hypothesis. Furthermore, one could
propose that the anteriorly and centrally placed dilator muscle could
account, perhaps in part, for the posterior bowing ofthe iris that is seen in
PDS. A different degree of IPE congenital abnormality in each eye of a
patient could account for the asymmetry often seen in a patient's eyes.
Dr Ritch's point about the high incidence ofPDS, lattice degeneration
ofthe retina, and retinal detachment is indeed interesting and also may be
explained by Dr Ritch's overall genetic hypothesis. Greater numbers of
patients with this association are needed for further meaningful analysis.
Many other fascinating points are raised in this paper, too many to discuss
in this brief time. I would like to ask Dr Ritch the following questions:
In light of his hypothesis, how does a peripheral iridectomy work to
cause a flattening ofthe iris?
2.Does a laser peripheral iridectomy reduce the amount of pigment
being shed? If so, how?
3.Does the development of a normal iris stroma depend on the prior
development of a normal iris PE, or vice versa?
expressed in myopia?
Although intuitively I agree with his statement that the diagnosis of
PDS often is missed, does he have evidence to back this statement?
In closing, I congratulate the author on pulling together a wealth of
material into a working hypothesis.
Is the genetic defect linked to myopia or only more likely to be
Brini, A, Porte A, Roth A. Atrophie des couches epitheliales de l'iris. Jttude d'un cas de
glaucome pigmentaire au microscope optique et au microscope 6lectronique. Doc
Opthalmol 1969; 26:403-423.
Fine BS, Yanoff M, Scheie HG: Pigmentary "glaucoma": a histologic study. Trans Am
Acad Ophthalmol OtQlaryngol 1974; 110:314-325.
Kupfer C, Kuwabara T, Kaiser-Kupfer M. The histopathology ofpigmentary dispersion
syndrome with glaucoma. AmJ Ophthalmol 1975; 80:857-862.
Rodrigues MM. Spectrum of trabecular pigmentation in open-angle glaucoma: a clini-
copathologic study. 1976; 81:258-276.
PAUL LICHTER, M.D. The curiosity about pigmentary glaucoma has been
that way for years and years. It is one ofthe more interesting entities that
Pigment Dispersion Syndrome
we see in ophthalmology and it does give us curiosity as to why this pig-
ment is there and what it does. But pigment dispersion syndrome, which
Dr. Ritch indicated had an incidence of 2.54% in his screening ofwhites,
is a fairly common finding. And so is glaucoma. The gene frequency for
glaucoma is quite high. It is a widespread gene. One of the parts of the
pigment dispersion syndrome that most interests us is that it can, if asso-
ciated with glaucoma, lead to blindness. I want to ask Dr. Ritch why can't
there simply be two genes, because pigment dispersion is by far, much
more frequent than pigmentary glaucoma. So why can't individuals with
pigment dispersion simply have the same incidence of glaucoma as the
ROBERT RITCH, M.D. Dr. Yanoffasked four questions. First, how does an
iridotomy work in pigment dispersion syndrome? Remember that pupil-
lary block and reverse pupillary block are two sides ofthe same coin. Just
as iridotomy eliminates relative pupillary block and allows aqueous to flow
from the posterior to the anterior chamber in angle-closure glaucoma, it
relieves the reverse pupillary block in pigment dispersion syndrome and
allows aqueous to flow from the anterior to the posterior chamber. When
the iris is penetrated, one can actually see the pigmentflowing from the
anterior into the posterior chamber, the same phenomenon but opposite
direction of the "mushroom cloud" of aqueous and pigment which flow
into the anterior chamber when the iris is penetrated in pupillary block.
In addition to allowing equilibration of aqueous humor between the two
chambers, the accentuation of the iris concavity with accommodation is
significantly reduced if not totally eliminated.
Second, does laser iridotomy completely eliminate pigment disper-
sion? No, it does not. Drs. William Haynes and Lee Alward together with
our group reported such a patient recently in Ophthalmic Surgery and
Lasers. This patient had massive pigment liberation while playing basket-
ball and this was completely eliminated by low-dose Pilocarpine pretreat-
ment. Nevertheless, I have performed only about 20 iridotomies. My pre-
ferred treatment is pilocarpine in those patients who do not have periph-
eral retinal abnormalities, but ofcourse the younger patients cannot toler-
ate miotic drops because they cause accommodative spasm and induced
myopia. However, they do very well with Ocuserts. We have started hun-
dreds ofpatients on these.
Third, does the development of the normal iris stroma depend on the
normal development ofthe iris pigment epithelium? I just cannot answer
that question. I am not a developmental biologist and I don't know if any
one has ever looked at this. It is possible that normal development ofone
is dependent on the other, or it is possible that both of them respond to
the same transmitter during differentiation and that their differentiation
occurs together as a parallel process.
Fourth, is the genetic defect linked to myopia or is myopia more like-
ly to be expressed in glaucoma? It is possible that the two are linked, since
it is very rare to see hyperopes with pigment dispersion.
toward the hypothesis that hyperopes can be carriers, but that myopia pre-
disposes to the phenotypic expression. Accommodation may play a much
greater role than we have previously thought and may account for why
myopes manifest the phenotypic expression.
between myopia and intelligence; pigment dispersion patients tend to be
highly intelligent, and prolonged accommodation leads to myopia. There
also seems to be a psychological profile which many patients with pigment
dispersion fit. They are often highly goal oriented, more tense than aver-
age, and somewhat hypomanic. Surgeons and lawyers are more likely to
have pigment dispersion than psychiatrists and accountants. There seems
to be a generalized adrenergic hypersensitivity. Future studies may clari-
Dr. Lichter asked the "how-many-hits-does-it-take-to-make-glaucoma"
question. I have always thought in terms ofthe three hit theory. You need
something to affect the trabecular meshwork, such as pigment in pigmen-
tary glaucoma or a gene causing decreased trabecular function in juvenile
"primary" open-angle glaucoma (JPOAG).
doubt prompted by the fact that not everyone with pigment dispersion,
even when the pigment on the meshwork appears massive, develops ele-
vated IOP. So the second hit is one which makes the meshwork suscepti-
ble to developing elevated IOP. I might add at this point, parenthetically,
that people who have pigment dispersion who do not develop elevated
IOP nevertheless may go on later to develop glaucoma at an earlier age
than they would have, had they not had some trabecular damage by pig-
ment earlier in life. We are presently looking at whether patients with pig-
ment dispersion go on to have a higher incidence of normal-tension glau-
coma later in life. The third hit would be susceptibility ofthe disc to dam-
age, since not all patients with elevated pressure develop disc damage.
However, I think that we are dealing with two different primary hits,
and it's not necessary to have two genes, at least not the genes we are
thinking of in this discussion. Pigment dispersion is very common in the
population but most of them remain undiagnosed. Most affected people
go through life never knowing they have it; in fact, most people have never
even heard of it. The juvenile glaucoma gene is common also, but proba-
I have leaned
There is a correlation
Dr. Lichter's question is no
Pigment Dispersion Syndrome
bly less common than the one for pigment dispersion. Nevertheless, the
only hard evidence we have are two studies presented at ARVO in 1995 by
Drs. Zeev Stegman and Joseph Sokol, in which we looked at trabecular
meshwork heights. Patients with pigmentary glaucoma had normal mesh-
work heights, while those with JPOAG had meshworks which were signif-
icantly smaller than normal.
I would like to take this opportunity to thank the Society for inviting
me to speak today and to thank Dr. Yanoff for his excellent discussion.