1442 INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE / October 1983
24
6. Enoch JM, Aulhorn E, Dubois-Poulsen A, Fankhauser F, Fried-
man A, Greve E, Harms H, and Verriest G, editors. Perimetric
Standards and Perimetric Glossary of the International Council
of Ophthalmology. Dr. W. Junk, bv, 1978.
7. Committee on Vision, The National Research Council, National
Academy of Science of the United States of America. First In-
terprofessional Standard for Visual Field Testing. National
Academy of Sciences, Washington, D.C., 1975.
8. Enoch JM: Perimetry, today and tomorrow. Doc Ophthalmol
(in press), 1983.
9. Heijl A and Airaksinen J: Correlation between retinal nerve fiber
layer defects and visual field defects determined by automatic
perimetry after optic disc hemorrhage. IPS, 1982, Doc Ophthal-
mol Proc Series 26: in press, 1983.
10. Airaksinen J: Cup-disc ratio, retinal nerve fiber layer (RNFL)
and manual perimetry in early glaucoma. IPS, 1982, Doc
Ophthalmol Proc Series 26: in press, 1983.
11. Hoyt WF, Frisen L, and Newman NM: Fundoscopy of nerve
fiber layer defects in glaucoma. Invest Ophthalmol 12:814, 1973.
12. Ogawa T, Furuno F, Miyamoto T, Seki A, and Ohta Y: Kinetic
perimetry of the retinal nerve fiber layer defect in glaucoma by
fundus photo-perimetry. IPS, 1982. Doc Ophthalmol Proc Ser
26: in press, 1983.
The X, Y, Z Hypothesis of Comeol Epitheliol Mointenonce
To the Editor:
For the past few years, studies of corneal epithelial
healing have focused on the changes that occur in the
remaining epithelial cells and their substrate following
acute epithelial removal. The processes of epithelial
cell sliding, proliferation, and replication have been
documented in the past,1"4 and more recent work has
illuminated addition details of these responses to in-
jury.5-6 These studies have produced useful general-
izations that help in understanding the pathologic pro-
cesses responsible for corneal epithelial defects in hu-
mans. However, we would suggest that a fresh look at
the factors involved in corneal epithelial maintenance
may serve to initiate new experiments and new ob-
servations which may further advance the therapy of
corneal epithelial failure.
The mass of corneal epithelium probably does not
change under normal circumstances. As shown in Fig-
ure 1, the corneal epithelial cell mass can be viewed
as the resultant of three separate, independent phe-
nomena. We have termed these: X, the proliferation
of basal epithelial cells; Y, the contribution to the cell
mass by centripetal movement of peripheral cells; and
Z, the epithelial cell loss from the surface. Corneal
epithelial maintenance thus can be defined by the
equation: X + Y = Z, which simply states that if the
corneal epithelium is to be maintained, cell loss must
be balanced by cell replacement.
The presence of the X component has been estab-
lished by tritiated thymidine labeling of epithelial cells,
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Vol.
13. Rabin S, Kolesar P, Podos SM, and Wilensky JT: A visual field
screening protocol for glaucoma. Am J Ophthalmol 92:530,
1981.
14. Enoch JM: Quantitative layer-by-layer perimetry. Proctor Lec-
ture. Invest Ophthalmol Vis Sci 17:208, 1978.
15. Enoch JM, Fitzgerald CR, and Campos EC: Quantitative layer-
by-layer perimetry: an extended analysis. Current Ophthalmology
Monographs. New York, Grune-Stratton, 1980.
16. Enoch JM, Fitzgerald CR, Campos EC, and Temme LA: Different
functional changes recorded in open angle glaucoma and anterior
ischemic optic neuropathy. Doc Ophthalmol 50:169, 1980.
17. Groneberg A and Teping C: Topodiagnostik von Sehstrorungen
durch Ableitung retinaler und kortikaler antworten auf Kon-
trastmuster. Ber Dtsch Ophthalmol Ges 77:409, 1980.
18. Maffei L and Fiorentini A: Electroretinographic responses to
alternating gratings before and after section of the optic nerve.
Science 211:953, 1981.
19. Drance S and Heijl A: Changes in differential threshold in glau-
coma patients during prolonged perimetry. IPS, 1982, Doc
Ophthalmol Proc Ser 26: in press, 1983. (See also, paper by
Campos, E. C. and Belli, S. and Discussion by Enoch, J. following
the Drance and Heijl paper in the same volume.)
identifying the actively dividing basal cells.3 However,
there remain numerous questions to be answered with
regard to X. Does the mitotic rate change in response
to increased or decreased epithelial attrition? Is the
rate under neuronal or pharmacologic control? What
happens to the rate of basal cell proliferation in a variety
of clinical circumstances, eg, inflammation, drug tox-
icity, denervation, or metabolic stress from contact
lenses?
The Y component is an ongoing, slow, centripetal
cell movement that occurs even in the absence of an
acute defect. It is important not to confuse Y with
another phenomenon, the rapid movement of periph-
eral cells in response to an acute central defect.7 While
as yet not proven, there is both direct and indirect
evidence for such an ongoing movement, even in the
absence of a defect. Analysis of the sex chromatin in
donor corneal epithelium shows that there is a loss of
donor epithelium from corneal grafts, even when there
is no acute rejection, but that this replacement of donor
by host epithelium takes many months.8 Indirectly,
clinical observation of centripetal movement of epi-
thelial dots after grafting,9 and the observation that
epithelial graft reactions were not seen more than 13
months after keratoplasty (presumably because no do-
nor epithelium remained to react)10 also indicate an
active Y component. These observations have been
made on surgically treated eyes. However, recent stud-
ies showing a radial pattern of hemidesmosome align-
ment along the basement membrane of normal murine
eyes are also consistent with the concept of centripetal
 No. 10 LETTERS TO THE EDITOR
X,Y,Z Hypothesis of Corneal Epithelial Maintenance
Fig. 1.
cell migration.'' Whether in addition to cell movement
from the peripheral to central cornea, there is also a
continual drift of conjunctival epithelial cells across
the limbus with transformation of the cell phenotype
from conjunctival to corneal remains to be determined.
If the later process does occur, however, its failure in
disease states characterized by concurrent conjunctival
and corneal involvement would explain many of the
clinical phenomena in these conditions.
The ongoing, normal loss of cells from the surface,
the Z component, has never been studied. It is, of
course, certain that such loss occurs in the special case
of failure of adhesion of the epithelium to the stroma
in some abnormal conditions. Occasionally, one sees
what seems to be cellular debris behind non-venting
contact lenses, but to date, cell loss from the surface
has not been quantitated.
Utilizing the X, Y, Z hypothesis, it is possible to
categorize both diseases and therapies according to the
specific component involved. Thus, an epithelial dis-
ease could be the result of inadequate basal cell pro-
liferation (decreased X), deficient centripetal cell
movement (decreased Y), or increased cell loss (in-
creased Z). By identifying the abnormal biologic pro-
cess, therapy then could be directed at correcting the
abnormal component, and therapeutic endeavors could
even be separated into those that affect basal cell pro-
liferation (eg, mitogens12 or changes in cyclic AMP
levels,13) those that affect centripetal cell movement
(eg, conjunctival transplantation14), and those that af-
fect cell loss (eg, protective measures such as soft con-
tact lenses and tarsorrhaphy). We suggest that inves-
tigating and observing the X, Y, and Z variables will
lead to new insights into the pathogenesis and therapy
of corneal epithelial disease.
Richard A. Thoft
Judith Friend
Eye Research Institute
Massachusetts Eye and Ear Infirmary
and
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1443
X = proliferation of basal cells
Y= centripetal movement of cells
Z = cell loss from the surface
X+Y= Z
Department of Ophthalmology
Harvard Medical School
Boston, Massachusetts
Supported by research grants EY 01830 and EY 04205 from the
National Eye Institute, National Institutes of Health, Bethesda,
Maryland. Submitted for publication: February 22, 1983. Reprint
requests: Richard A. Thoft, M.D., 243 Charles Street, Boston, MA
02114.
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