The Basement Membrane Exfoliation Ralph
C.
Eagle, Jr, MD; Ramon
L.
Syndrome
Font, MD; Ben S. Fine, MD
Previous observations suggest that of the lens capsule" may be a disease in which cells produce abnormal basement membrane material. Electron microscopic studies indicate that exfoliative material can be produced by cells throughout the anterior segment of the eye. This report describes abundant exfoliative material on the ciliary and iridie epithelia but not on the surface of the lens whose epithelial cells were completely necrotic. Exfoliative material also was observed in the anterior iridie stroma close to a newly formed abnormal endothelial basement membrane, sug¬ gesting that exfoliative material may be produced locally within the iris. Further¬ more, typical exfoliative material, best considered a filamentous, banded base¬ ment membrane with 500-A periodicity, in the wall of a short posterior ciliary artery in the orbit indicates that the exfoliative process is not solely limited to ocular tissues. The term "basement membrane exfoliation syndrome" is proposed for this •
"pseudoexfoliation
entity. (Arch Ophthalmol 97:510-515, 1979) the past two decades, investigators using the techniques of elec¬ tron microscopy have attempted to determine the nature and origin of
the characteristic material found in the controversial entity called "pseuAccepted for publication May 22, 1978. From the Registry of Ophthalmic Pathology, Armed Forces Institute of Pathology, Washing¬ ton, DC.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
Reprint requests to Ophthalmic Pathology Branch, Armed Forces Institute of Pathology, Washington, DC 20306 (Dr Font).
doexfoliation of the lens capsule."120 The term pseudoexfoliation was suggested by Dvorak-Theobald in 1954 to differentiate this presumed deposit on the lens capsule from an actual separation occurring within the capsule, a condition that then became known as "true" exfoliation of the lens capsule.21 Independently and almost simulta¬ neously, electron microscopic evidence was presented from two laborato¬ ries,24 evidence that clearly indicated that the lens epithelium was the site of production of typical exfoliative material, which is able to pass through the anterior capsule adjacent to the equatorial region of the lens.
Subsequent investigators working
with aging lenses or diseased eyes have generally agreed with these observations.612 Evidence (including recent clinical observations)48-22 now indicates that the iridie and ciliary epithelia also produce exfoliative ma¬ terial.2·4·5·7·9·14·15" In addition, the presence of exfoliative material around vessels in the limbal and palpe¬ brai conjunctivas of clinically noninvolved eyes as well as involved eyes strongly suggests that this disease is not limited to ocular tissues.131619 From these numerous observations evolved the concept that the char¬ acteristic exfoliation material in all probability represents a form of basement mem¬ abnormal brane.5·8"10-18·22 In concert with the above theory, the histopathologic and electron microscopic observations in the case presented here suggest that under certain circumstances synthesis of exfoliative material by the lens epi¬ thelium may be absent or interrupted, while elaboration by the iridie and
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ciliary epithelia continues. The con¬ cept of pseudoexfoliation as a disease of cells producing abnormal basement membranes here is also reexamined in
light of a recently proposed classifica¬ tion of pathologic ocular basement membranes.25
REPORT OF A CASE Clinical Data A 74-year-old man, blind in his right eye for approximately 13 years, sought medical attention for increasingly severe ocular pain. There was no history of previous surgery or trauma, and the patient's medi¬ cal status was characterized by a "heart condition" and obesity. The tension in the severely injected right globe was 80 mm Hg and the vision was no light perception. Bullous keratopathy and anterior chamber hemorrhage precluded adequate biomicro¬ scopic and ophthalmoscopic examination. Although the intraocular tension in the fellow eye was elevated (40 mm Hg), the visual acuity (20/20) and visual field were normal. The anterior chamber was deep and clear, and no exfoliative material was noted on the anterior lens capsule or pupil¬ lary margin. Clinically, the patient was thought to have neglected open-angle glau¬ coma bilaterally that had progressed to absolute glaucoma in his right eye. The blind, painful right eye was enucleated on July 26, 1976, and submitted to the Department of Ophthalmic Patholo¬ gy, Armed Forces Institute of Pathology, for histopathologic examination.
Pathologic Findings Macroscopic examination showed a firm right globe measuring 24 24 24 mm with 1 mm of attached optic nerve. Blood was seen in the anterior chamber through a cloudy 12 x 11-mm cornea. Transillumination disclosed an 11 6-mm equatorial staphyloma in the inferotemporal quad¬ rant. The globe was opened horizontally. The anterior chamber angle was closed by wide peripheral anterior synechias. Fine, fluffy deposits were noted on the pupillary
margin and posterior surface of the iris as well as on the ciliary processes and the anterior hyaloid face. The lens was catarac¬ tous, with a soft, fragile cortex and a brunescent nucleus. The anteriorly con¬ densed, hemorrbagic vitreous was totally detached posteriorly. The thickened retina contained diffuse hemorrhages. Multiple depigmented chorioretinal scars were seen in the region of the staphyloma and in the periphery inferiorly. The optic disc was
cupped.
submitted for routine light well as for scanning and transmission electron microscopy. Paraf¬ fin-embedded sections for light microscopy were stained with hematoxylin-eosin, PAS, alcian blue, alizarin red, and the Verhoeffvan Gieson elastic techniques. Samples for transmission electron microscopy were processed routinely and examined with an electron microscope. The material for scan¬ ning electron microscopy was osmicated, critical-point-dried, coated with gold-palla¬ dium, and examined with a scanning elec¬ Tissue
was
microscopy
as
microscope. Microscopically,
tron
the mildly vascularized showed bullous keratopathy. The anterior chamber contained scattered amounts of blood. The angle of the anterior chamber was closed by peripheral anterior synechias, and a mild ectropion uvea was present (Fig 1). A new membrane of endo¬ thelial cells lined the pseudoangle and anterior surface of the iris where it had produced a thin, PAS-positive layer of new Descemet's membrane (Fig 1, inset A, and Fig 2). The posterior circumferential ridges of the atrophie iris had coalesced to form the typical "sawtoothed" pattern characteristic of "pseudoexfoliation" (Fig 1, inset A). Eosinophilic material with a characteristic iron-filing pattern was pres¬ ent on the basilar surface of the posterior pigment epithelium of the iris and on the inner surface of the atrophied, hyalinized ciliary body. The material, which stained positive with alcian blue and PAS tech¬ niques, was also present on the zonules, anterior hyaloid face, and the anterior iridie surface. In the latter location, an especially dense band of material was pres¬ ent sandwiched between the anterior bor¬ der layer and the overlying membrane of endothelial cells and newly formed Desce¬ met's membrane. Exfoliative material was also present in the anterior iridie stroma but was not present on the apical surface of the endothelium lining the cornea. The lens epithelium was totally necrotic. Mild corti¬ cal liquefaction and nuclear sclerosis were present. Serial sections failed to demon¬ strate viable epithelium or exfoliative material on the surface of the lens capsule. Subcapsular fibrous plaques containing interwoven basement membranes indi¬ cated the sites of préexistent subcapsular epithelial cell proliferation (subcapsular cataracts) (Fig 1, inset C). The posteriorly detached vitreous contained a massive hemorrhage. The inner layers of the retina were atrophie. Projecting from the surface of the cupped disc was a large frond of fibrovascular tissue that was continuous with a layer of neovascularization on the cornea
surface of the disc and peripapillary retina. The optic nerve was moderately atrophie. The central retinal artery and vein were occluded by old thrombi. The venous thrombus was partially recanalized. Electron
Microscopy
Scanning microscopy demon¬ strated characteristically compressed and coalesced circumferential ridges on the posterior surface of the iris, which was festooned with exfoliative material. Transmission electron microscopy dem¬ onstrated typical exfoliative material on the iridie and ciliary epithelia, in the iris stroma, and surrounding the wall of a short posterior ciliary artery in the orbit. On the posterior portion of the iris, masses of typical exfoliative material were found beneath and interspersed with the reduplicated and focally interrupted base¬ ment membrane of the iris pigment epithe¬ lium (Fig 1). A faint banding pattern of approximately 500 A (50 nm) characterized the denser exfoliative fibrils (Fig 1, inset B). Exfoliative material was present be¬ neath and interspersed with the multilaminar basement membrane of the ciliary epithelium (internal basement mem¬ electron
brane).
Scattered fibrils and masses of exfolia¬ tive material were present in the superfi¬ cial iridie stroma beneath a new over¬ growth of endothelial cells. Near the pseu¬ doangle, the migrating endothelial cells had produced a moderately thick layer of multilaminar basement membrane that appeared to be undergoing desquamation in places. In this area, banded, flameshaped fibrils having an exfoliative ap¬ pearance were found in the vicinity and occasionally in continuity with the new multilaminar Descemet's membrane (Fig 2 and 3). In the orbital tissue adjacent to the posterior pole of the globe, masses of typi¬ cal exfoliative material were demonstrated external to the outer surface of the muscu¬ lar coat of a short posterior ciliary artery (Fig 4). Typical fibrils of exfoliative mate¬ rial were present adjacent to the basement membrane of the smooth muscle cells. In places the muscular basement membrane appeared fragmented and reduplicated (ie,
multilaminar).
material seen in the iris stroma beneath a new membrane of endothe¬ lial cells may represent aqueous-borne material trapped by subsequent endothelialization, the lack of material on the apical surface of this new cellular membrane and the proximity of the material with the new abnormal base¬ ment membrane suggest that some of the material may also be produced locally within the iris. To the best of our knowledge, this is the first demonstration of foci of typi¬ cal exfoliative material in the outer wall of a short posterior ciliary artery in the orbit and provides additional evidence that the exfoliative process is not limited to the anterior segment of the eye. The association of the abnormal material with the basement membranes of smooth muscle cells in the walls of an artery in the orbit also further supports the concept of pseudoexfoliation as a disorder of cells producing abnormal basement mem¬ brane. In 1929, Trantas proposed that the exfoliation syndrome was character¬ ized by senile degenerative changes that attacked not only the anterior lens capsule but also most of the other ocular tissues, especially the "glass membranes."23 Subsequent investiga¬ tors have indicated repeatedly that exfoliative material is always found early in relation to basement mem¬ branes lining the anterior or aqueous compartment of the eye.* Basement membranes, basic compo¬ nents in the microarchitecture of biologic tissues, are continuous layers of moderately electron dense material that are associated with but lie outside the basal plasma membranes of vari¬ ous epithelial, endothelial, and other specialized cells. Electron microscopic study of normal and pathologic tissues has disclosed a spectrum of basement membrane production within the
eye.24·25 COMMENT
It is clear that the absence of exfol¬ iative material on the lens capsule in this case is related to the total necrosis (determined on serial sectioning) of the lens epithelium. It is apparent that viable lens epithelium is neces¬ sary for the elaboration of lenticular pseudoexfoliation. The presence of abundant quantities of exfoliative material on both iridie and ciliary epithelia indicates that these struc¬ tures also produce the material, a conclusion supported by recently pub¬ lished clinical observations and pre¬ vious electron microscopic studies. Although much of the exfoliative
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The basement membrane of the lens epithelium, the lens capsule, is a thick filamentous to homogeneous basement membrane. The basement membranes of the posterior iris pig¬ ment epithelium and the nonpigmented ciliary epithelium are both multilaminar.24 In the former, howev¬ er, the multilaminar structure is thin and poorly formed (Fig 5). In a very early case of pseudoexfoliation, the thin basement membrane lining the posterior iridie pigment epithelium is either focally inter¬ rupted by masses of exfoliative mate•References 2, 4, 5, 8-11, 14, 15, 17, 18.
Fig 1 .—Inset A, Iris has sawtooth pattern of pigment epithelium, characteristic of pseudoexfoliation. Wide, peripheral, anterior synechia is overgrown by proliferating corneal endothelium (arrow). Small amount of hemorrhage (h) is present in anterior chamber. Electron micrograph shows masses of exfoliative material along posterior iridie pigment epithelium. Note abrupt termination of basement membrane (double arrows). PL indicates basal plasmalemma of posterior pigment epithelial cell. Inset B, 500-A banding of exfoliative material (double arrows). Inset C, Sample of lens capsule devoid of epithelium. Anterior subcapsular plaque containing interlacing basement membranes (arrow) indicates site of previous proliferation of lens epithelial cells (AFIP Neg 78-7303-1; stains and original magnifications: inset A, PAS, 35; inset , 42,000; inset C, PAS, 100; electron micrograph 13,500).
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Fig 2.—Inset, Endothelialization of iris with mild ectropion uveae. Arrow indicates site illustrated in electron micrograph. In larger photograph, newly proliferated endothelial cells (EN) have produced multilaminar basement membrane (M-BM) continuous with masses of filaments (F). Pseudoexfoliation fibrils, cut longitudinally at L and in cross section at X, are present within filamentous mass (AFIP Neg 78-7303-2; inset, PAS, original magnification 40; electron micrograph, original magnification 14,000).
separated from the plasmalemmasses of such material (Fig 6 and 7). In time, the normal basement membrane is slowly replaced by accu¬ mulating abnormal basement mem¬ brane. This clearly suggests in situ production by the underlying cells, a conclusion strongly supported by re¬ rial
or
ma
by
Fig 3.—Fibrils
in another
area
beneath
endothelium; note their filamentous
com¬
position and 500-A banding.
Arrows indi¬ cate filamentous, banded basement mem¬ brane; E, endothelium; fvl-BM, multilaminar basement membrane (AFIP Neg 78-7303-
3; original magnification
31,500).
Fig 4.—Exfoliative material adjacent to wall of short posterior ciliary vessel. SM indicates smooth muscle cell of vessel; BM, basement membrane; CO, collagen fibers (original magnification 25,200). Inset, Flame-shaped exfoliative fibrils (AFIP Neg 78-7303-4; original magnification
42,000).
cent clinical observations.1822 Similar
synthesis by lenticular and ciliary epithelia was demonstrated by pre¬ vious electron microscopic studies. The production of abnormal base¬ ment membranes is a recognized feature of many common systemic
and ocular diseases. A spectrum of pathologic ocular basement mem¬ branes can be found in diabetes melli¬ tus and in proliferations of the ciliary and retinal pigment epithelia, as well as in several corneal dystrophies such as in cornea guttata and the map-dot, fingerprint, and geographic patterns of epithelial dystrophy.25 Abnormally banded basement membrane of filamentous composi¬ tion with a periodicity of approxi¬ mately 1,000 A is well known, both in normal as well as abnormal ocular
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Fig 5— Top left, Normal posterior pigment epithelium of 76year-old patient whose eye was enucleated because of choroidal melanoma. Note thin basement membrane with few areas of early multilaminar basement membrane formation (arrows) (AFIP Neg 78-7303-5; original magnification 9,000).
Fig 6.—Top right, Sample of sporadic areas of early pseudoexfoliation along posterior iris from same patient as in Fig 5. Exfoliative
material is sandwiched between thin basement membrane
(arrows) and cell basal plasmalemmas. Similar material lies freely in posterior chamber outside thin basement membrane (AFIP Neg 78-7303-6; original magnification 9,000).
Fig 7.—Bottom left, Another sample from case of early pseudoexfoliation (same patient as in Fig 5). Small areas of normal, thin, basement membrane remain (arrows). Exfoliative material is cut longitudinally (L) and in cross section (X). Filamentous structure of fibrils and its 500-A banding is seen better in inset (AFIP Neg
78-7303-7; original magnifications
tissues.24 Abnormally banded base¬ ment membrane with 500-A crossbanding is also known, but is less well appreciated. Examination of obliquely sectioned exfoliative material with the electron microscope at high mag¬ nification shows bundles of very fine filaments or microfilaments greater than 100 A in diameter. The bundles have a periodicity of approximately 500 A. In the recently proposed clas¬ sification of pathologic basement
membrane, exfoliative material would be best classified as a filamentous, banded (ä;500 A) basement mem¬
brane. It therefore appears that exfolia¬ tive material is an abnormal basement membrane synthesized at multiple sites by abnormal ("aging") cells, a material that accumulates, replaces normal basement membranes, and causes or is related to subsequent epithelial atrophy. In addition to
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20,000; inset,
38,000).
multifocal
production, subsequent desquamation and aqueous dispersal throughout the anterior compartment of the eye
undoubtedly
occur, which
responsible for the deposits on the apical surface of the corneal endothe¬ are
lium and on noncellular structures such as the anterior hyaloid face and the zonular fibers. Since pseudoexfoliation of the lens capsule is not confined to the lens, a number of investigators have sug-
gested that the term "exfoliation syndrome" would be more appropriate
for this entity,I61S·22·26 especially since a small degree of true capsular exfol¬ iation or separation has recently been demonstrated.20 Unfortunately, how¬ ever, exfoliation syndrome fails to indicate the nature of the exfoliating substance. Therefore, the more expli-
cit term "basement membrane exfol¬ iation syndrome" is proposed. The presence of associated glaucoma can be indicated by the modifying phrase "with" or "without glaucoma." In this
proposed terminology, exfoliation of the lens capsule is retained for those examples of true capsular exfoliation such
as seen
with chronic infrared
exposure or occasionally in senile cata¬ racts that are characteristically con¬ fined to the lens.
This investigation was supported in part by research grants EY-00133 and training grant EY-07040 from the National Eye Institute, National Institutes of Health.
References 1. Blackstad TW, Sunde OA, Traetteberg J: On the ultrastructure of the deposits of Busacca in eyes with glaucoma simplex and so-called senile exfoliation of the anterior lens capsule. Acta Ophthalmol 38:587-598, 1960. 2. Bertelsen TI, Drablos PS, Flood PR: The so-called senile exfoliation (pseudoexfoliation) of the anterior lens capsule, a produce of the lens
epithelium: Fibrillopathia epitheliocapsularis.
Acta Ophthalmol 42:1096-1113, 1964. 3. Ashton NS, Shakib M, Collyear R, et al: Electron microscopic study of pseudoexfoliation of the lens capsule: I. Lens capsule and zonular fibers. Invest Ophthalmol 4:141-153, 1965. 4. Shakib M, Ashton N, Blach R: Electron microscopic study of pseudoexfoliation of the lens capsule: II. Iris and ciliary body. Invest Ophthalmol 4:154-161, 1965. 5. Ringvold A: Electron microscopy of the wall of the iris vessels in eyes with and without exfoliation syndrome (pseudoexfoliation of the lens capsule). Virchows Arch 348:328-341, 1969. 6. Dark AJ, Streeten BW, Jones D: Accumula¬ tion of fibrillar protein in the aging human lens capsule with special reference to the pathogene¬ sis of pseudoexfoliation disease of the lens. Arch Ophthalmol 82:815-821, 1969. 7. Ringvold A: Light and electron microscopy of the wall of the iris vessels in eyes with and without exfoliation syndrome (pseudoexfoliation of the lens capsule). Virchows Arch 349:1-9, 1970.
8. Ringvold A: Ultrastructure of exfoliation material (Busacca deposits). Virchows Arch 350:95-104, 1970. 9. Ringvold A: The distribution of exfoliation material in the iris from eyes with exfoliation syndrome (pseudoexfoliation of lens capsule). Virchows Arch 351:168-178, 1970. 10. Ringvold A, Vegge T: Electron microscopy of the trabecular meshwork in eyes with exfolia¬ tion syndrome. Virchows Arch 353:110-127, 1971. 11. Ringvold A: Electron microscopy of the limbal conjunctiva in eyes with pseudoexfoliation syndrome (PE syndrome). Virchows Arch 355:275-283, 1972. 12. Ghosh M, Speakman JS: Inclusions in human lens capsule and their relationship to senile lens exfoliation. Can J Ophthalmol 7:413427, 1972. 13. Ringvold A: On the occurrence of pseu¬ doexfoliation material in extrabulbar tissue from patients with pseudoexfoliation syndrome of the eye. Acta Ophthalmol 51:511-518, 1973. 14. Ghosh M, Speakman JS: The ciliary body in senile exfoliation of the lens. Can J Ophthalmol 8:394-403, 1973. 15. Ghosh M, Speakman JS: The iris in senile exfoliation of the lens. Can J Ophthalmol 9:289297, 1974. 16. Layden WE, Shaffer RN: Exfoliation syndrome. Am J Ophthalmol 78:835-841, 1974. 17. Dickson DH, Ramsey MS: Fibrillopathia
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/21/2015
epitheliocapsularis (pseudoexfoliation): A clinical and electron microscope study. Can J Ophthalmol 10:148-161, 1975. 18. Sugar HS, Harding C, Barsky D: The exfol¬ iation syndrome. Ann Ophthalmol 8:1165-1181,
1976. 19. Speakman JS, Ghosh M: The conjunctiva in senile lens exfoliation. Arch Ophthalmol 94:17571759, 1976. 20. Dark AJ, Streeten BW, Cornwall C: Pseudoexfoliative disease of the lens: A study in electron microscopy and histochemistry. Br J Ophthalmol 61:462-472, 1977. 21. Dvorak-Theobald G: Pseudoexfoliation of the lens capsule. Am J Ophthalmol 37:1-12, 1954. 22. Sugar HS: The exfoliation syndrome: Source of the fibrillar material on the capsule. Surv Ophthalmol 21:59-64, 1976. 23. Trantas M: Lesions seniles de la capsule antérieure du cristallin et bord pupillaire. Arch Ophthalmol 46:482-491, 1929. 24. Fine BS, Yanoff M: Ocular Histology: A Text and Atlas. New York, Harper & Row, 1972, pp 35, 133, 150, 184, 193, 225. 25. Yanoff MS, Fine BS: Ocular Pathology: A Text and Atlas Hagerstown, Pa, Harper & Row, 1975, pp 291-293, 308-309, 570, 638. 26. Sunde OA: On the so-called senile exfolia¬ tion of the anterior lens capsule: A clinical and anatomical study. Acta Ophthalmol 34(suppl 4445): 1-85, 1956. .
C.
Eagle, Jr, MD; Ramon
L.
Syndrome
Font, MD; Ben S. Fine, MD
Previous observations suggest that of the lens capsule" may be a disease in which cells produce abnormal basement membrane material. Electron microscopic studies indicate that exfoliative material can be produced by cells throughout the anterior segment of the eye. This report describes abundant exfoliative material on the ciliary and iridie epithelia but not on the surface of the lens whose epithelial cells were completely necrotic. Exfoliative material also was observed in the anterior iridie stroma close to a newly formed abnormal endothelial basement membrane, sug¬ gesting that exfoliative material may be produced locally within the iris. Further¬ more, typical exfoliative material, best considered a filamentous, banded base¬ ment membrane with 500-A periodicity, in the wall of a short posterior ciliary artery in the orbit indicates that the exfoliative process is not solely limited to ocular tissues. The term "basement membrane exfoliation syndrome" is proposed for this •
"pseudoexfoliation
entity. (Arch Ophthalmol 97:510-515, 1979) the past two decades, investigators using the techniques of elec¬ tron microscopy have attempted to determine the nature and origin of
the characteristic material found in the controversial entity called "pseuAccepted for publication May 22, 1978. From the Registry of Ophthalmic Pathology, Armed Forces Institute of Pathology, Washing¬ ton, DC.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
Reprint requests to Ophthalmic Pathology Branch, Armed Forces Institute of Pathology, Washington, DC 20306 (Dr Font).
doexfoliation of the lens capsule."120 The term pseudoexfoliation was suggested by Dvorak-Theobald in 1954 to differentiate this presumed deposit on the lens capsule from an actual separation occurring within the capsule, a condition that then became known as "true" exfoliation of the lens capsule.21 Independently and almost simulta¬ neously, electron microscopic evidence was presented from two laborato¬ ries,24 evidence that clearly indicated that the lens epithelium was the site of production of typical exfoliative material, which is able to pass through the anterior capsule adjacent to the equatorial region of the lens.
Subsequent investigators working
with aging lenses or diseased eyes have generally agreed with these observations.612 Evidence (including recent clinical observations)48-22 now indicates that the iridie and ciliary epithelia also produce exfoliative ma¬ terial.2·4·5·7·9·14·15" In addition, the presence of exfoliative material around vessels in the limbal and palpe¬ brai conjunctivas of clinically noninvolved eyes as well as involved eyes strongly suggests that this disease is not limited to ocular tissues.131619 From these numerous observations evolved the concept that the char¬ acteristic exfoliation material in all probability represents a form of basement mem¬ abnormal brane.5·8"10-18·22 In concert with the above theory, the histopathologic and electron microscopic observations in the case presented here suggest that under certain circumstances synthesis of exfoliative material by the lens epi¬ thelium may be absent or interrupted, while elaboration by the iridie and
Downloaded From: http://archopht.jamanetwork.com/ by a University of Michigan User on 06/21/2015
ciliary epithelia continues. The con¬ cept of pseudoexfoliation as a disease of cells producing abnormal basement membranes here is also reexamined in
light of a recently proposed classifica¬ tion of pathologic ocular basement membranes.25
REPORT OF A CASE Clinical Data A 74-year-old man, blind in his right eye for approximately 13 years, sought medical attention for increasingly severe ocular pain. There was no history of previous surgery or trauma, and the patient's medi¬ cal status was characterized by a "heart condition" and obesity. The tension in the severely injected right globe was 80 mm Hg and the vision was no light perception. Bullous keratopathy and anterior chamber hemorrhage precluded adequate biomicro¬ scopic and ophthalmoscopic examination. Although the intraocular tension in the fellow eye was elevated (40 mm Hg), the visual acuity (20/20) and visual field were normal. The anterior chamber was deep and clear, and no exfoliative material was noted on the anterior lens capsule or pupil¬ lary margin. Clinically, the patient was thought to have neglected open-angle glau¬ coma bilaterally that had progressed to absolute glaucoma in his right eye. The blind, painful right eye was enucleated on July 26, 1976, and submitted to the Department of Ophthalmic Patholo¬ gy, Armed Forces Institute of Pathology, for histopathologic examination.
Pathologic Findings Macroscopic examination showed a firm right globe measuring 24 24 24 mm with 1 mm of attached optic nerve. Blood was seen in the anterior chamber through a cloudy 12 x 11-mm cornea. Transillumination disclosed an 11 6-mm equatorial staphyloma in the inferotemporal quad¬ rant. The globe was opened horizontally. The anterior chamber angle was closed by wide peripheral anterior synechias. Fine, fluffy deposits were noted on the pupillary
margin and posterior surface of the iris as well as on the ciliary processes and the anterior hyaloid face. The lens was catarac¬ tous, with a soft, fragile cortex and a brunescent nucleus. The anteriorly con¬ densed, hemorrbagic vitreous was totally detached posteriorly. The thickened retina contained diffuse hemorrhages. Multiple depigmented chorioretinal scars were seen in the region of the staphyloma and in the periphery inferiorly. The optic disc was
cupped.
submitted for routine light well as for scanning and transmission electron microscopy. Paraf¬ fin-embedded sections for light microscopy were stained with hematoxylin-eosin, PAS, alcian blue, alizarin red, and the Verhoeffvan Gieson elastic techniques. Samples for transmission electron microscopy were processed routinely and examined with an electron microscope. The material for scan¬ ning electron microscopy was osmicated, critical-point-dried, coated with gold-palla¬ dium, and examined with a scanning elec¬ Tissue
was
microscopy
as
microscope. Microscopically,
tron
the mildly vascularized showed bullous keratopathy. The anterior chamber contained scattered amounts of blood. The angle of the anterior chamber was closed by peripheral anterior synechias, and a mild ectropion uvea was present (Fig 1). A new membrane of endo¬ thelial cells lined the pseudoangle and anterior surface of the iris where it had produced a thin, PAS-positive layer of new Descemet's membrane (Fig 1, inset A, and Fig 2). The posterior circumferential ridges of the atrophie iris had coalesced to form the typical "sawtoothed" pattern characteristic of "pseudoexfoliation" (Fig 1, inset A). Eosinophilic material with a characteristic iron-filing pattern was pres¬ ent on the basilar surface of the posterior pigment epithelium of the iris and on the inner surface of the atrophied, hyalinized ciliary body. The material, which stained positive with alcian blue and PAS tech¬ niques, was also present on the zonules, anterior hyaloid face, and the anterior iridie surface. In the latter location, an especially dense band of material was pres¬ ent sandwiched between the anterior bor¬ der layer and the overlying membrane of endothelial cells and newly formed Desce¬ met's membrane. Exfoliative material was also present in the anterior iridie stroma but was not present on the apical surface of the endothelium lining the cornea. The lens epithelium was totally necrotic. Mild corti¬ cal liquefaction and nuclear sclerosis were present. Serial sections failed to demon¬ strate viable epithelium or exfoliative material on the surface of the lens capsule. Subcapsular fibrous plaques containing interwoven basement membranes indi¬ cated the sites of préexistent subcapsular epithelial cell proliferation (subcapsular cataracts) (Fig 1, inset C). The posteriorly detached vitreous contained a massive hemorrhage. The inner layers of the retina were atrophie. Projecting from the surface of the cupped disc was a large frond of fibrovascular tissue that was continuous with a layer of neovascularization on the cornea
surface of the disc and peripapillary retina. The optic nerve was moderately atrophie. The central retinal artery and vein were occluded by old thrombi. The venous thrombus was partially recanalized. Electron
Microscopy
Scanning microscopy demon¬ strated characteristically compressed and coalesced circumferential ridges on the posterior surface of the iris, which was festooned with exfoliative material. Transmission electron microscopy dem¬ onstrated typical exfoliative material on the iridie and ciliary epithelia, in the iris stroma, and surrounding the wall of a short posterior ciliary artery in the orbit. On the posterior portion of the iris, masses of typical exfoliative material were found beneath and interspersed with the reduplicated and focally interrupted base¬ ment membrane of the iris pigment epithe¬ lium (Fig 1). A faint banding pattern of approximately 500 A (50 nm) characterized the denser exfoliative fibrils (Fig 1, inset B). Exfoliative material was present be¬ neath and interspersed with the multilaminar basement membrane of the ciliary epithelium (internal basement mem¬ electron
brane).
Scattered fibrils and masses of exfolia¬ tive material were present in the superfi¬ cial iridie stroma beneath a new over¬ growth of endothelial cells. Near the pseu¬ doangle, the migrating endothelial cells had produced a moderately thick layer of multilaminar basement membrane that appeared to be undergoing desquamation in places. In this area, banded, flameshaped fibrils having an exfoliative ap¬ pearance were found in the vicinity and occasionally in continuity with the new multilaminar Descemet's membrane (Fig 2 and 3). In the orbital tissue adjacent to the posterior pole of the globe, masses of typi¬ cal exfoliative material were demonstrated external to the outer surface of the muscu¬ lar coat of a short posterior ciliary artery (Fig 4). Typical fibrils of exfoliative mate¬ rial were present adjacent to the basement membrane of the smooth muscle cells. In places the muscular basement membrane appeared fragmented and reduplicated (ie,
multilaminar).
material seen in the iris stroma beneath a new membrane of endothe¬ lial cells may represent aqueous-borne material trapped by subsequent endothelialization, the lack of material on the apical surface of this new cellular membrane and the proximity of the material with the new abnormal base¬ ment membrane suggest that some of the material may also be produced locally within the iris. To the best of our knowledge, this is the first demonstration of foci of typi¬ cal exfoliative material in the outer wall of a short posterior ciliary artery in the orbit and provides additional evidence that the exfoliative process is not limited to the anterior segment of the eye. The association of the abnormal material with the basement membranes of smooth muscle cells in the walls of an artery in the orbit also further supports the concept of pseudoexfoliation as a disorder of cells producing abnormal basement mem¬ brane. In 1929, Trantas proposed that the exfoliation syndrome was character¬ ized by senile degenerative changes that attacked not only the anterior lens capsule but also most of the other ocular tissues, especially the "glass membranes."23 Subsequent investiga¬ tors have indicated repeatedly that exfoliative material is always found early in relation to basement mem¬ branes lining the anterior or aqueous compartment of the eye.* Basement membranes, basic compo¬ nents in the microarchitecture of biologic tissues, are continuous layers of moderately electron dense material that are associated with but lie outside the basal plasma membranes of vari¬ ous epithelial, endothelial, and other specialized cells. Electron microscopic study of normal and pathologic tissues has disclosed a spectrum of basement membrane production within the
eye.24·25 COMMENT
It is clear that the absence of exfol¬ iative material on the lens capsule in this case is related to the total necrosis (determined on serial sectioning) of the lens epithelium. It is apparent that viable lens epithelium is neces¬ sary for the elaboration of lenticular pseudoexfoliation. The presence of abundant quantities of exfoliative material on both iridie and ciliary epithelia indicates that these struc¬ tures also produce the material, a conclusion supported by recently pub¬ lished clinical observations and pre¬ vious electron microscopic studies. Although much of the exfoliative
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The basement membrane of the lens epithelium, the lens capsule, is a thick filamentous to homogeneous basement membrane. The basement membranes of the posterior iris pig¬ ment epithelium and the nonpigmented ciliary epithelium are both multilaminar.24 In the former, howev¬ er, the multilaminar structure is thin and poorly formed (Fig 5). In a very early case of pseudoexfoliation, the thin basement membrane lining the posterior iridie pigment epithelium is either focally inter¬ rupted by masses of exfoliative mate•References 2, 4, 5, 8-11, 14, 15, 17, 18.
Fig 1 .—Inset A, Iris has sawtooth pattern of pigment epithelium, characteristic of pseudoexfoliation. Wide, peripheral, anterior synechia is overgrown by proliferating corneal endothelium (arrow). Small amount of hemorrhage (h) is present in anterior chamber. Electron micrograph shows masses of exfoliative material along posterior iridie pigment epithelium. Note abrupt termination of basement membrane (double arrows). PL indicates basal plasmalemma of posterior pigment epithelial cell. Inset B, 500-A banding of exfoliative material (double arrows). Inset C, Sample of lens capsule devoid of epithelium. Anterior subcapsular plaque containing interlacing basement membranes (arrow) indicates site of previous proliferation of lens epithelial cells (AFIP Neg 78-7303-1; stains and original magnifications: inset A, PAS, 35; inset , 42,000; inset C, PAS, 100; electron micrograph 13,500).
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Fig 2.—Inset, Endothelialization of iris with mild ectropion uveae. Arrow indicates site illustrated in electron micrograph. In larger photograph, newly proliferated endothelial cells (EN) have produced multilaminar basement membrane (M-BM) continuous with masses of filaments (F). Pseudoexfoliation fibrils, cut longitudinally at L and in cross section at X, are present within filamentous mass (AFIP Neg 78-7303-2; inset, PAS, original magnification 40; electron micrograph, original magnification 14,000).
separated from the plasmalemmasses of such material (Fig 6 and 7). In time, the normal basement membrane is slowly replaced by accu¬ mulating abnormal basement mem¬ brane. This clearly suggests in situ production by the underlying cells, a conclusion strongly supported by re¬ rial
or
ma
by
Fig 3.—Fibrils
in another
area
beneath
endothelium; note their filamentous
com¬
position and 500-A banding.
Arrows indi¬ cate filamentous, banded basement mem¬ brane; E, endothelium; fvl-BM, multilaminar basement membrane (AFIP Neg 78-7303-
3; original magnification
31,500).
Fig 4.—Exfoliative material adjacent to wall of short posterior ciliary vessel. SM indicates smooth muscle cell of vessel; BM, basement membrane; CO, collagen fibers (original magnification 25,200). Inset, Flame-shaped exfoliative fibrils (AFIP Neg 78-7303-4; original magnification
42,000).
cent clinical observations.1822 Similar
synthesis by lenticular and ciliary epithelia was demonstrated by pre¬ vious electron microscopic studies. The production of abnormal base¬ ment membranes is a recognized feature of many common systemic
and ocular diseases. A spectrum of pathologic ocular basement mem¬ branes can be found in diabetes melli¬ tus and in proliferations of the ciliary and retinal pigment epithelia, as well as in several corneal dystrophies such as in cornea guttata and the map-dot, fingerprint, and geographic patterns of epithelial dystrophy.25 Abnormally banded basement membrane of filamentous composi¬ tion with a periodicity of approxi¬ mately 1,000 A is well known, both in normal as well as abnormal ocular
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Fig 5— Top left, Normal posterior pigment epithelium of 76year-old patient whose eye was enucleated because of choroidal melanoma. Note thin basement membrane with few areas of early multilaminar basement membrane formation (arrows) (AFIP Neg 78-7303-5; original magnification 9,000).
Fig 6.—Top right, Sample of sporadic areas of early pseudoexfoliation along posterior iris from same patient as in Fig 5. Exfoliative
material is sandwiched between thin basement membrane
(arrows) and cell basal plasmalemmas. Similar material lies freely in posterior chamber outside thin basement membrane (AFIP Neg 78-7303-6; original magnification 9,000).
Fig 7.—Bottom left, Another sample from case of early pseudoexfoliation (same patient as in Fig 5). Small areas of normal, thin, basement membrane remain (arrows). Exfoliative material is cut longitudinally (L) and in cross section (X). Filamentous structure of fibrils and its 500-A banding is seen better in inset (AFIP Neg
78-7303-7; original magnifications
tissues.24 Abnormally banded base¬ ment membrane with 500-A crossbanding is also known, but is less well appreciated. Examination of obliquely sectioned exfoliative material with the electron microscope at high mag¬ nification shows bundles of very fine filaments or microfilaments greater than 100 A in diameter. The bundles have a periodicity of approximately 500 A. In the recently proposed clas¬ sification of pathologic basement
membrane, exfoliative material would be best classified as a filamentous, banded (ä;500 A) basement mem¬
brane. It therefore appears that exfolia¬ tive material is an abnormal basement membrane synthesized at multiple sites by abnormal ("aging") cells, a material that accumulates, replaces normal basement membranes, and causes or is related to subsequent epithelial atrophy. In addition to
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20,000; inset,
38,000).
multifocal
production, subsequent desquamation and aqueous dispersal throughout the anterior compartment of the eye
undoubtedly
occur, which
responsible for the deposits on the apical surface of the corneal endothe¬ are
lium and on noncellular structures such as the anterior hyaloid face and the zonular fibers. Since pseudoexfoliation of the lens capsule is not confined to the lens, a number of investigators have sug-
gested that the term "exfoliation syndrome" would be more appropriate
for this entity,I61S·22·26 especially since a small degree of true capsular exfol¬ iation or separation has recently been demonstrated.20 Unfortunately, how¬ ever, exfoliation syndrome fails to indicate the nature of the exfoliating substance. Therefore, the more expli-
cit term "basement membrane exfol¬ iation syndrome" is proposed. The presence of associated glaucoma can be indicated by the modifying phrase "with" or "without glaucoma." In this
proposed terminology, exfoliation of the lens capsule is retained for those examples of true capsular exfoliation such
as seen
with chronic infrared
exposure or occasionally in senile cata¬ racts that are characteristically con¬ fined to the lens.
This investigation was supported in part by research grants EY-00133 and training grant EY-07040 from the National Eye Institute, National Institutes of Health.
References 1. Blackstad TW, Sunde OA, Traetteberg J: On the ultrastructure of the deposits of Busacca in eyes with glaucoma simplex and so-called senile exfoliation of the anterior lens capsule. Acta Ophthalmol 38:587-598, 1960. 2. Bertelsen TI, Drablos PS, Flood PR: The so-called senile exfoliation (pseudoexfoliation) of the anterior lens capsule, a produce of the lens
epithelium: Fibrillopathia epitheliocapsularis.
Acta Ophthalmol 42:1096-1113, 1964. 3. Ashton NS, Shakib M, Collyear R, et al: Electron microscopic study of pseudoexfoliation of the lens capsule: I. Lens capsule and zonular fibers. Invest Ophthalmol 4:141-153, 1965. 4. Shakib M, Ashton N, Blach R: Electron microscopic study of pseudoexfoliation of the lens capsule: II. Iris and ciliary body. Invest Ophthalmol 4:154-161, 1965. 5. Ringvold A: Electron microscopy of the wall of the iris vessels in eyes with and without exfoliation syndrome (pseudoexfoliation of the lens capsule). Virchows Arch 348:328-341, 1969. 6. Dark AJ, Streeten BW, Jones D: Accumula¬ tion of fibrillar protein in the aging human lens capsule with special reference to the pathogene¬ sis of pseudoexfoliation disease of the lens. Arch Ophthalmol 82:815-821, 1969. 7. Ringvold A: Light and electron microscopy of the wall of the iris vessels in eyes with and without exfoliation syndrome (pseudoexfoliation of the lens capsule). Virchows Arch 349:1-9, 1970.
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epitheliocapsularis (pseudoexfoliation): A clinical and electron microscope study. Can J Ophthalmol 10:148-161, 1975. 18. Sugar HS, Harding C, Barsky D: The exfol¬ iation syndrome. Ann Ophthalmol 8:1165-1181,
1976. 19. Speakman JS, Ghosh M: The conjunctiva in senile lens exfoliation. Arch Ophthalmol 94:17571759, 1976. 20. Dark AJ, Streeten BW, Cornwall C: Pseudoexfoliative disease of the lens: A study in electron microscopy and histochemistry. Br J Ophthalmol 61:462-472, 1977. 21. Dvorak-Theobald G: Pseudoexfoliation of the lens capsule. Am J Ophthalmol 37:1-12, 1954. 22. Sugar HS: The exfoliation syndrome: Source of the fibrillar material on the capsule. Surv Ophthalmol 21:59-64, 1976. 23. Trantas M: Lesions seniles de la capsule antérieure du cristallin et bord pupillaire. Arch Ophthalmol 46:482-491, 1929. 24. Fine BS, Yanoff M: Ocular Histology: A Text and Atlas. New York, Harper & Row, 1972, pp 35, 133, 150, 184, 193, 225. 25. Yanoff MS, Fine BS: Ocular Pathology: A Text and Atlas Hagerstown, Pa, Harper & Row, 1975, pp 291-293, 308-309, 570, 638. 26. Sunde OA: On the so-called senile exfolia¬ tion of the anterior lens capsule: A clinical and anatomical study. Acta Ophthalmol 34(suppl 4445): 1-85, 1956. .
