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).
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.
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.
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.
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.
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.
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.
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.
The stimulus field consisted of a 51° × 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.
An electro-oculogram record of response amplitude vs time.
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.
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.
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).
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.
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.
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: firstname.lastname@example.org).
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