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Unilateral or Asymmetric Pseudoexfoliation Syndrome?
An Ultrastructural Study
Thomas Hammer, MD;
Ursula Schlötzer-Schrehardt, MD;
Gottfried O. H. Naumann, MD
Arch Ophthalmol. 2001;119:1023-1031.
ABSTRACT
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Background Clinically, most patients with pseudoexfoliation (PEX) syndrome reveal
only unilateral ocular involvement. However, the generalized nature of the
disorder suggests that PEX syndrome is clinically asymmetric rather than strictly
unilateral.
Objective To perform an ultrastructural study of the contralateral eyes in patients
with unilateral PEX syndrome.
Methods Five pairs of donor eyes with slitlamp microscopic, macroscopic, and
light microscopic evidence of unilateral PEX syndrome and 6 normal control
eyes were investigated by transmission electron microscopy and light and electron
microscopic immunohistochemistry using antibodies against the human natural
killer (HNK-1) epitope and against latent transforming growth factor  1–binding protein, both markers for the identification of PEX
deposits.
Results Ultrastructural alterations were observed in anterior segment tissues
of all apparently not involved fellow eyes. These included (1) deposits of
typical PEX fibrils on the iris and ciliary epithelia and in the dilator muscle
of the iris; (2) increased accumulation of extracellular matrix, including
microfibrils and reduplicated basement membrane material in the periphery
of iris vessels, in the dilator muscle and in the juxtacanalicular tissue
of the trabecular meshwork; and (3) degenerative changes of the iris pigment
epithelium and dilator muscle cells. Latent transforming growth factor 1–binding protein– and HNK-1–positive deposits indicating
PEX material accumulations were detected in the periphery of iris vessels
and in the dilator muscle in all affected and contralateral eyes, but not
in the control eyes.
Conclusions These subclinical alterations of contralateral eyes in clinically so-called
unilateral PEX syndrome support the concept that PEX syndrome is a generalized
basically bilateral disorder with a clinically marked asymmetric manifestation.
The iris changes may account for the clinical signs characteristic of early
stages, such as melanin dispersion, peripupillary atrophy, trabecular meshwork
pigmentation, and insufficient asymmetric mydriasis. The findings should be
considered in the clinical management of the patients.
Clinical Relevance In view of the fact that PEX syndrome is the most common identifiable
cause of open-angle glaucoma worldwide and as it is an important risk factor
for a wide spectrum of ocular complications, particularly during cataract
surgery, the potential involvement of both eyes in the PEX process is of clinical
significance.
INTRODUCTION
THE pseudoexfoliation (PEX) syndrome is a degenerative fibrillopathy
characterized by the production and accumulation of an abnormal extracellular
fibrillar material in the anterior segment of the eye and in various extraocular
tissues. Clinically, ocular involvement is described as unilateral in 48%
to 76% (ie, most) patients.1-3
In these apparently monocular cases, the fellow eye often has abnormal aqueous
humor dynamics,4 a higher intraocular pressure,2 and more pronounced trabecular meshwork pigmentation5 compared with normal eyes. Clinically, unilateral
involvement is often a precursor to bilateral involvement, and progression
to bilaterality was reported in up to 50% of patients within 5 to 10 years
after diagnosis.6-9
Patients with bilateral involvement tend to be older and tend to have a higher
prevalence of glaucoma than those with a unilateral manifestation.2, 6
Recent studies10-13
have demonstrated that PEX syndrome is a systemic process with a wide distribution
of PEX material deposits in the body, including the skin, meninges, lungs,
heart, and other visceral organs. In accordance, typical PEX accumulations
have been detected by electron microscopy in the conjunctiva and in other
peribulbar tissues of clinically involved and virtually all uninvolved fellow
eyes.14-16 Another
light microscopic immunohistochemical study17
demonstrated abnormal deposits similar to those of classic PEX syndrome in
the periphery of iris vessels of clinically unaffected eyes. Together, these
findings indicate that so-called unilateral PEX syndrome is clinically asymmetric
rather than truly unilateral.
In view of the fact that PEX syndrome is the most common identifiable
cause of open-angle glaucoma worldwide18 and
as it is an important risk factor for a wide spectrum of ocular complications,
particularly during cataract surgery,19-21
the potential involvement of both eyes in the PEX process is of clinical significance.
However, to our knowledge, a detailed ultrastructural analysis of the histopathologic
alterations in the fellow eyes of patients with unilateral PEX manifestation
has not been performed.
To review the concept of presumed unilateral PEX syndrome, we investigated
possible histopathologic alterations in clinically uninvolved eyes of patients
with unilateral PEX syndrome by electron microscopy and immunohistochemistry
using antibodies against the HNK-1 carbohydrate epitope and against latent
transforming growth factor 1–binding protein (LTBP-1),
both suitable markers for the identification of PEX deposits.17, 22
MATERIALS AND METHODS
TISSUE
Anterior segment tissues were obtained from 5 pairs of donor eyes (mean
± SD age, 74.3 ± 10.0 years; 4 women and 1 man) that revealed
PEX deposits on anterior segment structures in only 1 eye by slitlamp microscopic,
macroscopic, and light microscopic investigations. The diagnosis of unilateral
PEX syndrome was made postmortem by slitlamp microscopic observation of PEX
deposits on the anterior lens surface and was subsequently confirmed by macroscopic
and light microscopic observation of PEX material on the posterior iris surface,
the ciliary processes, the lens, and the zonules. The slitlamp microscopic
diagnosis of PEX syndrome had prevented the excision and transplantation of
the corneas because of the known PEX-associated corneal endotheliopathy.
Six normal-appearing donor eyes (mean ± SD age, 75.0 ±
7.3 years) without any known ocular disease were used as controls.
ELECTRON MICROSCOPY
The tissue specimens were fixed 2 to 19 hours postmortem in
a solution of 4% paraformaldehyde and 1% glutaraldehyde in a 0.1M phosphate
buffer (pH, 7.4), and were embedded in epoxy resin (EPON 812) using a standard
protocol. The semithin sections were stained with toluidine blue and the ultrathin
sections with uranyl acetate and lead citrate, and examined with a transmission
electron microscope (model 906E; LEO, Oberkochen, Germany).
IMMUNOHISTOCHEMISTRY
Because previous studies have shown that antibodies against the carbohydrate
epitope HNK-117 and against LTBP-122 are suitable markers for identifying PEX deposits
in ocular tissues, we investigated the immunolocalization of HNK-1 and LTBP-1
on the light and electron microscopic level.
For indirect immunofluorescence, tissue specimens were embedded in ornithine
carbamyltransferase compound and snap-frozen in a combination of isopentane
and liquid nitrogen. Cryostat sections (5-7 µm) were fixed in cold acetone,
incubated in a 10% solution of normal goat serum in phosphate-buffered saline,
and then incubated in primary antibody (polyclonal LTBP-1; Pharmingen, Hamburg,
Germany) diluted 1:750 in phosphate-buffered saline overnight at 4°C.
Antibody binding was detected by incubating the sections with an Alexa-488–conjugated
secondary antibody (Molecular Probes, Leiden, the Netherlands) diluted 1:100
in phosphate-buffered saline for 30 minutes at room temperature.
For postembedding immunogold labeling, tissue specimens were fixed in
a freshly made solution of 4% paraformaldehyde and 0.1% glutaraldehyde in
a 0.1M cacodylate buffer (pH, 7.4) for 1 to 2 hours at 4°C. After being
rinsed, the specimens were dehydrated serially to 70% ethanol at -20°C
and embedded in LR White (London Resin Co Ltd, Woking, England) resin using
a standard protocol. After blocking unspecific binding sites with 0.5% ovalbumin
and 0.5% fish gelatin, the ultrathin sections were incubated in primary antibody
solution (monoclonal HNK-1; Becton Dickinson, Erembodegem-Aalst, Belgium)
diluted 1:50 in Tris-buffered saline with 0.5% ovalbumin overnight at 4°C.
Antibody detection was performed with a 10-nm gold-conjugated secondary antibody
(BioCell International, Cardiff, Wales) diluted 1:30 in a combination of Tris-buffered
saline, ovalbumin, and gelatin for 1 hour at room temperature. After being
rinsed, the sections were stained with uranyl acetate and examined with an
electron microscope (model 906E; LEO).
RESULTS
Under a dissecting microscope, all involved eyes, but not the contralateral
eyes, showed PEX material deposits on anterior segment surfaces. Typical PEX
material could be demonstrated by light and electron microscopy in the involved
eyes in all known sites of PEX material deposition, such as the lens, the
iris pigment epithelium, the iris stroma, the ciliary epithelium, and the
trabecular meshwork.23 A light microscopic
examination of the apparently noninvolved contralateral eyes confirmed the
absence of PEX material in ocular tissues. However, by electron microscopy,
subtle ultrastructural changes were found in all fellow eyes examined. All
5 eyes showed alterations of iris vessels, including basement membrane abnormalities
and excessive microfibrillar deposits. In addition, minute foci of characteristic
PEX fibers could be demonstrated on the iris pigment epithelium and on the
unpigmented ciliary epithelium in 1 and in the area of the dilator muscle
in 3 of the 5 fellow eyes.
ELECTRON MICROSCOPY
Iris
Whereas the iridic pigment epithelial cells of eyes with manifest PEX
syndrome displayed a highly irregular basal cell surface covered by masses
of PEX material, the pigment epithelial cells of contralateral eyes showed
a rather regular cell surface covered by small PEX flakes in one case (Figure 1). Areas of degenerative changes
of the iris pigment epithelium, such as intracellular vacuolation, swollen
mitochondria, dilated rough endoplasmic reticulum, and disrupted cell membranes
with liberation of melanin granules, were, however, evident in all contralateral
eyes.
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Figure 1. Electron micrographs of the iris
pigment epithelium (ipe). A, The regular basal cell surface of intact ipe
in control eyes. B, Degenerative ipe with a small PEX aggregate (star) adhering
to the surface in a contralateral eye. C, Degenerative ipe cells with a vacuolar
cytoplasm and an irregular basal cell surface covered by a thick layer of
PEX material (star) in eyes with manifest PEX syndrome. PEX indicates pseudoexfoliation;
pc, posterior chamber; and nc, nucleus.
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Degenerative alterations were also observed in the dilator muscle of
contralateral eyes (Figure 2). Compared
with normal eyes, the muscle cells appeared thinned and rarefied and were
separated by widened intercellular spaces filled with an excess of microfibrillar
material. Typical PEX fibers were found within these intercellular spaces
in 3 of the 5 contralateral eyes. In some places, the muscle cells contained
clumped myofilaments and degenerated cell organelles in an electron-lucent
vacuolar cytoplasm. Whirl-like membrane structures were found between the
epithelial cells of the anterior portion of the pigment epithelium.
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Figure 2. Electron micrographs of the dilator
muscle. A, Regular organization of mcs of the anterior ipe in control eyes.
B, PEX deposits (star) between irregular mcs in eyes with manifest PEX syndrome.
C, Widened extracellular spaces between rarefied mcs (arrows) filled with
microfibrillar material and aggregates of PEX fibers (star) in a contralateral
eye. D, Microfibrils and PEX fibers (star) in association with an mc in a
contralateral eye. mcs indicates muscle cell process; ipe, iris pigment epithelium;
and PEX, pseudoexfoliation.
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Compared with the control eyes, a subpopulation of iris vessels showed
ultrastructural alterations in each of the 5 fellow eyes (Figure 3). These alterations included a pronounced thickening and
multilayering of the endothelial basement membrane and the excessive accumulation
of a fibrillar-granular extracellular material and microfibrils 10 to 12 nm
in diameter in the perivascular space. Whereas mature PEX fibers were not
detected, PEX fibers at different stages of maturity were observed within
the perivascular matrix in 2 cases. Degenerative changes of adventitial cells,
particularly pericytes, were represented by vacuolation of their cytoplasm
and many pinocytotic vesicles; electron-dense extracellular granules accumulated
in the vessel periphery.
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Figure 3. Electron micrographs of the iris
vessels. A, Normal vascular en with single-layered basement membrane (arrows)
and perivascular collagen fibers in control eyes. B, Pronounced multilayering
of the basement membrane (arrows) and typical perivascular PEX fibrils (star)
in eyes with manifest PEX syndrome. C, Abnormal fibrillar-granular extracellular
material (star) and multilayered basement membrane (arrows) between en and
pc in contralateral eyes. D, Sheets of basement membrane (arrows) and a thick
sheath of fibrillar-granular material (star) with immature PEX fibers (arrowheads)
in the perivascular space of a contralateral eye. en indicates endothelial
cells; lu, lumen; PEX, pseudoexfoliation; and pc, pericytes.
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Ciliary Body
With the exception of one contralateral eye revealing minute PEX aggregates
on the surface of the unpigmented ciliary epithelium, the ciliary epithelial
cells appeared normal (Figure 4).
In this specific case, the epithelial cells associated with small PEX flakes
displayed a regular surface outline and no ultrastructural signs of PEX fiber
production. Instead, the PEX clumps seemed to be loosely adhering to the surface
of the ciliary epithelium. In contrast, the unpigmented epithelial cells of
obviously affected eyes were characterized by irregular invaginations of the
basal cell surface containing PEX fibers. The attachment site of zonular fibers
in the epithelial basement membrane of the contralateral eyes showed no alterations
compared with the control eyes.
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Figure 4. Electron micrographs of unpigmented
ciliary epithelium (upe). A, The regular basal cell surface of intact upe
in control eyes. B, A small PEX flake (star) in loose association with an
epithelial cell of a contralateral eye. C, Irregular basal surface of upe
covered by massive PEX accumulations (star). pc indicates posterior chamber;
nc, nucleus; and PEX, pseudoexfoliation.
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Trabecular Meshwork
No typical PEX deposits could be demonstrated in the trabecular meshwork
or in the area of the Schlemm's canal in any of the contralateral eyes. However,
an increased amount of extracellular matrix material, including basement membrane–like
and elastotic material, microfibrils, collagen fibrils, and long-spacing collagen,
was detected in the juxtacanalicular connective tissue of all contralateral
eyes compared with control eyes.
IMMUNOHISTOCHEMISTRY
For the immunohistochemical detection of PEX-specific antigens in tissue
sections of affected eyes and contralateral eyes, antibodies against LTBP-1
were used on the light microscopic level and against the HNK-1 epitope on
the electron microscopic level.
Immunofluorescent labeling with anti–LTBP-1 antibodies showed
a positive immunoreaction in the periphery of a subpopulation of iris vessels
and in the dilator muscle of all eyes with PEX and all contralateral eyes
(Figure 5A-B and Table 1). Latent transforming growth factor 1–binding
protein–positive deposits could also be found on the surface of the
iris pigment epithelium in eyes with PEX only. In the control eyes, a weak
immunoreaction was confined to delicate fibrillar structures in the area of
the dilator muscle. Furthermore, LTBP-1–positive plaquelike deposits
were detected in the conjunctival stroma and in the periphery of conjunctival
vessels in eyes with PEX and in all fellow eyes (Figure 5C).
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Figure 5. Latent transforming growth factor 1–binding protein (LTBP-1) immunofluorescence of the iris and
the conjunctiva. A, LTBP-1–positive deposits in the periphery of iris
vessels (arrows), in the dilator muscle (arrowheads), and on the surface of
the ipe in eyes with manifest PEX syndrome. B, LTBP-1–positive deposits
around iris vessels (arrows) and in the dilator muscle (arrowheads), but not
on the surface of the ipe, in contralateral eyes. C, LTBP-1–positive
plaquelike deposits in the conjunctival stroma, partly perivascular deposits
(arrowheads), of contralateral eyes. ipe indicates iris pigment epithelium;
PEX, pseudoexfoliation; and ep, conjunctival epithelium (A-C, original magnification
x175).
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Distribution of LTBP-1- and HNK-1-Positive Deposits in
Normal Eyes, Eyes With PEX, and Contralateral Eyes*
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The immunogold label for HNK-1 epitopes was associated with fibrillar-granular
deposits in the periphery of some iris vessels of contralateral eyes (Figure 6B). In the dilator muscle, the gold
marker could be localized to electron-dense extracellular fibers, most probably
representing PEX fibers (Figure 6A).
The immunolocalization of the HNK-1 epitope in normal eyes and in eyes with
manifest PEX syndrome corresponded to the results of previous studies24 and confirmed differences in composition between
intraocular and extraocular PEX deposits in the conjunctiva (Table 1).
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Figure 6. Electron microscopic immunogold
detection of the human natural killer (HNK-1) epitope in the iris of contralateral
eyes. A, Dilator muscle: association of the gold marker (arrowheads) with
fibrillar-granular material in the extracellular matrix (star) between the
mc. B, Iris vessels: localization of the gold marker (arrowheads) on perivascular
microfibrillar deposits (star). mc indicates muscle cell processes; lu, lumen;
en, endothelial cells; and pc, pericyte.
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COMMENT
The present comparative study of pairs of eyes with so-called unilateral
PEX syndrome demonstrated subtle PEX-specific ultrastructural changes of anterior
segment tissues, particularly the iris, of all apparently not involved fellow
eyes. These alterations, which were not observed in control eyes, include
(1) deposits of typical PEX fibrils on the iris and ciliary epithelia and
in the dilator muscle of the iris; (2) increased accumulation of extracellular
matrix material, including microfibrils and basement membrane material in
the periphery of iris vessels, in the dilator muscle, and in the juxtacanalicular
connective tissue of the trabecular meshwork; and (3) degenerative changes
of the iris pigment epithelium and dilator muscle tissue. Latent transforming
growth factor 1–binding protein– and HNK-1–positive
deposits indicating PEX material accumulations could be detected in the periphery
of iris vessels and in the dilator muscle by light and electron microscopic
immunolabeling in all affected and contralateral eyes, but not in the control
eyes.
In addition to PEX deposits in the conjunctiva of all contralateral
eyes, typical mature PEX fibers could be demonstrated on the surface of the
iris and ciliary epithelia in 1 of the 5 and in the dilator muscle in 3 of
the 5 contralateral eyes. These focal and rather inconspicuous PEX deposits
have apparently not been visible by macroscopic and light microscopic examination
of the fellow eyes. The involvement of the dilator muscle in 3 cases suggests
that the iris muscles may be affected early in the PEX process. The accumulation
of abnormal extracellular matrix, including PEX material, and the atrophic
changes of dilator muscle cells may account for poor pupillary dilation, which
is characteristic of eyes with manifest PEX syndrome25-26
but can also be observed to a minor degree in contralateral eyes. Thus, the
histopathologic findings of this study indicate a bilateral, but asymmetric,
compromise of the pupillomotoric function as an early manifestation of PEX
syndrome.
The degenerative changes of the iris pigment epithelium in all fellow
eyes may represent the morphological correlate for the well-known clinical
signs characterizing early stages of PEX syndrome (melanin dispersion, peripupillary
atrophy, and increased trabecular meshwork pigmentation).5, 27-28
These pigment-related signs are observed in most of the unaffected fellow
eyes.15
Iris vasculopathy is a well-recognized and constant clinical feature
of eyes with PEX, and involvement of blood vessel walls has been shown by
many investigators. Characteristic features of this vasculopathy comprise
PEX deposits in the periphery of the iris vessels; thickening and reduplication
of basement membranes; and degeneration of adventitial cells,29-31
explaining hypoperfusion, fluorescein leakage, and microneovascularizations
on fluorescein angiography.32-35
Although typical perivascular PEX fibers could not be identified, abnormal
accumulations of microfibrillar structures and PEX fibers at different stages
of maturity were found together with basement membrane abnormalities in the
periphery of a subset of iris vessels in all contralateral eyes. Comparable
changes, such as basement membrane reduplications and excessive formation
of microfibrils, have been described in iris vessels devoid of perivascular
PEX material in eyes with manifest PEX syndrome.36
Furthermore, PEX fibers have been shown to be composed of and to originate
from microfibrillar subunits,37 and elastic
microfibrils have been related to the pathogenesis of PEX syndrome.38-39 In the iris stroma, PEX fibers have
been reported to be associated with a fine granular matrix and to be generally
shorter and thinner than PEX fibers on ocular surfaces.40
Positive immunolabeling of these perivascular deposits in contralateral eyes
with antibodies against HNK-1 and LTBP-1 (similar to those of classic PEX)
suggests that these deposits may represent early forms of PEX material. Thus,
the results of the present study are in perfect agreement with the findings
of a recent study17 demonstrating HNK-1–positive
subendothelial deposits around the iris vessels of both eyes in patients with
clinically unilateral PEX syndrome, indicating that iris vasculopathy is a
constant feature of the fellow eyes.
Similarly, typical PEX accumulations could not be found in the trabecular
meshwork of any of the contralateral eyes. The only alterations observed comprised
an excessive accumulation of extracellular matrix material, including basement
membrane–like material and microfibrillar structures in the juxtacanalicular
tissue. Studies41 on aqueous humor dynamics
showed a significant increase in outflow resistance in eyes with PEX compared
with the fellow eyes, but also a slightly increased resistance in the fellow
eyes compared with normal control eyes. Similarly, Pohjanpelto4
suggested a basic bilateral disturbance in aqueous humor dynamics leading
to ocular hypertension in the fellow eyes of patients with unilateral PEX
syndrome. The abnormal accumulation of extracellular materials in the critical
area of the juxtacanalicular tissue could account for this increase in outflow
resistance in the contralateral eyes.
The present demonstration of typical PEX fibers, microfibrillar precursors,
basement membrane alterations, and degenerative cellular changes in virtually
all contralateral eyes examined supports the concept that PEX syndrome is
a basically bilateral disease with a clinically markedly asymmetric manifestation,
as suggested by previous studies.15, 17
However, the alterations are not limited to iris blood vessels but also involve
the iris pigment epithelium, the dilator muscle, and the juxtacanalicular
tissue of the trabecular meshwork. Minute deposits of typical PEX aggregates
along the posterior chamber may even be present. Therefore, the contralateral
eyes are in an early preclinical stage mainly characterized by alterations
of the iris vessels, iris pigment epithelium, and dilator muscle, which precede
clinically visible PEX material accumulations on ocular surfaces. The predominant
iris changes might account for the clinical signs characteristic of early
stages of PEX syndrome, such as melanin dispersion, peripupillary atrophy,
trabecular meshwork pigmentation, poor mydriasis, and an increased protein
content in the aqueous humor measured by laser tyndallometry.15, 27, 42
Although iris blood vessels become abnormal early in the PEX process, the
clinical signs of the iris vasculopathy appear, however, to develop after
the clinically visible occurrence of PEX deposits.33
Since both eyes are obviously affected by the PEX process, the term unilateral PEX syndrome, which is most common in clinical
practice, is actually misleading, and the PEX syndrome is probably never truly
unilateral. The reasons for this marked asymmetry remain unknown, but it may
be influenced by local modulating factors, such as imbalances of growth factors,
or by subtle differences in hemodynamics or aqueous humor dynamics between
both eyes. In view of the wide spectrum of ocular complications associated
with PEX syndrome,21 these findings should
be considered in the clinical and surgical management of the patients.
AUTHOR INFORMATION
Accepted for publication March 6, 2001.
This study was supported by grants HA 2995/1-1 and SFB 539 from the
Deutsche Forschungsgemeinschaft, Bonn, Germany.
We thank Elke Meyer for her excellent technical assistance.
Corresponding author and reprints: Thomas Hammer, MD, Universitätsklinik
und Poliklinik für Augenheilkunde der Martin-Luther-Universität
Halle-Wittenberg, Magdeburger Strasse 8, 06097 Halle/Saale, Germany (e-mail: thomas.hammer{at}medizin.uni-halle.de).
From the Departments of Ophthalmology, University of Erlangen-Nürnberg,
Erlangen (Drs Hammer, Schlötzer-Schrehardt, and Naumann), and University
of Halle-Wittenberg, Halle/Saale (Dr Hammer), Germany.
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