Autopsy Analysis of Clinically Unilateral ExfoliationSyndrome
Tero Kiveld, Jaana Hietanen, and Marita Uusitalo
Purpose. To study the pathogenesis of clinically unilateral exfoliation syndrome by localizingexfoliation deposits in involved and fellow eyes during autopsy.
Methods. The formalin-fixed and paraffin-embedded involved and fellow eyes were obtainedat autopsy from five patients (age range, 72 to 88 years) with clinically unilateral exfoliation.Exfoliation deposits were identified with monoclonal antibodies (mAb) HNK-1 and NC-1 tothe HNK-1 carbohydrate epitope, and with five lectins (Bauhinia purpurea agglutinin, Conca-navalin A, Lens culinaris agglutinin, Phaseolus vulgaris erythroagglutinin, and Ricinus communisagglutinin I) using the avidin-biotinylated peroxidase complex (ABC) method.
Results. Marked exfoliation deposits in all involved eyes, and weak exfoliation deposits in onefellow eye were consistently detected in light microscopic, immunohistochemical, and lectinhistochemical examinations. Similarly labeled deposits were present around a population ofblood vessels of the iris in every involved and fellow eye. Particularly in fellow eyes, thesesubendothelial deposits were better visualized with mAbs to the HNK-1 epitope than theywere with lectins. In the only fellow eye with early exfoliation, the reactivity around bloodvessels was more conspicuous than the exfoliation deposits, whereas the reverse was true inthe involved eyes.
Conclusions. Clinically unilateral exfoliation is asymmetric, rather than truly monocular. Thefindings in fellow eyes suggest that iris blood vessels become abnormal early in the process,even before exfoliation deposits are histopathologically seen in the posterior chamber. Markedasymmetry in exfoliation indicates an influence of modulating local factors that may beinternal or external to the eye, and that also may be functional in bilateral exfoliation. InvestOphthalmol Vis Sci. 1997;38:2008-2015.
JCjxfoliation syndrome is characterized by whitish ma-terial of unknown composition and origin that gradu-ally accumulates in the posterior and anterior cham-ber on the free surfaces of the ciliary epithelium, zo-nules, hyaloid face, anterior lens capsule, iris, cornealendothelium, and trabecular meshwork, and withinthe iris stroma.1'2 Fibrils that resemble those of exfolia-tion material have been found in electron microscopicexamination of several extraocular tissues.3"10 Al-though exfoliation eventually tends to affect both eyes,as would be expected of a systemic disorder, up to two
From the Department of Ophthalmology, Helsinki University Central Hospital,Finland.Supported in part by grants from the Paulo Foundation, the Helsinki UniversityCentral Hospital Institute, and the Friends of the Visually Handicapped, Helsinki,Finland.Submitted for publication February 24, 1997; revised May 2, 1997; accepted May6, 1997.Proprietary interest category: N.Reprint requests: Tero Kiveld, Ophthalmic Pathology Laboratory, Department ofOphthalmology, Helsinki University Central Hospital, Haartmaninkatu 4 C, FIN-00290 Helsinki, Finland.
thirds of patients have deposits in one eye only.11"15
Occasionally this unilaterality persists until advancedage.
Studies that focus on seemingly unilateral exfolia-tion are surprisingly rare,316"23 but their results showthat the involved eye has a reduced outflow facility,16
more pigment in the chamber angle,12'24 a higher in-traocular pressure,13'16"19'21'22 more evidence of discdamage,22 poorer visual acuity,21'23 and more advancedlens opacity1215'21'23 than does the fellow eye. With dieexception of ultrastructural studies of conjunctiva,4
the intriguing problem of monocular exfoliation hasnot received the attention of pathologists; yet it mightwell shed light on the unresolved pathogenesis of exfo-liation in general.
To study the histopathology of unilateral exfolia-tion, we examined five pairs of eyes taken during au-topsy from patients in whom heavy exfoliation in oneeye had recently been diagnosed, with no exfoliationin the fellow eye. These eyes were analyzed with two
monoclonal antibodies (mAb) to the HNK-1 carbohy-drate epitope, which is a marker for exfoliation mate-rial,25'26 as well as with five lectins that have proved tobe useful in identifying exfoliation deposits.10'27"30
MATERIAL AND METHODS
Histologic Specimens
Five consecutive pairs of formalin-fixed, paraffin-em-bedded eyes (Table 1) obtained during autopsy within1 to 3 days after death from patients with clinicallyunilateral exfoliation syndrome were collected fromthe files of the Ophthalmic Pathology Laboratory, De-partment of Ophthalmology, Helsinki University Cen-tral Hospital. Each patient's chart indicated that, inbiomicroscopic studies made through dilated pupils,marked exfoliation deposits had been noted in oneeye, whereas no deposits had been seen in the felloweye (Table 1). The eyes had been studied during au-topsy because of a history of prior ocular disease orsurgery (Table 1). Tenets of the Declaration of Hel-sinki were followed in the study.
The phakic eyes were sectioned horizontally andthe pseudophakic ones at the equator. Macroscopicexfoliation deposits were searched for using a high-powered dissecting microscope (Olympus SZH, Olym-pus Optical, Tokyo, Japan). If an intraocular lens waspresent, the posterior capsule and the haptics of thelens were cut, the optic of the intraocular lens was
removed, and the anterior segment was sectioned ver-tically before processing for embedding.
Sections (5-/im thick) were cut from the speci-mens and mounted on chromium-gelatin-treatedglass slides to ensure tissue adherence (0.05 g potas-sium chromium III sulfate dodecahydrate and 0.5 ggelatin in 100 ml of distilled water). The routine histo-pathologic stains were hematoxylin-eosin, van Gie-son, and periodic acid-Schiff.
Immunohistochemical Staining
Two mouse monoclonal immunoglobulin M antibod-ies (mAbs) to the HNK-1 carbohydrate epitope, HNK-1 (Leu-7, lot 30015, Becton Dickinson, San Jose, CA;diluted 1:4O)S1 and NC-1 (CD57, lot 2204-01-02, Cen-traal laboratorium van de bloedtransfusiedienst, Am-sterdam, The Netherlands; diluted 1:25)32 were ob-tained commercially. An unrelated immunoglobulinM mAb to cytokeratin 14 (CKB1, lot 100H4800, SigmaSt. Louis, MO; diluted 1:300) was used as a negativecontrol.
The immunoperoxidase staining was done usinga commercial version (Vectastain ABC Elite Kit forMouse IgG, Vector Laboratories, Burlingame, CA) ofthe avidin-biotinylated peroxidase complex (ABC)method and 3-amino-9-ethylcarbazole as chromogen,as has been described previously in detail.2b Omissionof the primary antibody, the secondary antibody, orthe ABC resulted in loss of all immunoreaction.
TABLE 2. Characteristics of the Five Lectins Used and Their Hapten Sugar Inhibitors*
Plant of Origin Nominal Carbohydrate Specificity InhibitorBinding toExfoliation^
Bauhinia purpurea alba (BPA)Canavalia ensiformis (ConA)Lens culinaris (LCA)Phaseolus vulgaris (PHA-E)Ricinus communis (RCA-I)
Met = methyl; Gal = galactose; Glc = glucose; Man = mannose; GalNAc = ALacetylgalactosamine; GlcNAc = /V-acetylglucosamine.* Data from Goldstein and Poretz.33
f Data from Hietanen and Tarkkanen27 and Hietanen et al.29
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Agglutinins (Table 2)33 from Bauhinia purpurea alba(lot 27F-4021), Canavalia ensijormis (Concanavalin A,lot 49F-8030), Lens culinaris (lot 61H-3903), Phaseolusvulgmis (erythroagglutinin, PHA-E, Type III-B, lot 77F-4012) and Ricinus communis (agglutinin I, RCA-120,lot 20H-4051) conjugated to biotin were commerciallyobtained (Sigma), diluted with phosphate-buffered sa-line (PBS, pH 7) to a protein concentration of 500//g/ml, and stored at —20°C until needed. When used,they were further diluted to a concentration of 100
The lectin histochemical staining was done using
a commercial version (Vectastain ABC Elite Kit, VectorLaboratories) of the ABC method, as described ear-lier.29'30 The sections were pretreated with pepsin toenhance the availability of lectin-binding sites in for-malin-fixed, paraffin-embedded material.34 Parallelnegative control sections were stained after preincu-bating the lectins with their corresponding haptensugar inhibitors (Table 2).
RESULTS
Under a dissecting microscope, all five clinically in-volved eyes showed typical exfoliation deposits on the
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FIGURE l. Light microscopic (A to F; periodic acid-Schiff) and immunohistochemical (Gto J) analysis of exfoliation deposits in the involved {left column) and corresponding fellow{right column) eyes in clinically unilateral exfoliation syndrome. (A) In an involved eye, theiris epithelium has an irregularly serrated contour, is flattened, and is covered by a layer ofexfoliation deposits, whereas (B) in the corresponding fellow eye, the epithelium is normalin thickness, regularly serrated, and without exfoliation deposits. Note that stromal collarsof blood vessels {arrowheads) are moderately periodic-acid-Schiff-positive in the involvedeye. (C) In one patient, the involved iris epithelium is covered by a thick layer of partlybush-like exfoliation deposits, and (D) weak deposits {arrowhead) are additionally found inthe fellow eye. (E) In the ciliaiy sulcus, exfoliation deposits are prominent in an involvedeye, whereas (F) no deposits are seen in the fellow eye. (G) Monoclonal antibody NC-1 tothe HNK-1 epitope labels thick layers of exfoliation on the surface of the nonpigmentedciliaiy epithelium in an involved eye, whereas (H) only its basement membrane {anoiuheads)is immunoreactive in the fellow eye. (I) Monoclonal antibody NC-1 likewise reacts withheavy exfoliation deposits on the surface of the lens capsule and in the zonular lamella{arroruhead) in an involved eye, but (J) labels only the normal zonular lamella {arrowheads)in the fellow eye. ce = ciliary epithelium cs = ciliaiy sulcus; ex = exfoliation deposits; ie =iris epithelium; le = lens. Original magnifications, (A,B) X210; (C to J) X420.
zonules and on the ciliary processes, and the iris epi-thelium was characteristically irregularly serrated. Noexfoliation deposits were noted in four of the fivefellow eyes. Trace exfoliation was suspected to be pres-ent in the fifth eye (Table 1).
Light microscopic examination confirmed thepresence of heavy exfoliation in the posterior cham-ber and marked degeneration of the iris epitheliumin all involved eyes, compared with that noted in thefellow eyes (Figs. 1A to IF), as well as the completeabsence of such deposits on the surface of the iris(Figs. 1A, IB, IE, IF), the nonpigmented ciliary epi-thelium (Figs. 1G, 1H), and the lens capsule (Figs. II,1J) in four fellow eyes, compared with the presenceof the deposits in those areas of the correspondinginvolved eyes. In particular, no deposits were seen inthe ciliaiy sulcus of the fellow eyes, whereas prominentdeposits were present in all involved eyes (Figs. IE, IF).
Weak deposits along the iris epithelium (Fig. ID)were noted in the only fellow eye in which macro-scopic examination revealed trace exfoliation. The de-posits were minor, however, compared with the partic-ularly heavy exfoliation diagnosed in the correspond-ing involved eye (Fig. 1C).
Immunohistochemistry and LectinHistochemistry
The immunohistochemical and lectin histochemicalfindings in the involved eyes and fellow eyes are sum-marized in Figure 2.
Anterior Chamber
Antibodies to the HNK-1 epitope intensely labeled ex-foliation deposits in all involved eyes (Fig. 2A) on theciliaiy epithelium (Fig. 1G), on the lens capsule (Fig.II), and on the epithelium of the iris. Heavy exfolia-tion was detected in four involved eyes and moderate
in the fifth one. In spite of the heavy exfoliation, nolabeling of the corneal endothelium or keratocyteswas detected in any of the involved eyes. The five lec-tins used also strongly labeled the exfoliation deposits,but the reaction intensity with Lens cM&wmwas some-what weaker than with the other lectins (Fig. 2A).
In all fellow eyes, antibodies to the HNK-1 epitopelabeled the basement membrane of the nonpig-mented ciliary epithelium (Fig. 1H) that also boundthe five lectins used. No unequivocal deposits consis-tent with exfoliation material were revealed in fourfellow eyes (Fig. 2B). In the fifth eye, in which weakexfoliation was seen in light microscopic study, weakdeposits on the iris epithelium were confirmed, withboth antibodies to the HNK-1 epitope and with thefive lectins (Fig. 2B).
Iris Stroma and Blood Vessels
Both antibodies to the HNK-1 epitope consistentlybound to the subendothelial region of a populationof iris blood vessels in all involved eyes (Fig. 3A). Asimilar perivascular labeling that was less extensive wasregularly found in all fellow eyes (Fig. 3B). The granu-lar pattern of the immunoreaction formed a thick,uniform layer beneath the vascular endothelium (Figs.3A to 3C). The immunoreaction involved the zoneof the thick, laminated basement membrane and theinner part of the loose collagenous zone of iris bloodvessels (Figs. 3A to 3C). However, in involved (Fig. 3C)and fellow eyes, the intensity of the immunoreactionvaried widely from vessel to vessel, and a notable num-ber of vessels remained essentially unlabeled, even ininvolved eyes.
In addition, many small immunopositive deposits,apparently unassociated with blood vessels, were pres-ent within the stroma of the iris in the involved eyes,particularly close to the anterior border layer (Figs.
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FIGURE 2. Presence of exfoliation deposits along the posterior chamber of (A) involved eyesand (B) of fellow eyes, and of subendothelial immunoreaction around blood vessels of theiris in (C) involved eyes and (D) in fellow eyes in the five patients studied, identified withmAb HNK-1 and NC-1 to die HNK-1 epitope and with five lectins (for abbreviations, seeTable 2). Weak exfoliation deposits were identified in one fellow eye; all deposits had avasculopathy that was similar to die one observed in the involved eyes.
3C, 3D). Identical perivascular and stromal depositswere revealed with the five lectins used (Figs. 3E to3H), although the slides were more difficult to inter-pret because of additional labeling of normal stromalelements (Figs. 3E, 3F), particularly in staining withConcanavalin A, Phaseolus fu/gara-erythroagglutinin,and Ricinus communis agglutinin. Regarding the suben-dothelial deposits, all lectins and antibodies to theHNK-1 epitope gave essentially identical labelingpatterns when adjacent sections were stained (Figs.3G, 3H).
The subendothelial perivascular immunoreactionwas heavy in one involved eye and moderate in four(Fig. 2C), although the reaction was more variable inintensity than was labeling of the classic exfoliationdeposits in the posterior chamber. In fellow eyes, thesubendothelial vascular deposits were generally weak(Fig. 2D), but always easily detectable, in particularwith mAb NC-1 to the HNK-1 epitope, which was themost sensitive reagent for detecting the subendothe-lial deposits.
DISCUSSION
Consistent with clinically unilateral exfoliation syn-drome in the eyes of the five patients studied, routineexamination under light microscope revealed mark-edly asymmetric exfoliation deposits. Indeed, no evi-
dence of even weak exfoliation in the posterior cham-ber was detected in four fellow eyes. The apparentunilaterality was further verified in these patients withtwo antibodies to the HNK-l epitope2526 and with fivelectins that strongly react with exfoliation mate-rial.10'27"30 In the fellow eye of the fifth and oldestpatient in the series, early deposition of exfoliationmaterial on the epithelium of the iris was detected.Even in this patient, the syndrome was remarkablyasymmetric.
Whereas results of immunohistochemical and lec-tin histochemical studies were mainly of confirmatoryvalue in localizing exfoliation deposits in the posteriorchamber, they added significantly to elucidation ofthe vasculopathy that is known to be present in theiris of eyes with exfoliation but that is not readily seenwithout electron microscopy.8'34"38 Subendothelial la-beling identical to that of classic exfoliation materialwas regularly detected in the iris, not only in all in-volved eyes, but also in every fellow eye. In accordancewith results of ultrastructural studies, these apparentexfoliation deposits occurred only in a population ofiris blood vessels, and they were unevenly distrib-uted.35"38 The vasculopathy was more advanced in in-volved eyes, in which similarly labeled stromal depositswere also highlighted by lectin and immunohisto-chemistry, reflecting the severity of exfoliation syn-drome in them. Such stromal deposits have previously
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se*
FIGURE 3. Immunohistochemical {A to D,G) and lectin histochemical (E,FJH) analysis of exfolia-tion-related vasculopadiy in irides of involved (A,C to E,G,H) and corresponding fellow (B,F)eyes in clinically unilateral exfoliation syndrome. (A) In an involved eye, mAb NC-1 to the HNK-1 epitope reveals a thick subendothelial layer of granular immunoreaction around blood vesselsof the iris. (B) In the fellow eye, a similar but less pronounced immunoreaction is present. Notethat the immunoreaction involves the thick laminated basement membrane and part of the loosecollagenous zone of the vessel wall, but the dense collagenous zone (deliwuted by anvtuheads) isunlabeled. (C) In an involved eye, tlie subendothelial immunoreaction varies from strong (anmo)to weak (utrrnvheads). Note a stromal deposit (double arrmu/iead) adjacent to a vessel. (D) Similarinimunopositive deposits (airowheads) are present at die anterior border layer of die iris alongthe anterior chamber and widiin the stroma, apparently unassociated with vessels. (E) In aninvolved eye, the subendotheliat layer of many iris vessels also strongly binds Phaseolus vidgariserythroagglutinin. Only the endothelium (arrmo) of other vessels is labeled. (F) In a fellow eye,the subendothelial layer variably and weakly binds Bauhinia pwpurea agglutinin. Note diat bothlectins also bind to stromal cells (arixrwheads). (G) Monoclonal antibody NC-1 and (H) Bauhiniapwpurea agglutinin identically label the subendothelial layer of an involved eye in adjacent sections,ac = anterior chamber; se = subendothelial layer; str = stroma. Original magnifications, (A,B)X420; (C) X210; (D to H) X420.
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been seen in electron microscopic examination ofeyes with exfoliation syndrome.37'39'40
An identical vasculopathy has been noted previouslywith antibodies to the HNK-1 epitope in all studied eyeswith exfoliation syndrome, as well as in approximatelyone third of eyes of patients without exfoliation depositsvisible in light microscopic examination.23 Such an immu-noreactivity was more common in older than in youngerage groups. Because exfoliation syndrome develops withage, the evidence supports the theory that the vasculopa-thy may represent an early preclinical stage of this syn-drome and that it is an integral part of the disease.Whether the vasculopathy is causally related to develop-ment of classic exfoliation deposits in the posterior cham-ber is not yet known, however. Nevertheless, we haveshown conclusively that vasculopathy is detectable earlierthan are frank exfoliation deposits on the ciliary epithe-lium and lens capsule.
How is strikingly asymmetric exfoliation to be ex-plained if the fibrillopathy seen by electron microscopyis a systemic condition?3"10 It appears obvious that oneor more local factors, either internal or external to theeye, must be invoked that expedite deposition of exfolia-tion material in one eye or slow it down in the other.The eye in which classic exfoliation deposits fonn maybe compromised in some way—for example, in the rateof aqueous flow,1019 in the arterial circulation,2041 or insome other as yet unidentified factor.
In the current series, a cataract necessitating surgery,glaucoma, and vascular accidents had been present inall involved eyes, whereas no complications traditionallyrelated to exfoliation had occurred in the fellow eyes, asis common in clinical practice.11214'29'42 We do not knowfor sure whether they are logical sequelae of exfolia-
tion12.14.17,20 or are parallel findings 0> to which as yet
unknown factors also leading to clinical exfoliation con-tribute in a compromised eye.
Even though most investigators currently appear tohold the view that exfoliation syndrome results from ex-cess production or hyperactive proteolysis of basementmembrane components, elastic fibers, or zonules,37'43"46
it is good to keep in mind that in most storage diseasesas well as in amyloidosis, tissue deposition is ultimatelyrelated to a failure to degrade normally or to clear theprecursor molecules.47 In particular, the iris vasculopathyin exfoliation syndrome might be either a cause for or aconsequence of failed clearance from the eye of materialthat ultimately aggregates as exfoliation deposits. For ex-ample, although it has been proposed that exfoliationmaterial is produced in the iris,38'43 the vasculopathymight alternatively be secondary to decreased solubility47
or increased adhesiveness25 of abnormally processed in-traocular macromolecules.
In summary, exfoliation deposits can be markedlyasymmetric to the extent that they appear to be unilateral,even in routine histopathologic evaluation. Secondly, avasculopathy characterized by subendothelial deposits
that react identically to exfoliation material is universalin the fellow eyes and also is common in eyes of olderpeople without visible classic exfoliation deposits.25 Suchvasculopathy apparently heralds clinical exfoliation andis more advanced in eyes with visible exfoliation deposits.Thus, although frequently asymmetric, exfoliation proba-bly is never truly unilateral. Obviously, any theory of exfoli-ation should include explanation of the lack of exfoliationdeposits in the face of a systemic fibrillopathy, the com-mon occurrence of asymmetric exfoliation, and the early,scattered vasculopathy. In the future, we should probablyconcentrate our efforts on understanding why and howexfoliation deposits form, rather than solely on what theycontain.
The authors thank Mrs. Marjatta Koikkalainen and Mrs. Pir-oko Ylihaiju for expert technical assistance.
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