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Retinal Pigment Epithelial Dysfunction in Patients With Pigment Dispersion Syndrome
Implications for the Theory of Pathogenesis
Vivienne C. Greenstein, PhD;
William Seiple, PhD;
Jeffrey Liebmann, MD;
Robert Ritch, MD
Arch Ophthalmol. 2001;119:1291-1295.
ABSTRACT
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Objective To test the hypothesis that the retinal pigment epithelial/photoreceptor
complex is affected in patients with pigment dispersion syndrome and/or in
patients with pigmentary glaucoma.
Methods Electro-oculograms were recorded from patients with pigment dispersion
syndrome, pigmentary glaucoma, ocular hypertension, and primary open-angle
glaucoma and from control subjects. Electro-oculograms were recorded during
15 minutes of dark adaptation followed by 15 minutes of light adaptation.
For each subject, dark-trough amplitudes, dark-trough latencies, light-peak
amplitudes, light-peak latencies, and ratios of the light-peak amplitude to
the dark-trough amplitude (Arden ratios) were calculated.
Results A 1-way analysis of variance of the Arden ratios indicated significant
differences among the groups of subjects. Results of a post hoc Newman-Keuls
test revealed that the mean Arden ratios of patients with pigment dispersion
syndrome and patients with pigmentary glaucoma were significantly lower than
the mean ratios of the controls, the patients with primary open-angle glaucoma,
and those with ocular hypertension.
Conclusions The results provide support for the hypothesis that the integrity of
the retinal pigment epithelial/photoreceptor complex is affected in patients
with pigment dispersion syndrome and in those with pigmentary glaucoma. Congenital
and/or structural abnormalities of the retinal pigment epithelial/photoreceptor
complex should be considered when models of the etiology of pigment dispersion
syndrome are proposed.
INTRODUCTION
PIGMENT dispersion syndrome (PDS) and pigmentary glaucoma (PG) are characterized
by disruption of the iris pigment epithelium and by deposition of the dispersed
pigment granules throughout the anterior segment, producing the classic diagnostic
triad of corneal pigmentation (Krukenberg spindle); slitlike, radial, midperipheral
iris transillumination defects; and dense trabecular pigmentation.1 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
the 1950s, the discovery of iris transillumination defects led to the concept
that the trabecular pigment originated from the iris pigment epithelium and
perhaps the ciliary body.2-3 Congenital
weakness or atrophy of the iris pigment epithelium was suggested as a cause
of loss of iris pigment.4-6
In 1979, Campbell7 proposed that mechanical
damage to the iris pigment epithelium caused by iridozonular friction during
physiologic pupillary movement resulted in iris pigment loss.
Eyes with PDS have a high incidence of retinal detachment8-10
and lattice degeneration.11-12
Isolated reports13-14 of patients
with PDS and retinal pigment epithelial (RPE) changes have been published.
Electro-oculographic studies15-16
have suggested that RPE function may be affected in patients with PDS and
in those with PG. As the clinical electro-oculogram (EOG) reflects the integrity
of the RPE/photoreceptor complex, a subnormal EOG result suggests that the
RPE is affected in patients with PDS. We obtained EOGs from patients with
PDS and from those with PG and compared the results with those obtained from
patients with ocular hypertension (OHT), patients with primary open-angle
glaucoma (POAG), and control subjects.
SUBJECTS AND METHODS
SUBJECTS
The clinical characteristics of the patients are summarized in Table 1. Fourteen patients with PDS, 11
with PG, 10 with OHT, and 10 with POAG (1 was diagnosed as having juvenile
open-angle glaucoma) were tested. The age range was from 27 to 70 years (mean
± SD, 44.0 ± 14.8 years) for the patients with PDS, from 32
to 70 years (mean ± SD, 49.7 ± 12.6 years) for the patients
with PG, from 36 to 65 years (mean ± SD, 52.5 ± 8.1 years) for
the patients with OHT, and from 31 to 70 years (mean ± SD, 52.3 ±
13.6 years) for the patients with POAG.
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Clinical Characteristics of the Subjects and Arden Ratios
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The diagnosis of PDS was based on the presence of corneal pigmentation
(Krukenberg spindle); slitlike, radial, midperipheral iris transillumination
defects; and dense trabecular pigmentation. Twelve of the patients with PDS
also had OHT based on a history of intraocular pressures (IOPs) of 22 mm Hg
or higher on 2 or more occasions. None of the patients in this PDS group showed
any evidence of visual field defects or clinically significant glaucomatous
cupping. The IOPs were controlled by medication at the time of testing. The
diagnosis of OHT was applied to 10 patients who showed no evidence of glaucomatous
cupping or visual field defects but who had IOPs of 22 mm Hg or higher on
2 or more occasions. The IOPs for these patients were also controlled by medication
at the time of testing. Patients with glaucoma showed evidence of abnormal
optic discs and abnormal Humphrey 30-2 or 24-2 visual fields with corrected
pattern standard deviation outside 95% or Glaucoma Hemifield Test result outside
99% of age-specific norms. None of the eyes studied in the 5 groups showed
evidence of ocular motility dysfunction, age-related macular degeneration,
or retinal detachment. Eleven subjects, ranging in age from 24 to 67 years
(mean ± SD, 45.5 ± 18.0 years), with no known abnormalities
of the visual system, no evidence of PDS or exfoliation syndrome, Humphrey
30-2 visual fields within normal limits, normal IOPs, and normal cup-disc
ratios comprised the control group. The refractive errors of the tested eyes
for the control subjects are shown in Table
1; the range of refractive errors is similar to that for the patients
with PDS. A linear regression analysis showed that there was no significant
effect of refractive error on the Arden ratio (AR) (F = 0.48, P = .51).
Informed consent was obtained from all subjects before their participation.
Procedures followed the tenets of the Declaration of Helsinki, and the protocol
was approved by the committee of the Institutional Board of Research Associates
of New York University Medical Center and Bellevue Hospital, New York.
PROCEDURE
The stimulus field consisted of a 51° x 34° (width times
height) light box that was evenly illuminated (2700 candela [cd]/m2).
The fixation targets consisted of a horizontal row of red light–emitting
diodes placed along the center of the stimulus field. The light-emitting diodes
were sequentially illuminated from left to right and from right to left at
a sinusoidal rate of 0.3 Hz. Skin electrodes were applied to the medial and
temporal canthi using conductive paste. Pupils were dilated with 1% tropicamide
(pupil diameters ranged from 7-9 mm in all subjects). Eyes were preadapted
to room light levels of 60 lux for 20 minutes. The EOG was recorded during
15 minutes of dark adaptation followed by 15 minutes of light adaptation to
2700 cd/m2. Subjects were instructed to follow the illuminated
red LED array using smooth-pursuit eye movements for 20-second periods followed
by 20-second rest periods.
The input from the patients was amplified (500 times) and band pass
filtered (from 0.1-30 Hz) (Grass preamplifier model 511; Astro-Med. Inc, West
Warwick, RI), and the signal was digitized (1000 times per second) for analysis.
Fourier amplitude and phase were calculated for each 20-second data acquisition
period, and the amplitudes were plotted as a function of time. For each eye,
dark-trough amplitudes (DTAs), dark-trough latencies, light-peak amplitudes,
light-peak latencies, and ratios of the light-peak amplitude to the DTA (ARs)
were calculated. The procedures used in this study were based on the recommendations
and standards proposed by the International Society for Clinical Electrophysiology
of Vision.17 An example of an EOG record of
response amplitude vs time is shown in Figure
1. For statistical analysis, when data were obtained from both eyes
of a subject, one eye was chosen at random and the data averaged for each
group of subjects. Data are given as mean ± SD unless otherwise indicated.
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Figure 1. An electro-oculogram record of
response amplitude vs time.
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RESULTS
Table 1 shows the ARs for
the patients and the control subjects. The distributions of the ARs for the
control subjects and for the 4 groups of patients are shown in Figure 2. Although there is overlap among the 5 distributions, the
ARs tend to be higher for the control subjects than for the patients with
OHT, POAG, or PDS. The patients with PG have the lowest ARs. A 1-way analysis
of variance of the data indicated significant differences among the 5 groups
(F4,51 = 11.33, P<.001). Results of
a post hoc Newman-Keuls test revealed that the mean ARs of the PDS group (2.00
± 0.33) were significantly lower than the mean ARs of the control (2.68
± 0.52) (P<.001) and the POAG (2.51 ±
0.40) (P = .005) groups. The mean ARs of the PG group
(1.78 ± 0.29) were significantly lower than the mean ARs of the control
(2.68 ± 0.52) (P<.001), the OHT (2.32 ±
0.23) (P = .003), and the POAG (2.51 ± 0.40)
(P<.001) groups.
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Figure 2. The distributions of the Arden
ratios for the 5 groups. CNT indicates control subjects; OHT, patients with
ocular hypertension; POAG, patients with primary open-angle glaucoma; PDS,
patients with pigment dispersion syndrome; and PG, patients with pigmentary
glaucoma.
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The distributions of the dark-trough latencies and light-peak latencies
for the 5 groups are shown in Figure 3A-B.
A 1-way analysis of variance indicated no significant differences among the
groups (dark-trough latencies, P = .59; light-peak
latencies, P = .23). The DTAs were also calculated.
The mean DTAs of the PDS (589 ± 163 µV) and PG (665 ±
137 µV) groups were similar to the mean DTA of the control group (668
± 178 µV). Although the mean DTAs of the OHT and POAG groups
were lower (523 ± 135 and 434 ± 66 µV, respectively),
a 1-way analysis of variance indicated no significant differences among the
groups (P = .06).
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Figure 3. The distribution of dark-trough
latencies (A) and light-peak latencies (B) for the 5 groups. CNT indicates
control subjects; OHT, patients with ocular hypertension; POAG, patients with
primary open-angle glaucoma; PDS, patients with pigment dispersion syndrome;
and PG, patients with pigmentary glaucoma.
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COMMENT
Any hypothesis regarding the underlying causes of PDS must take into
account the associated findings. This hereditary disorder is associated with
retinal abnormalities, retinal detachment being the most notable association.8-10 Eyes with PDS or PG
have roughly a 6% to 7% cumulative lifetime incidence of retinal detachment,
irrespective of a history of miotic therapy.8
The prevalence of lattice degeneration of the retina appears to be higher
for patients with PDS11 than for the general
population with similar amounts of myopia.18
Isolated reports13-14 have linked
PDS with RPE disturbances. However, PDS may affect more than 2% of the white
population,19 and these associations may well
be by chance.
More intriguing are previous findings of generalized RPE dysfunction
in eyes with PDS or PG as determined by electro-oculography.15-16
In this study, we used electro-oculography, which provides a measure of the
standing potential between the anterior and the posterior pole of the eye,
to test the hypothesis that the integrity of the RPE/photoreceptor complex
is affected in patients with PDS and/or PG. Light adaptation produces a slow
change in the EOG, reflecting a change in potential of the RPE basal membrane.20-22 It is postulated
that a diffusible substance in the subretinal space mediates this change.
This has an effect on the RPE, either directly or through a secondary messenger.23 Therefore, the light rise of the EOG is of RPE origin,22-23 but it is related to the combined
activity of the photoreceptors and the RPE.23-25
In agreement with Scuderi et al,15 we found
that the light rise of the EOG was significantly reduced for patients with
PDS compared with subjects in the control group. In addition, the ARs for
patients with PG were significantly lower than the ARs for patients with POAG.
These results support the hypothesis that the integrity of the RPE/photoreceptor
complex is affected in patients with PDS and in those with PG. Whereas eyes
with PG have greater functional compromise than eyes with POAG, the finding
that eyes with PDS and normal IOPs have significantly lower ARs than controls
suggests that there is an inherent defect in the RPE/photoreceptor complex
that goes beyond any contribution from glaucomatous damage.
Although iridozonular friction appears indisputably to be the direct
cause of iris pigment epithelial disruption, whether this is of itself sufficient
to result in PDS has recently been questioned.1
The pigment epithelia of the anterior and posterior segments of the eye share
a common embryological origin. Eyes with PDS have a characteristic midperipheral
iris concavity that is increased during accommodation26-28
and disappears with inhibition of blinking.29
However, accommodation has been noted to produce a marked peripheral iris
concavity, particularly in patients with myopia, without the development of
PDS.29-31 The
iris insertion tends to be more posterior in eyes with PDS,32
but there is significant overlap between eyes with PDS and normal eyes. A
more posterior iris insertion, bringing the iris closer to the zonular apparatus,
does not appear to be a sufficient condition to explain why some eyes with
marked iris concavities develop pigment dispersion and why some do not.
Although the presence of a marked iris concavity in patients with myopia
or the development of one during accommodation does not necessarily prove
that iridozonular contact is occurring, it is suggestive. The implications
of the electro-oculographic findings are that congenital or structural abnormalities
of the RPE/photoreceptor complex and, by implication, the iris pigment epithelium
have also to be taken into consideration when underlying causes of PDS are
proposed. It is worth reexploring the old hypothesis that an underlying weakness
of the iris pigment epithelium may predispose an eye to damage, which would
occur during iridozonular friction.
AUTHOR INFORMATION
Accepted for publication February 23, 2001.
This study was supported by grant RO1-EY-02115 from the National Eye
Institute, Bethesda, Md; a grant from the Helen Hoffritz Foundation, New York,
NY; and the Donald Engel Research Fund of the New York Glaucoma Research Institute,
New York.
Presented in part at the meeting of the International Society for Clinical
Electrophysiology, Sydney, Australia, February 14, 2000.
Corresponding author and reprints: Vivienne C. Greenstein, PhD, Department
of Ophthalmology, New York University School of Medicine, 550 First Ave, New
York, NY 10016 (e-mail: vcg1{at}nyu.edu).
From the Departments of Ophthalmology, New York University School of
Medicine (Drs Greenstein and Seiple) and The New York Eye and Ear Infirmary
(Drs Liebmann and Ritch), New York, and The New York Medical College, Valhalla
(Drs Liebmann and Ritch).
REFERENCES
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1. Ritch R. A unification hypothesis of pigment dispersion syndrome. Trans Am Ophthalmol Soc. 1996;94:381-409.
PUBMED
2. Bick MW. Pigmentary glaucoma in females. Arch Ophthalmol. 1957;58:483-494.
FULL TEXT
3. Scheie HG, Fleischhauer HW. Idiopathic atrophy of the epithelial layers of the iris and ciliary
body: a clinical study. Arch Ophthalmol. 1958;59:216-228.
FULL TEXT
4. Brini A, Porté A, Roth A. Atrophie des couches epithéliales de l'iris: étude d'un
cas de glaucome pigmentaire au microscope optique et au microscope électronique. Doc Ophthalmol. 1969;26:403-423.
FULL TEXT
|
ISI
| PUBMED
5. Rodrigues MM, Spaeth GL, Weinreb S, Sivalingam E. Spectrum of trabecular pigmentation in open-angle glaucoma: a clinicopathologic
study. Trans Am Acad Ophthalmol Otolaryngol. 1976;81:258-276.
PUBMED
6. Kupfer C, Kuwabara T, Kaiser-Kupfer M. The histopathology of pigmentary dispersion syndrome with glaucoma. Am J Ophthalmol. 1975;80:857-862.
ISI
| PUBMED
7. Campbell DG. Pigmentary dispersion and glaucoma: a new theory. Arch Ophthalmol. 1979;97:1667-1672.
ABSTRACT
8. Scheie HG, Cameron JD. Pigment dispersion syndrome: a clinical study. Br J Ophthalmol. 1981;65:264-269.
FREE FULL TEXT
9. Brachet A, Chermet M. Association glaucoma pigmentaire et decollement de rétine. Ann D'Oculist. 1974;207:452-457.
10. Delaney WV Jr. Equatorial lens pigmentation, myopia, and retinal detachment. Am J Ophthalmol. 1975;79:194-196.
ISI
| PUBMED
11. Weseley P, Liebmann J, Walsh JB, Ritch R. Lattice degeneration of the retina and the pigment dispersion syndrome. Am J Ophthalmol. 1992;114:539-543.
ISI
| PUBMED
12. Scuderi GL, Papale A, Nucci C, Cerulli L. Retinal involvement in pigment dispersion syndrome. Int Ophthalmol. 1995-96;19:375-378.
13. Chew EY, Deutman AF. Pigment dispersion syndrome and pigmented pattern dystrophy of retinal
pigment epithelium. Br J Ophthalmol. 1983;67:538-541.
FREE FULL TEXT
14. Piccolino FC, Calabria G, Polizzi A, Fioretto M. Pigmentary retinal dystrophy associated with pigmentary glaucoma. Graefes Arch Clin Exp Ophthalmol. 1989;227:335-339.
FULL TEXT
|
ISI
| PUBMED
15. Scuderi GL, Ricci F, Nucci C, et al. Electro-oculography in pigment dispersion syndrome. Ophthalmic Res. 1998;30:23-29.
FULL TEXT
|
ISI
| PUBMED
16. Demailly P, Plane E, Simons S, Luton JP. Glaucome pigmentaire. Bull Soc Ophthalmol Fr. 1979;79:179-181.
17. Marmor MF, Zrenner E. Standard for clinical electro-oculography. Doc Ophthalmol. 1993;85:115-124.
FULL TEXT
|
ISI
| PUBMED
18. Byer NE. Lattice degeneration of the retina. Surv Ophthalmol. 1979;23:213-248.
FULL TEXT
|
ISI
| PUBMED
19. Ritch R, Steinberger D, Liebmann JM. Prevalence of pigment dispersion syndrome in a population undergoing
glaucoma screening. Am J Ophthalmol. 1993;115:707-710.
ISI
| PUBMED
20. Skoog KO. The directly recorded standing potential of the human eye. Acta Ophthalmol (Copenh). 1975;53:120-132.
21. Marmor MF. Clinical electrophysiology of the retinal pigment epithelium. Doc Ophthalmol. 1991;76:301-313.
FULL TEXT
|
ISI
| PUBMED
22. Linsenmeier RA, Steinberg RH. Mechanisms of hypoxic effect on the cat DC electroretinogram. Invest Ophthalmol Vis Sci. 1986;27:1385-1394.
FREE FULL TEXT
23. Steinberg RH. Monitoring communications between photoreceptors and pigment epithelial
cells: effects of "mild" systemic hypoxia. Invest Ophthalmol Vis Sci. 1987;28:1888-1904.
FREE FULL TEXT
24. Nilsson SE. Electrophysiology in pigment epithelial changes. Acta Ophthalmol Suppl. 1985;173:22-27.
25. Steinberg RH. Interactions between the retinal pigment epithelium and the neural
retina. Doc Ophthalmol. 1985;60:327-346.
FULL TEXT
|
ISI
| PUBMED
26. Potash SD, Tello C, Liebmann J, Ritch R. Ultrasound biomicroscopy in pigment dispersion syndrome. Ophthalmology. 1994;101:332-339.
ISI
| PUBMED
27. Liebmann JM, Tello C, Ritch R. Pigment dispersion syndrome, iris configuration, and blinking [abstract]. Invest Ophthalmol Vis Sci. 1994;35(suppl):1558.
28. Pavlin CJ, Macken P, Trope G, et al. Accommodation and iridotomy in the pigment dispersion syndrome. Ophthalmic Surg Lasers. 1996;27:113-120.
ISI
| PUBMED
29. Liebmann JM, Tello C, Chew SJ, et al. Prevention of blinking alters iris configuration in pigment dispersion
syndrome and in normal eyes. Ophthalmology. 1995;102:446-455.
ISI
| PUBMED
30. Ueda J, Sawaguchi S, Watanabe J, et al. Posterior iris bowing after accommodation: elucidation of the etiology
of pigment dispersion syndrome. Nippon Ganka Gakkai Zasshi. 1997;101:187-191.
PUBMED
31. McWhae JA, Crichton ACS, Reimer J. A dynamic study of accommodation using ultrasound biomicroscopy. In: Cennamo G, Rosa N, eds. Ultrasonography in
Ophthalmology. Dordrecht, the Netherlands: Kluwer Academic Publishers;
1997:233-240.
32. Sokol J, Stegman Z, Liebmann JM, Ritch R. Location of the iris insertion in pigment dispersion syndrome. Ophthalmology. 1996;103:289-293.
ISI
| PUBMED
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