SURVEY OF OPHTHALMOLOGY

VOLUME

41 . NUMBER

4 -JANUARY-FEBRUARY

1997

ELSEVIER

MAJOR REVIEW
Chemical Injuries of the Eye: Current
Pathophysiology
and Therapy
MICHAEL

D. WAGONER,

Concepts

in

MD

Ante-rior Segment/External
Disease Division,
King Khakd Eye Specialist Hospital, Riyadh, Saudi Arabia;
Cornea Service, Massachusetts Eye and Ear Injirmary,
Boston, MA, USA; and Department
of Ophthalmology,
Harvard
Medical School, Boston, MA, USA
Chemical injuries of the eye may produce extensive damage to the ocular surface epithelium, cornea, and anterior segment, resulting in permanent
unilateral or bilateral visual impairment. Pathophysiological
events which may influence the final visual prognosis and which are amenable to therapeutic
modulation
include 1) ocular surface injury, repair, and differentiation,
2)
cornea1 stromal matrix injury, repair and/or ulceration,
and 3) cornea1 and stromal inflammation.
Immediately
following
chemical injury, it is important
to estimate and clinically grade the severity
of limbal stem cell injury (by assessing the degree of limbal, conjunctival,
and scleral ischemia and
necrosis) and intraocular
penetration
of the noxious agent (by assessing clarity of the cornea1 stroma
and anterior segment abnormalities).
Immediate
therapy is directed toward prompt irrigation
and
removal of any remaining
reservoir of chemical contact with the eye. Initial medical therapy is
directed toward promoting
re-epithelialization
and transdifferentiation
of the ocular surface, augmenting cornea1 repair by supporting
keratocyte collagen production
and minimizing
ulceration
related to collagenase activity, and controlling
inflammation.
Early surgical therapy, if indicated, is
directed toward removal of necrotic cornea1 epithelium
and conjunctiva,
prompt re-establishment
of an adequate limbal vascular+, and re-establishment
of limbal stem cell populations
early in the
clinical course, if sufficient evidence exists of complete limbal stem cell loss. Re-establishment
of
limbal stem cells by limbal autograft or allograft transplantation,
or by transfer in conjunction
with
large diameter penetrating
keratoplasty, may facilitate development
of an intact, phenotypically
correct cornea1 epithelium.
Limbal stem cell transplantation
may prevent the development
of fibrovascular pannus or sterile cornea1 cornea1 ulceration,
simplify visual rehabilitation,
and improve the
visual prognosis. Advances in ocular surface transplantation
techniques which allow late attempts at
visual rehabilitation
of a scarred and vascularized cornea include limbal stem cell transplantation
for incomplete
transdifferentiation
and persistent cornea1 epithelial dysfunction, and conjunctival
and/or mucosal membrane
transplantation
for ocular surface mechanical
dysfunction. Rehabilitation of the ocular surface may be followed, if necessary, by standard penetrating
keratoplasty if all
aspects of ocular surface rehabilitation
are complete, or by large diameter penetrating
keratoplasty
if successful limbal stem cell transplantation
cannot be achieved but other ocular surface rehabilitation is complete. (SW-V Ophthalmol
41:275-313,
1997. 0 1997 by Elsevier Science Inc. All rights
reserved.)

Abstract.

words.
acid alkali
chemical injury
conjunctival
cornea1 limbus
cornea1 stroma
inflammation
limbal
membrane
transplantation
ocular surface
penetrating
Key

Chemical
injuries
of the eye may produce
extensive damage
to the ocular surface epithelium,
cornea,
and anterior
segment,
resulting
in permanent
unilateral
or bilateral
visual
impair-

0 1997 by Elsevier
All rights resend.

Science

Inc.

merit

transplantation
cornea1 epithelium
autograft
limbal allograft
mucous
keratoplasty
tenoplasty
l

37,172.173.0~.21.~,~~9,~~~-~9~l,3~7,.1~3

In addition
to causing
ocular
surface
injury,
alkalies readily
penetrate
into the eye, damaging
the cornea1
stroma
and endothelium,
as well as

0039.6257/97/$17.00
PI1 S0039-6257(96)00007-O

276

Surv Ophthalmol41

(4) January-February

1997

other anterior
segment structures
such as the
iris, lens, and ciliary body. Most acidic substances
tend to remain confined
to the ocular surface,
where they may threaten
vision by producing
profound
disturbances
of the ocular surface.
Strong acids, such as hydrofluoric
acid, may
readily penetrate
as quickly as alkalies, producing the same spectrum
of ocular injury.32.35
Extensive laboratory
and clinical studies of the
basic repair and ulcerative processes of the chemically-injured
eye have elucidated
some of the
pathophysiological
processes that determine
the
ultimate outcome of these injuries, and have facilitated the development
of medical and surgical
strategies to maximize the potential for successful
management.

I. Etiology
The frequency and distribution
of chemical injuries of the eye have been addressed comprehenMost
victims
are
sively. 11,52.208,216,217,257.336,348,350
216,217.257,336,350
and in most large series expoyoung,
sure occurs in industrial
accidents,216,217s?57,350at
home, 216*217,257,350
and in association with criminal
assaults.11,z57,336 Because of their more frequent
presence
in household
cleaning agents and in
many building materials, alkali injuries occur more
frequently than acid injuries.257
Morgan257 reviewed 221 chemical injuries in 180
patients presenting to the Croydon Eye Unit, United Kingdom (which serves a largely residental area
of population
300,000) between January
1, 1985
and February 28, 1986. One hundred thirty six patients (75.6%) were male, while 44 (24.4%) were
female. Most patients were between 16 and 25 years
of age. Alkali injuries were nearly twice as common
as acid injuries. Most injuries (161 [89.4%]) were
accidental, while 19 (10.6%) resulted from chemical assault. Among the accidental cases, 63% occurred at work, 33% at home, and 3% at school.
Only 14 (7.7%) patients required hospital admission. Eight of these were due to accidents and six
were due to assaults with ammonia. Only one patient suffered severe, permanent
visual loss.
In a subsequent large series by Kuckelkorn2i6
of
all patients seen at the eye center serving Aachen,
Germany,
between
September
1990 and August
1991, there were 236 chemically injured eyes in I71
patients. Of these, 121 (70%) were adult males, 39
(23%) were adult females, and 11 (7%) were children. Most patients were between the ages of 16
and 45 years. Industrial
accidents accounted for
104 injuries (61%), 64 (37%) were due to household accidents, and 3 (2%) were of unknown
origin. Fortunately, 208 (88%) injuries were classified
as mild, with a favorable outcome, confirming
Mor-

WAGONER
gan~~ previous observation
that most chemical
injuries are mild.
A large series by Kuckelkorn217 which examined
the epidemiology
and outcome of 42 patients with
severe chemical injuries which required admission
to the RWTH Aachen, Germany, between 1985 and
1992 confirmed the poor prognosis in severe cases.
In this series, only six (14.5%) patients achieved
adequate visual rehabilitation.
Most of the patients
were between 20 and 40 years old. Most (73.8%)
of the accidents were industrial, while the remainder occurred
at home. The industrial
accidents
were almost equally divided among construction
and labor industry, chemical plants, and machine
factories.
At home, most of the injuries were
caused by lime and drain cleaners.
The most important agents causing chemical injuries of the eye are summarized
in Table l.?4q,403
A. ALKALI

The most common causes of alkali injury are

ammonia (NH,), lye (NaOH), potassium hydroxide (KOH) , magnesium hydroxide (Mg [OH] 2),
and lime (Ca[OH]2).24q
The most serious alkali injuries are associated
with ammonia,24g a common ingredient in many
household cleaning agents and lye,217,24g
a common
ingredient in drain cleaners. Both penetrate immediately into the eye, potentially producing serious damage to the anterior segment. Magnesium
hydroxide, which is present in fireworks, may produce a particularly devastating injury because of
combined thermal injury.4q
The most common alkali-producing ocular injury is lime, which fortunately does not inflict as
much damage as the more rapidly penetrating alkalies.135After transversing the epithelial cell membrane, lime forms calcium soaps that precipitate
and hinder further penetration.24g Lime particles
retained in the superior fornix provide a continuous reservoir of alkali after injury and may result
in severe injury if they are not identified and removed.
B. ACID

The most common causesof acid injury are sulfuric (H,SO,) , sulfurous (H,SO,) , hydrofluoric
(HF) , acetic (CH,COOH) , chromic, and hydrochloric (HCI) acids.24gThe most serious ocular
acid injuries are due to hydrofluoric acid.24g-250Due
to its low molecular weight and small size, fluoride
penetrates readily into and through the cornea1
stroma, producing severe cornea1 and anterior segment injury.24g-20
Sulfuric acid is the most common cause of acid
injury.249 Sulfuric acid reacts with water in the pre-

CHEMICAL

INJURIES

277

OF THE EYE
TABLE

Compound

Class

Ammonia

Alkali

Common

Causes of Chemical

Common

Source/uses

1. Fertilizers
2. Refrigerants
3. Cleaning agents
tion)
1. Drain cleaners
1. Caustic potash

[NH,1
Lye [NaOH]
Potassium hydroxide

1
Comments
1. Combines with water to form NH,OH
2. Very rapid penetration

(7%

[CAO-U,I

Acid

1. Penetrates almost as rapidly as ammonia

1. Severity similar to that of lye

1. Sparklers

1. Produces combined

1. Plaster

1. Most common cause of chemical injury in work

place
2. Poor penetration
3. Toxicity increased by retained particulate matter

2. Mortar
3. Cement
4. Whitewash
1. Industrial cleaners

Sulfuric acid

W$Q,l
2. Battery acid
Sulfurous

acid

1. Formed from sulfur dioxide

(SOJ by combination
with
cornea1 water
2. Fruit and vegetable preservatives
3. Bleach
4. Refrigerants
1. Glass polishing
2. Glass frosting
3. Mineral refining
4. Gasoline alkylation
5. Silicone production
1. Vinegar 4-10%
2. Essence of vinegar 80%
3. Glacial acetic acid 90%
1. Used in the chrome plating
industry
1. Used as a 31-38% solution

W,SO,I

Hydrofluoric

acid

WI

Acetic acid
[CH,COOH]
Chromic

acid

[CrAl
Hydrochloric

acid

t HCLI
* Reproduced

by Permission,

thermal and alkali injury

1. Combines with water to produce cornea1 thermal

injury
2. May have associated foreign body or laceration
from battery acid
1. Penetrates more easily than other acids

1. Penetrates easily
2. Produces severe injury

1. Mild injury with less than 10% contamination

2. Severe injury with higher concentration
1. Chronic exposure produces chronic conjunctivitis with brown discoloration
1. Severe injury only with high concentration and
prolonged exposure

Reference 403, P 236

cornea1 tear film to produce

heat and charring
of
the cornea1 and conjunctival
epithelium.4g
It seldom produces
serious injury unless there is additional damage from thermal
injury or high-velocity
penetration
of a foreign
body into the eye, such as
following
automobile
battery explosions.?4Y

II.

fumes

solu-

[KOHI
Magnesium hydroxide
bk@W,I
Lime

Injury*

Pathophysiology

The severity of ocular injury after chemical

exposure is related to the surface area of contact and the
degree of penetration.
In general,
alkalies tend to
penetrate
more effectively than acids.132-1s5J55,244,245,335
The hydroxylion
(OH) saponifies the fatty acid components
of cell membranes,
resulting
in cell disrup
tion and death, while the cation is responsible
for
the penetration
of the specific aIkali.24g Cations react
with the carboxyl
groups (COOH)
of stromal colla-

gen and glycosaminoglycans.135

Hydration
of the glycosaminoglycans
results in loss of clarity of the stroma.135 H Ydration
of collagen
fibrils results in thickening and shortening,
which distorts the trabecular
meshwork,
and release of prostaglandins
are responsible for the elevation in intraocular
pressure which
is often
seen immediately
following
alkali
injuries.56,277,278,367

Depending
on the degree
of penetration,
there
may be damage
to the cornea1
and conjunctival
epithelium,
basement
membrane,
stroma1 keratocytes,
stromal
nerve endings,
endothelium, lens epithelium,
and vascular
endothelium
of the conjunctiva,
episclera,
iris and ciliary
into the anterior
body. 5.135,215,217.244,24.5,289Penetra~on
chamber
may be seen almost immediately
after ammonia injury and within
3-5 minutes
after sodium

278

Surv Ophthalmol

41 (4) January-February

19987

hydroxide
injury. 133z7gIf the external pH is restored to normal, the aqueous pH levels return to
normal within 30 minutes to three hours, depending upon the amount of penetration.27g Damage to
the ciliary body epithelium results in decreased secretion of ascorbate and a reduction in its anterior
chamber concentration,
potentially compromising
subsequent
cornea1 keratocyte
collagen synthesis
Irreversible
intram
and stromal repair. 23%293309,311312
ocular damage with hypotony and phthisis bulbi
may follow prolonged aqueous pH levels of 11.5 or
greater.27gs2g3
With the exception of hydrofluoric
acid and, to
a lesser extent, sulfurous
acid, acids penetrate
much less readily into the corneal stroma than alkalies.132*135The hydrogen (H+) ion causes damage
due to pH alteration, while the anion produces
protein precipitation
and denaturation
in the corneal epithelium and superficial stroma.1061t is this
coagulation
of proteins which produces the characteristic ground glass appearance of the epithelium, functions as a barrier to further penetration,
and limits further intraocular
injury.lo6 Often the
stroma has a surprisingly
clear appearance after debridement
of the necrotic epithelium.lm
If penetration
occurs into the stroma, alterations
in tissue similar to those seen in alkali injury may
occur. These changes include precipitation
of extracellular glycosaminoglycans
and cornea1 opacification,106,134z342hydration
and shortening
of collagen fibrils with a transient elevation in intraocular pressure due to trabecular
meshwork
distortion,56~277,278,367
anterior
chamber pH alterations,
anterior segment damage, and lowered aqueous
ascorbate levels.233,30g
Kuckelkorn215
assessed the clinical course of 90
severely chemically-injured
eyes in 66 patients to
determine the actual incidence of short- and longterm complications
related to intraocular
penetration. In the early phase, 23 (25.6%) eyes developed
secondary cataract and 14 (15.6%) eyes had secondary glaucoma. Subsequently,
an additional 41
(45.6%) eyes developed secondary cataract and 20
(22.2%) eyes developed secondary glaucoma.
In addition to complications
related to corneal
and intraocular
injury, many short- and long-term
complications may occur related to damage to proximal and distal bulbar conjunctiva, tarsal conjunct&
and ant&or
orbid ~ssues.214~~20~325~329.330~341,375
Net-e
sis of bulbar conjunctival tissue is associated with infiltration of leukocytes, which is a source of continued ocular surface inflammation,
and associated release of increased levels of N-acetylglucosaminidase
and Cathepsin-D
into the preocular
tear film.325
There may be retention of contaminating
particles
from the trauma itself and these may contribute to

WAGONER

Schematicdepiction of the ocular surface, demonstrating the continuity of the conjunctival (blue), limbal (red), and cornea1 (green) epithelium, and the interactive relationship (arrows) between the cornea1epithelium and stromal keratocytes.

Fig. 1.

continued inflammation.541 In a study of chemicallyinjured conjunct&a with scanning electron microscopy and energy-dispersive X-ray analysis, Schirne? confirmed traumatic contamination with calcium in Ca(OH), and CaO burns, aswell as silicone
in a peroxidase plus silicone spray burn. There is a
loss of vascularization at the limbus due to ischemic
necrosis of the conjunct&a, and this reduces the
availability of vascularly-derived collagenase inhibitors (see below) 16,68,142
which may contribute partially
to subsequent corneal ulceration and perforation.375
Late sequelae of severe conjunctival injury include
disorders of ocular surface wetting due to mucous
membrane abnormalities, cicatricization of the conjunctiva with sytnblepharon formation, and enn-opion. 220,267,349
Irrespective of the substance responsible for
chemical injuries, the principles guiding evaluation and management require an understanding of
the complex interactions between regenerating ocular surface epithelium, stromal matrix repair and
degradation, and inflammatory infiltration of the
cornea. In this review, chemical injuries will be
considered generically, unless otherwise noted.
A. EPITHELIAL INJURY, REPAIR, AND
DIFFERENTIATION

1. The Ocular Surface

In 1977Thoft and Friend coined the term ocular
surface to emphasize the potential interdependence of the stratified, nonkeratinizing epithelium of
cornea and conjunctiva (Fig. 1) .107,376385
Initially
posed only as an anatomic classification, subsequent
clinical and research insights of Thoft3763s5and others28,44,45,69,7O.73,75,79,lO4-lO7,ll7.146,l47,l5O~l68,l7O,2O2-2O7.226228,287,332,346,361,364,389-396

provided compelling evidence

CHEMICAL

INJURIES

OF THE

279

EYE

of the functional relationships between these two adjacent cell populations. This functional unity is especially relevant to the pathophysiology and therapy
of chemical injury of the eye.
The cornea1 epithelium is composed of 5-6 cell
layers of stratified squamous epithelium which has
no goblet cells and is nonkeratinized under normal circumstances.3g2It is a rapidly renewing tissue
which loses its surface cells into the tear film, with
a turnover period of 46 days.1*6,1471t
plays an important optical role in maintaining the smoothness
of the optical surface and a physiological role in
excluding microorganisms from the cornea1 stroma, maintaining the deturgence of the cornea1
stroma, and regulating the metabolic activity of
stromal keratocytes.so-84~254~370
At the cornea1 limbus, the stratified squamous
epithelium thickens to approximately 10 cell layers.2g~124~139~400~401
Recent evidence has shown that
the basal epithelial cells of the limbal zone are of
paramount importance in the maintenance of ocular surface epithelium, both in normal health and
following ocular surface injury.287~385,3sg
The conjunctival epithelium consists of two or
more layers of stratified columnar epithelium with
numerous goblet cells. It is well established that
the conjunctival epithelium is capable of repopulating the cornea1 epithelial surface following traumatic injury.7s,104-106.47
The conjunctival portion
has many other important functions which may be
compromised following severe chemical injury.
These include facilitation of smooth movement of
the eyelid over the cornea, maintenance of normal
lid-globe apposition, production of mucous essential for tear film stability, and provision of the limbal vascular supply.
2. Limbal

Stem

Cell Hypothesis

Numerous studies have supported the hypothesis

that centripetal movement of cells from the peripheral cornea, limbus, or conjunctiva is responsible for
normal@.45.3

and

post-traumaticlO4,10~.195,2~

replace-

ment of cornea1 epithelium. Hannal% showed that

the mitotic index of peripheral cornea1 epithelium
is higher than that of central epithelium. BrorP suggested that the vortex pattern of the corneal epithelium in toxic keratopathy, striate melanokeratosis, Fabrys disease,and superficial iron lines of the cornea
is attributable to a centripetal slide of epithelium
from limbus to visual axis. KinoshinP documented
that the donor epithelium of lamellar or penetrating
keratoplasty is completely replaced by host epitheliurn. He demonstrated a gradual dilution of sex chromatin on female donor grafts by male recipients over
a period of 12 weeks, with complete replacement in
about one year. Alldredge noted an absence of epi-

Fig. 2. Schematic depiction of the cornea1basalepithelial cells. Basalepithelial cells which are stem cells (approximately 30%2*6)migrate centripetally along the basal
epithelial layer and then anteriorly toward the surface.
(Reprinted from Wagoner MD, Kenyon KR, Shore JS408
with permissionof Churchill Livingstone.)

thelial graft rejections greater than one year after

penetrating keratoplasty despite continued occurrence of endothelial rejection. Kayelg5described centripetal movement of epithelial cysts, originating
around sutures, onto the donor cornea after keratoplasty. Buck44,45marked epithelium and subjacent
stroma with India ink and noted that the epithelial
ink moved centrally at a rate of 17microns/day, leaving behind the ink in the cornea1 stroma.
Based on these observations, Thoft and FriendsGo
proposed the X,Y,Z hypothesis that normal cornea1
epithelial mass is maintained by continuous centripetal movement of peripheral cornea1 epitheliurn toward the visual axis. This balances the cellular loss resulting from anterior movement of basal epithelial cells to the surface and into the tear
film. Sharma and Coles347have provided evidence
to support the X,Y,Z hypothesis of cornea1 epithelial maintenance with a mathematical model demonstrating that the rate of exfoliation of epithelial
cells is consistent with their production from limbal cells. The half-time of cornea1 epithelial replacement is nine weeks, while the time required
for 95-99% replacement is 9-12 months.
In the original X,Y,Z hypothesis, it was not necessary to ascribe an origin for the cells. Still, evidence
for the existence of stem cells responsible for cellular
maintenance has been identified for a number of
other cell populations, including the epidermis,
intestinal epithelium, seminiferous tubule epithelia,

and

blood-forming

228.231,252.859.319.321,3.59

of location,

o~gan~.423..50.145,159.2OY.Z26
Stem<ell

populations,

irrespective

share many common

~~~~4~50~145~22~228~231.238,239,31~321.389

They

are

characterisI)

present

in

self-renewing tissues, 2) long-lived, and 3) quite

280

Surv Ophthalmo141 (4) January-February 1997

primitive with few or no differentiation products in

the cytoplasm, and 4) located in extremely protected
positions, such as the bone marrow (hematopoetic
system), deep crypts of the intestinal epithelium, or
the deep rete pegs of the monkey palmar epidermis.
In addition, stem cells have very low mitotic activity
and slow cell-cycling. They give rise to ttansient-amplifying cells which are mitotic factories, often giving
rise to 1000 terminally differentiated cells per stem
cell, although this has not been demonstrated with
respect to limbal stem cell populations.
Vogt400,401
described ridges perpendicular to the
cornea in the perilimbal conjunctiva. The basal
cells, which lie deep in a thickened epithelial cell
layer, are tightly attached to the underlying basement membrane and have a rich network of blood
These limbal palisades of Vogt are
supply. 124,13g
remarkably anatomically similar to the stem-cell
arrangement
of the monkey palmar epidermis.75~227~228
Davanger and Evensen postulated,
without supporting experimental evidence, that
the limbal epithelial structure described by Vogt
serves as the generative organ for cornea1 epithelial cells (Fig. 2). Later experimental studies provided convincing support for this hypothesis.
Schermer340showed that a 64K (MW=64,000) keratin typical of the cornea1 epithelial phenotype was
absent from the limbal basal cells in rabbits. It appeared, however, in the superficial cells of that region and in all epithelial cells of the central cornea. Cotsarellis6g~70
verified relatively slow-cycling
periods for basal limbal epithelial cells. Lavker2j
demonstrated that up to 30% of mouse limbal basal cells might represent stem cell populations
based on prolonged (3H) thymidine incorporation, a phenomenon not seen in central basal cells.
While most studies have provided indirect evidence that the limbal basal epithelial cells may be
the stem cells of the cornea1 epithelium, the first
possible direct ability to identify actual limbal basal
stem cells came from the work of Zieske.4z7*42s
He
developed a monoclonal antibody designated
4G10.3 that immunolocalized to limbal basal cells
in rat corneas and reacted with a 50-kDa
(MW=50,000) antigen in rat and rabbit cornea1
epithelium and a 48-kDa to 49kDa antigen in human epithelium. The 50-kDa antigen proved to be
alpha-enolase, a glycolytic enzyme.4*8 This enzyme
is localized to basal limbal stem cells, as demonstrated by immunofluorescent staining, and shows
a pattern of increased activity in limbal basal epithelial cells following epithelial debridement and
thermal injury. It is absent from post-mitotic SUperhcial limbal cornea1 epithelium and terminally
differentiated cornea1 and conjunctival cells,427.428
providing evidence that it may serve as an immu-

WAGONER

nological marker of the hypothetical

thelial stem cells.
3. Limbal

Stem

Cell/Ocular

Surface

cornea1 epiInjury

Following cornea1 epithelial injury, recovery is

dependent upon centripetal movement of the
most proximal, viable epithelium.1s6~2z1~346
For epithelial defects involving only a portion of the cornea, adjacent cornea1 epithelium fills the epithelial
defect.44~104-106~260~3gs
A complete cornea1 epithelial
defect
requires epithelium
from the limbus.7g,168,382,385
With extensive cornea1 and limbal
injury, the surrounding conjunctival epithelium
provides the only source for epithelial regeneration

104-106.168.346

The rate of re-epithelialization and the ultimate

functional competence of the ocular surface depends upon the source of the regenerating epithelium. Central epithelial defects, which heal by migration of adjacent epithelium, close at a rate of
0.69-1.46 mm2/hour.186~246~260~3g8
Epithelial injury
involving a large area of the cornea heals at a faster
rate than smaller, central epithelial defects, presumably due to the increased mitotic rates of transient amplifying cells, although the absolute time
period until complete recovery is longer.7Y,235,246
If
complete limbal stem cell loss occurs and the conjunctiva is the only source of regenerating epithelium, the rate of epithelial recovery may be greatly
prolonged.
Irrespective of the source of regenerating epithelium, the rate of migration after chemical injury may be slowed by persistent inflammation,407
epithelial basement membrane damage,11S.?g1*2g2
and degradation of basement membrane fibronectin by plasminogen activator.18-0,131Epithelial migration may be enhanced by adequate ocular lubrication, reduction of inflammation, epidermal
growth factor (which promotes epithelial mitosis),130~163,33g,s51,387
and fibronectin (which facilitates
adhesion). *2,*71.*eCorticosteroids have no effect on
the rate of epithelial migration.164
Regardless of the source of regenerating epithelium, an intact epithelium effectively prevents the
development of microbial or nonmicrobial (sterIt is well recognized
ile) cornea1 ulceration. lg6x405
that sterile ulceration is never seen in the presence
of an intact epithelium. Further, progression of
sterile ulceration is promptly halted when re-epithelialization is complete. Experimental studies
provide a possible explanation for the paramount
role of an intact epithelium in regulation of sterile
cornea1 ulceration. Cornea1 epithelium secretes a
cytokine which inhibits keratocyte type I collagenase production,180-1s4~370
preventing the inappropriate appearance of collagenase when epithelium

CHEMICAL

INJURlES

281

OF THE EYE

is intact. While evidence suggests that both transforming

growth factor (TGF)-beta,120,370 interleukin-1,2O and interleukin-1
receptor antagonist
(IL1ra) 370 may be involved in epithelial-mesenchymal
interactions
regulating
cornea1 development,
homeostatic mechanisms,
and repair,120,370 cell culture
studies suggest that cornea1 epithelial TGF-beta 2
is the major inhibitor
of collagenase synthesis by
stromal keratocytes. 370When the epithelium is disrupted the inhibitory
function of the cornea1 epithelium may be lost.
Cornea1 epithelium
can be induced in vitro to
secrete a stimulatory
cytokine for keratocyte
collagenase production,*-ls3
suggesting that not only
is the inhibitory
function lost due to absence of
epithelium,
but that regenerating
epithelium may
actually stimulate keratocyte
collagenase activity.
Following
re-epithelialization,
normal
inhibitory
function appears to be restored.
The source of the regenerating
epithelium may
have some effect on the phenotypic function of the
restored cornea1 epithelium.
Following
epithelial
debridement
of the entire cornea1 and limbal epithelium, the surrounding
conjunctival epithelium
which resurfaces
the cornea may phenotypically
come to resemble normal cornea1 epithelium.346
Shapiro346 observed the progression
from a histologically undifferentiated
initial phase showing neither goblet cells nor cornea1 epithelial basal cells
to the appearance
of numerous
goblet cells
throughout
the cornea1 epithelium,
multicentric
nests of cornea1 cells in the midst of the evanescent
conjunctival cells and, finally, histologically normal
cornea1 epithelium.
This is the process of transdifferentiation,l50,20:~.383
which was exploited in the
development
of conjunctival
autografts as a means
of re-establishing
a more normal ocular surface in
the chemically-injured
eye.381
There is evidence, however, to suggest that complete transdifferentiation
of conjunctival
epitheliurn is rarely, if ever, complete. Experimental
studies which suggest complete transdifferentiationX4
may have resulted from retention of some Iimbal
stem cells, while those which show failure of complete

chemical injury the resurfacing of cornea with conjunctival epithelium is associated with delayed re-epithelialization,113J62 superficial and deep stromal neovascularization,38g persistence of goblet cells within
the cornea1 epithelium,3X and recurrent
epithelial
erosions due to abnormal basement membrane epihelid
adheSion.55~113~162~166,205~247~3355.364
Tr~sdifferentiation of a cornea1 epithelial phenotype is adversely
affected by local deficiency of vitamin A and the presence of corneal neovascularization.171~3gW3g5Altbough
the amount of post-injury cornea1 neovascularization
may be marginally influenced by topical progestational steroids,141 final vascularization seems to be determined by the severity of limbal stem cell injury: 784.394If limbal stem cell loss is complete, severe
superficial pannus invariably occurs (often in ass*
ciation with stromal vascularization)
resulting in
complete conjunctival phenotypic characteristics
or
conjunctivalization
of the new ocular
surface 117,389.394
Because of poor transdifferentiation
and conjunctivalization
of the ocular surface following
complete
limbal stem cell loss, Kenyon
and
Tseng199.36
proposed that limbal stem cells are the
most qualified cells to restore functional
competence after extensive ocular surface and limbal
stem cell injury. Tsai385 compared the efficiency of
limbal transplantation
to that of bulbar conjunctival transplantation
for cornea1 surface reconstruction in rabbit eyes in which the cornea1 and limbal
epithelia had been removed by a combination
of
chemical debridement
plus surgical scraping. Limbal transplantation
resulted in a smooth, lustrous
surface without cornea1 neovascularization.
Bulbar
conjunctival
transplantation
resulted in vascularized corneas with irregular
epithelium.
Huang@
used a battery of monoclonal
antibodies to cellspecific markers, including ocular mucin, to demonstrate evidence of restoration
of cornea1 phenotype after limbal transplantation,
but not after
bulbar conjunctival
transplantation.
B. CORNEAL STROMAL
MATRIX
REPAIR, AND ULCERATION

INJURY,

~~~~~~~ff~~~~~~~~~~1~~7~113,l5~~1~~.l70,2~~2,335,383,389,394,4~f~

support the hypothesis

that conjunctival
epitheliurn will never produce a true cornea1 epithelial
phenotype,
especially after severe injuries. Following severe experimental
chemical injuries alterations in glycogen and glycolytic enzyme content,H
tensile strength, I K12 keratin
(an acidic 55kDa
polypeptide)
production,0,4
epithelial protein
profiles,
basement membrane components,,
and paracellular
permeability
provide evidence
of incomplete
differentiation.
Clinically, it is well established that after severe

1. Collagen
Collagen constitutes approximately 80% of the
organic constituents of the cornea1 stroma.L.274Fibrillar collagens (predominantly type I) provide
the major tensile strength of the cornea.51,274The
orderly arrangement of cornea1 stromal fibrillar
collagen (types I, III, V) insures uniform distribution of tensile strength radially in all directions,
minimizes light scattering, and contributes to corn&

transparency.?~.""-"4.'~1.~'7.*9~)~~74

gen plays an important

Type

VII

co&-

role in anchoring fibrils

Surv Ophthalmol41

(4) January-February

1997

Fig. 3. Severe alkali injury. The entire epithelium

is either absent or devitalized. Due to stromal and intraocular penetration,
the cornea1 stroma is cloudy, in contrast
to the appearance in Fig. 4.

WAGONER

Fig. 4. Acid injury due to exploding car battery. A 100%

epithelial defect is present. Following debridement
of necrotic epithelium
(some remaining
peripherally)
which
had served as an effective barrier to penetration,
the corneal stroma is remarkably clear. (Reprinted
by permis
sion from Mandel ER, Wagoner MD: Atlas of Cornea1 Disease. Philadelphia,
WB Saunders, 1989, p 71.)

between the basal epithelial cells, the basement

membrane, and the anterior stroma.1*8J1gNonfibrillar collagen (type IV) is the main component
fere with keratocyte migration and collagen synof the epithelial basement membrane and Descethesis and must be used with caution after the end
mets membrane.61,274
of the first week following severe chemical injuThe maintenance and regeneration of the cornea1
ries.10Joo~114~317~31sProgestational
steroids have only a
stroma is the primary responsibility of the keratocyte.
minimal effect on keratocyte function and can be
Keratocytes are pluripotential cells of neuroectoderused with relative safety in the management of
ma1 origin. 185
They are usually static and relatively inThe use of ,-ortjacute chemical injury. 141224270317
active metabolically, with no appreciable synthesis of
costeroids and progestational steroids following
collagen or collagenase.igODuring development*41
chemical injury is discussed extensively below.
and repair following stromal injury,58-63J10J21Jgo~242
Following chemical injury, type I collagen synthesis
they are capable of a wide variety of fibroblastic cais
maximum
between days 7 and 56, with a peak at
pabilities including phagocytosis of collagen fiday
21
.110J90
To
offset the degradation of collagen
brils 223*253,337
as well as the secretion of collafibrils
by
collagenolytic
processesfollowing chemical
glycosaminoglycan ground subgen, i,61,64~110~177~1go
109,110,121,165.166.178,180.182,222,242,269,416
injury,
sufficient
synthesis
of collagen by keratocytes
stance,1g0 collagenase,
is
essential
for
successful
repair and prevention of
and collagenase inhibitors. Metabolic functions of
cornea1
ulceration
and
perforation.
Keratocyte synthe keratocyte may be regulated by cytokines from
180,182-184.370,4(X!
inflammatory
c-lls,86,269,402
thesis
of
collagen
may
be
compromised
by deficient
epithelium,
levels of ascorbate in the aqueous following severe
and from other keratocytes.rsl
is a ce
chemical injury. 97,s33,30o,so5,307-s,312.315~corbate
Following cornea1 injury, keratocytes are mobifactor in the hydroxylation of proline and lysine, the
lized from adjacent regions to repopulate the area
of injury,

with

migration

usually

beginning

on the

endothelial side.O In mild injuries, such as corneal lacerations, type I collagen may be detected
at the edge of the wounded area as early as one
day after injury. 177,1go-1g3
In moderately severe
chemical injuries, complete repopulation may be
delayed, taking as long as 7-14 days.l*OJgOInsevere
injuries with complete keratocyte destruction, repopulation may be completely absent, although
some evidence suggests that monocyte transformation to functionally competent fibroblastic cells
may occur. 24gWhile corticosteroids are of considerable value in reducing inflammation and tissue
destruction following chemical injury, they inter-

rate-limiting

step in ribosomal

collagen

synthesis.lm

Systemic ascorbate deficiency results in unstable triple-helical structure of extracellular fibrillar collagen334and the clinical syndrome of scurvy, Deficiency of anterior chamber ascorbate following experimental chemical injury results in morphological abnormalities in collagen-synthesizing fibroblastsm,334
and cornea1 ulceration or perforation.Ws~309
2. Collagenase
Collagenase is the enzyme responsible for cleavage of the collagen molecule at a site three quarters from

the amino

terminus.*5~30~40~*48~412 It is now

recognized that a closely related family of enzymes

CHEMICAL,

INJURIES

283

OF THE EYE

Fig 5. (A) Grade I chemical injury: schematic. The epithelial

defect involves only cornea1 epithelium.
(B) Type I
healing pattern: schematic. During the brief period required for re-epithelialization
with normal phenotypic epithelium, all interactions
between epithelium,
inflammatory
cells, and keratocytes are appropriate
for proper repair. (C)
Grade I chemical injury: clinical appearance.
Epithelial
defect involving one quadrant without significant
limbal
&hernia
or evidence of limbal stem cell loss. (D) Type I healing pattern: clinical appearance.
Prompt re-epithelialization with normal cornea1 epithelial
appearance without vascularization
confirms that limbal stem cells adjacent to
the cornea1 epithelial defect were unaffected by the chemical injury.

called
matrix
metalloproteinases
(MMP)
are responsible
for the initial
rate-limiting
cleavage of
collagen
molecules.
81,82,84,85 Three
well-characterized corneal-MMP
are type I collagenase,
strome?6,167.174,242
These
three
enlysin, and gelatinase.
zymes share many common
features, including
significant
amino acid homology,261
optimal
activity at
neutral
pH, 82.148,p61requirement
for zinc as a cofactor and calcium
ions for stability,30~5~21 secretion
as an inactive zymogen
or proenzyme,14s,261
and activation
by enzymatic
or organomercurial
cleavage
of a small amino peptide.g0,148
Type I collagenase,
also known
as MMP-1,
is usually
not detectable
in the normal
cornea.1pg~176~180~182Its presence
has been demonstrated
in cornea1 repair following
mechanical
injury,21 in
keratoconus76.89,268,324
and in actively ulcerating
corneas.

tance

15~17~21,40~41~4~3~129.178,306,353,355,356

of MMP-1

activity

in conjunction

The

imporwith

cor-

neal repair is emphasized

by its detection
as late as
nine months
following
mechanical
injury.*l
Type I collagenase
cleaves types I, II, and III fibrillar
collagen
molecules.15~30J40J~~41s It is the only
known
enzyme which can cleave the native, type I
collagen
helix at the neutral
pH of the extracellular
space. s~140~148
Originally,
the epitbelium
was believed
to be the source
of cornea1
type I collagenase,38J78,Z51,306,355*356
but it was later demonstrated
that
epitbelium
does not produce
type I collagenase.2g
Cornea1 type I collagenase
is now known to be pro
180,182,2?2.?69.415
polyduced by keratocytes. 109.110,165,166,178,
morphonuclear
neutrophils
can also produce
a type
I collagenase
(MMP-S) .33J88~229~2W~237~z~
Stromelysin,
also known
as MMP-3,
has broad
proteolytic
activity on casein, proteoglycan,
and fibronectin,
as well as limited
proteolytic
activity on
laminin,
elastin, gelatin
(denatured
collagen),
alpha-1-proteinase
inhibitor,
and type IV collagen. 30.57.65

284

Surv Ophthalmol41

(4) January-February 1997

WAGONER

Gelatinase has marked specificity for gelatin,

nes,402and plasmin,13 suggesting a possible role of
types IV, V, and VII collagens, and possibly fibrothis regulatory mechanism in vivo.
nectin.30,66,160,161,241,263,266
Gelatinase is actually two
Latent type I collagenase may be activated
separate gene products, commonly referred to as
by the plasmin-plasminogen
activator
sys~em~l3,l8.20,l15.l16,l3l,l5Z,l53,458,276,338,386,4O9
T
type IV and type V collagenase.66~s2~123~174~417Type
IV
ype I collagenase may be inactivated by tissue inhibitors
collagenase, also known as MMP-2, is a 72-kDa enof metalloproteinases (TIMP), which are elabozyme 66,174,242
which is secreted predominantly by
rated by all cells (except PMN leukocytes) prokeratocytes** in a precursor form complexed with
ducing
metalloproteina~es~6*,*1~~~4~*~*~*64.275~36*,369A
a Pl-kDa protein capable of inhibiting its activity.30
number of serum factors (including alpha-l-macUnlike type I collagenase, it may be present in norroglobulin, alpha-2-macroglobulin,
beta-l-macromal cornea in significant amounts,30*84and is the
globulin, and platelet derived inhibitors) derived
only MMP which is constitutively expressed in prifrom limbal vasculature and cornea1 neovascularmary keratocyte cell culturess3 The concentration
ization may inhibit type I collagenase.i6,68.142
of MMP-2 is increased in keratoconus.87 Matsubara
and collegues 84.242hypothesize that MMP-2 perC. INFLAMMATION
forms a surveillance function in normal cornea,
The final component influencing outcome folcatalyzing the degradation of collagen molecules
lowing
chemical injury is inflammation. Infiltrathat occasionally become damaged. Like MMP-1,
tion
of
inflammatory cells into injured tissue is a
MMP-2 may play a role in stromal remodeling after
hallmark
of wound repair.71x1g7
The association of
cornea1 injury and during repair.z42
PMN
leukocyte
infiltration
with
st.erile ulceraType V collagenase, also known as MMP-9, is a
tion1g6-1g8,357,406
and
the
cessation
of
sterile ulcera92-kDa enzyme417produced mainly by cornea1 eption
following
exclusion
of
inflammatory
cells
ithelium,** and to a lesser extent by monofrom
the
cornea
stroma
is
well
recognized.Y8.1g8
cytes, 112.160,161
stromal keratocytes,z4* and polymorWithin 12-24 hours after chemical injury, infilphonuclear (PMN) leukocytes.*@ MMP9 is active
tration of the peripheral cornea with PMN and
against gelatin and against types IV and VII collamononuclear leukocytes results from outpouring
gen. 263An inhibitor of MMP9 is synthesized by corof blood elements from injured vesselsin the conneal epithelium. *It is not detectable in normal
junctiva and uvea and from necrotic tissue of the
cornea,81.84but has been detetected in a pro-form
bulbar and tarsal conjunctiva. 40.46.98,198.289.325,326,331,420
in keratoconus.* It probably is involved in conThese cells are chemotactically attracted by prodtrolling the resynthesis of the epithelial basement
and
alkaliucts of the epithelium 71.143,296299,304.399.419
membrane during cornea1 injury and repair.*1x24Z
degraded stromal tissue.*g6Stromal adhesion is faActivation of MMP-981,B4and degradation of basecilitated
by intercellular
adhesion molecule
ment membrane collagen is a step which always
(ICAM-1).16 The PMN leukocytes undergo a reprecedes sterile ulceration of the cornea1 strospiratory burst to fuel their phagocytic and
ma
1~,19.84,94,112,15R,176,243.245,291
degranulation activities,Zsg releasing important enType I collagenase is the only enzyme that can
zymes such as PMN leukocyte type 1 collagenase
perform the initial cleavage of the type I collagen
and plasminogen activa(MMP-8), 18*,*zg,230,937
molecule.140 The production, activation, and inactor
131,273
tivation of this enzyme is of importance in repair
If the chemical injury is severe, a second wave
following cornea1 injury and has been the subject
of inflammatory cell infiltration begins at seven
As
pr&ously
emphaof intensive study. 153122,353.356
days and peaks during the period when cornea1
sized, active cornea1 stromal ulceration requires
repair and degradation are maximal-between
14the absence of the cornea1 epithelium and degra281.282
Cornea1
stromal
inflammation
per21 days.
dation of the epithelial basement membrane by
sistsas long as the epithelial defect remains,.,58
MMP-9.*xs4 Type I collagenase may be apparent as
or as long as necrotic conjunctival tissue provides
soon as nine hours following injury,1Zgz306
but is not
a foci of inflammatory infiltration.35~32.431Retarpresent in significant amounts until 14-21 days latdation of epithelial recovery by persistent inflamer, corresponding to the maximal production and
mation,07 enzymatic products of degranulating
Trpe
1 collageand stimulation of kerrepair of collagen. 17.21,40.41.43.17R.355
PMN leukocytes, I**229~*30,*37
nase production by keratocytes is normally inhibatocyte collagenase by mononuclear leukocyte cyited by epithelial cytokines.80-1 Under experitokines40?all contribute toward sterile enzymatic digestion of the cornea1 stroma during the second
mental conditions keratocytes can be stimulated to
and third post-injury weeks.
secrete type I collagenase in response to epithelial
Therapeutic strategies which exclude PMN and
cytokines,,
mononuclear leukocyte cytoki-

CHEMICAL

INJURIES

OF THE EYE

285

scure iris details, ischemia of one-third to one-half

mononuclear leukocytes from the corneal stroma
of the limbus, and the prognosis is guarded. In
contribute to prevention and arrest of stromal ulcerGrade IV injury, the cornea is opaque with no view
ation.g61g8Prompt debridement of necrotic bulbar
of the iris or pupil, there is ischemia of more than
and tarsal conjunctival tissue eliminates a source of
one-half of the limbus, there is ischemic necrosis
continuous leukocyte infiltration and release of pro325~?6,~3~
PMN
leukocytes
which
infilof the proximal conjunctival and sclera, and the
teolytic enzymes.
trated the cornea in the first wave may be critical for
prognosis is dismal.
recruitment in the second wave.285~3gg~411~421~422
TreatThe modified Hughes classification scheme evalment of the first-wave infiltration with citrate144isefuated extent of injury by degree of limbal ischemia
fective in preventing the second wave and reducing
without realizing that this is an excellent indirect
the incidence of corneal ulceration in experimental
means of assessmentof limbal stem cell injury. The
alkali injuries.~s1~2g4~295~~s~3W303~307
If citrate is used latassessmentof limbal ischemia can be used to more
er, it is ineffective in preventing PMN leukocyte inappropriately provide an initial grade of severity
filtration and sterile ulceration.lM Similarjustification
based upon the presumptive degree of limbal stem
may also apply for the early use of other therapeutic
cell loss (Figs. 5-8). Clinical observation of evoluagents that are known to reduce initial inflammatory
tion of the healing pattern then allows a precise
cell infiltration and ameliorate the second-wave infildetermination of whether or not total or subtotal
tration, such as corticosteroids,g177progestationalsterlimbal stem cell loss has actually occurred. This faoids 141~*24~270
nonsteroidal anti-inflammatory drugs
cilitates final classification into a confirmed healing
all of which
(N&D) ,362,363
and tetracycline, 111225236
pattern (Figs. 5-S). This use of a grading system
are discussed extensively below.
to estimate and then confirm actual limbal stem
cell
injury is therapeutically useful since it can
III.
Clinical
Course and Evaluation
form the basis of recommendations regarding apMcCulley24g has divided the clinical course of
propriate consideration for early limbal stem cell
chemical injury into four distinct pathophysiologic
replacement.
and clinical phases: the immediate, acute (day OUsing a limbal-stem-cell-injury based model, a
day 7), early repair (day 7-day 21), and late repair
Grade I injury involves little or no loss of stem cells
(after 21 days) phases.
(Fig. 5A), a Grade II injury involves subtotal stem
cell
loss (Fig. 6A), a Grade III injury has complete
A. IMMEDIATE
stem cell loss with retention of some proximal conThe clinical findings present immediately followjunctival epithelium and vascularity (Fig. ?A), and
ing a chemical injury are related to the area of
a Grade IV injury has complete stem cell loss and
involvement, depth of penetration, and relative
loss of proximal conjunctival epithelium (Fig. 8A).
toxicity of the substance (Figs. 3 and 4). The area
Grade IV injuries may also be associated with neof involvement can be accurately assessedby the
crosis of bulbar and conjunctival epithelial and
extent of fluorescein staining. The depth of corsubepithelial tissue, significant conjunctival and
neal penetration can be estimated by evaluating
limbal
ischemia, and extensive damage to the enthe loss of stromal clarity. The depth of conjunctire
anterior
segment.
tival penetration can be assessedby direct obserIn
the
absence
of stains specific for limbal stem
vation of vascular ischemia and/or necrosis of limcell
loss
or
injury,
limbal ischemia patterns form
bal and bulbar conjunctiva. Anterior segment fluthe
best
clinical
basis
for estimated stem cell loss.
orescein angiography may be useful in estimating
When there is very little or no evidence of limbal
conjunctival and intraocular penetration by docuischemia (Hughes I, Fig. 5C), the eye can be prementing the severity of anterior segment vascular
sumed to have a Grade I stem cell injury. When less
ischemia.
than one-half of the limbus is ischemic (Hughes
In recognition of the relationship of initial apII/III, Fig. 6C), the eye can be presumed to have a
pearance to ultimate prognosis, the Hughes clasGrade II stem cell injury. When more than onesification,172,73as modified by Ballen and Roperhalf of the limbus is ischemic (Hughes IV, Fig. 7C),
Hall,3JY correlates the loss of cornea1 clarity and
a presumed Grade III stem cell injury may have ocdegree of limbal ischemia with the ultimate progcurred. The clinical appearance of complete limnosis. In Grade 1 injury, there is no cornea1 opacity
or limbal ischemia and the prognosis is excellent.
bal ischemia associated with loss of proximal conIn Grade II injury, the cornea is hazy with visible
junctival epithelum, and evidence of significant
iris details, there is ischemia of less than one-third
damage to the entire surface of the globe and anof the limbus, and the prognosis is good. In Grade
terior segment (Fig. 8C), is strong evidence of a
III injury, there is sufficient stromal haze to obpresumed Grade IV stem cell injury.

286

Surv Ophthalmo141

(4) January-February

1997

WAGONER

Fig. 6. (A) Grade II chemical injury: schematic. There is injury to cornea1 epithelium
and partial limbal stem cell
loss. (B) Type II healing pattern: schematic. Re-epithelialization
from areas of normal limbal stem cells proceeds
normally, while re-epithelialization
in areas of limbal stem cell loss is initially from conjunctival epithelium.
Transient
subepithelial
vascularization
may accompany the conjunctival
epithelium.
Interactions
between epithelium,
inflammatory cells, and keratocytes are usually appropriate
for proper repair. (C) Grade II chemical injury: clinical appearance. In the quadrant with epithelial
defect there is obvious limbal &hernia
and probable loss of limbal stem cells
(in contrast to the appearance in 5C). (D) Type II healing pattern: clinical appearance. Following re-epithelialization
there is persistent epitheliopathy,
subepithelial
vascularization.
and stromal haze.

B. ACUTEPHA!SE
Grade I injuries usually heal without incident
during the acute phase. Grade II injuries have early re-epithelialization and slow recovery of stromal
clarity. Grade III and IV injuries have little or no
re-epithelialization, with early keratocyte proliferation, first wave inflammatory cell infiltration, little
or no collagenase production, and no cornea1 neovascularization.
C.EARLYREPAIRPHASE
During

the

early

repair

phase,

epithelial

mi-

with respect to the serious consequences of complete limbal stem cell loss. Because Grade IV injuries involve extensive damage and necrosis to
the proximal conjunctival epithelium (as well as
distal bulbar conjunctival epithelium, in some
cases) with associated limbal ischemic necrosis
(Fig. 8C), there is usually little change in the
clinical appearance during this phase, especially
if early debridement
of necrotic
tissue and advancement
of conjunctiva
or Tenons tissue (see

below) has not been performed

ical course 240.325,326,329,374

early in the clin-

gration continues in less severe injury (Grade

II), but becomes
alarmingly
delayed
in more severe injury (Grades III/IV).
Grade III injuries
may show little or no re-epithelialization,
but a
surprisingly normal appearance to the limbal region (Fig. 7C) and a relatively clear cornea,

Keratocyte proliferation,
along with resultant
collagen and collagenase production, and the second wave of inflammatory cell infiltration,
becomes very important in this stage for Grade II and
III injuries which have not been managed with aggressive anti-inflammatory therapy. It is even more

which

important

leads

the physician

to become

complacent

in Grade

IV injuries

if debridement

of

CHEMICAL

INJURIES

287

OF THE EYE

necrotic conjunctival
tissue has not removed an additional source of leukocyte accumulation
and enzymatic release. 325The combination
of additional
inflammation,
loss of limbal blood supply, and lack
of vascularly-derived
collagenase inhibitors may result in evidence of anterior segment necrosis and
sterile cornea1 ulceration,
even at this early stage
in Grade IV injuries.375

2. Type II: Delayed Differentiation

Normal epithelial recovery occurs in the quadrants with intact limbal stem cells. Because progeny
of the limbal stem cells usually do not cross the
visual axis, there may be delayed re-epithelialization from the quadrant(s)
of limbal stem cell loss.
Experimental
studies78 suggest that transient amplifying cells from limbal stem cells may migrate
circumferentially
into the area of limbal stem cell
loss and then migrate centripetally.
Pending completion of this process, epithelialization
may occur
from conjunctival
epithelium
with transient neovascularization.

Type II healing patterns (Fig. 6B-D), which correspond to Grade II limbal stem cell injuries, complete re-epithelialization in the quadrants where
the limbal stem cells are preserved, but may still
have a sectoral epithelial defect in the quadrant
with complete limbal stem cell loss at the beginning of the late repair phase. While the healing
pattern will not be complete at this stage, there can
be a reasonable expectation that the subsequent
course will be one of delayed re-epithelialization
and superficial vascular pannus due to the initial
reliance on conjunctival epithelium. Because the
injury has been sufficient to damage some of the
well-protected limbal basal epithelial cells, there is
a much greater likelihood of associated goblet cell
dysfunction than with Grade I injury. There may
be persistent ocular surface wetting abnormalities,
which may persist for weeks or months after reepithelialization is complete. Persistent epitheliopathy may result in subnormal vision for several
months.

2. Grades

3. Type III: Fibrovascular Pannus

1. Grade II

III/IV

Because complete limbal stem cell loss has occurred, epithelial recovery is rate-limited by the total
reliance on the slow migration of conjunctival epithelium onto the cornea. Clinical suspicion of a COIZjirwzd
total limbal stem cell loss should develop by
the end of the early repair phase if there is no epithelialiiation inside the limbus.
D.

LATE

REPAIR

PHASE

At the beginning of the early repair phase corneal inflammation, collagen synthesis, collagenase
synthesis, and collagenase activation are peaking.
Based on the epithelial healing which has occurred
by this stage, it is possible to classify the injury into
a conjirmed healing pattern. This classification can
accurately predict the functional outcome in the
absence of aggressive intervention and form the
basis of recommendations for surgical intervention.
1. Type I: Normal Epithelial Recovery
Type I healing patterns (Fig. 5B-D), which correspond to Grade I limbal stem cell injuries, result
in complete re-epithelialization by the beginning
of the late repair phase. The cornea1 epithelium
will be clinically and phenotypically normal. Gob
let cell injury is unusual in Grade I injury, but, if
present, it may result in abnormal mucus secretion
with transient ocular surface wetting abnormalities
and mild cornea1 epitheliopathy.

Type III healing patterns (Fig. 7B-D) , which correspond to Grade III injuries, have little or no reepithelialization during the first three weeks after
injury, although the limbal conjunctival appearance may be relatively normal and the cornea may
be deceptively clear. The anticipated healing pattern can be predicted at this stage based upon the
clinical status of the cornea1 epithelium, but the
actual completion of the pathophysiologic process
which will result in the final clinical appearance
and outcome may not be complete for several
months in surgically-neglected cases(Fig. 7D). The
only unsettled issue at this point is whether conjunctivallyderived
epithelium will provide enough
fibrovascular
pannus for the cornea1 surface
(conjunctivalization)
and vascularly-derived collagenase inhibitors to prevent sterile cornea1 ulceration and perforation. In addition to progressive and complete fibrovascular pannus of the corneal surface , the ocular surface abnormalities may
be exacerbated by late progressive symblepharon
formation, cicatricial entropion, trichiasis, and additional cornea1 scarring. In such cases, the best
outcome that can be anticipated with complete
limbal stem cell loss is one of fibrovascular pannus
with slow conjunctival ingrowth and cornea1 stroma1 neovascularization (Fig. 7D). While this may
result in a tectonically stable eye, it may pose significant problems for subsequent late rehabilitation.

288

Surv Ophthalmol41

(4) January-February

1997

WAGONER

Fig. 7. (A) Grade III chemical injury: schematic. There is loss of all corneal epithelial
and limbal stem cells, but
preservation
of the proximal conjunctival
epithelium.
(B) Type III healing pattern: schematic. All re-epithelialization
must come from conjunctival epithelium,
which is usually considerably delayed. Interactions between the conjunctival
epithelium,
inflammatory
cells, and keratocytes may or may not result in appropriate
corneal repair. (C) Grade III
chemical injury: clinical appearance. There is complete corneal and proximal conjunctival
epithelial defect, with loss
of corneal stromal clarity. (D) Type III healing pattern: clinical appearance.There is complete coverageof the cornea
with conjunctivaliied
epithelium
and superficial and deep stromal vascularization.
(C and D reprinted
from Wagoner MD, Kenyon KR, Shore JSs with permission of Churchill
Livingstone.)

4. Qpe Iv: Sterile Corneal Ulceration

Type lV healing patterns (Fig. 8 B-D), which
correspond to Grade IV injuries, have continued
absence of epithelium from both the proximal
conjunctiva and cornea during the entire first
three weeks, along with continued evidence of
proximal conjunctival and limbal &hernia and necrosis (Fig. 8C). In these cases, progressive sterile
ulceration due to enzymatic destruction may have
already been initiated in the early repair phase. If
not, it can almost certainly be expected in the late
repair phase if appropriate therapeutic intervention is not performed. The anticipated healing pattern can be predicted
at this stage based upon the
clinical status of the corneal epithelium and the
appearance of the bulbar conjunct&a at the beginning of the late repair phase (if not before), but
the actual completion of the pathophysiologic process which

will

result

in the final

clinical

appear-

ance and outcome may not be complete for several

months (Fig. 7D). Because the entire anterior segment may have been devastatingly injured in these
cases, evidence

of anterior

segment

necrosis,

retre

cornea1 membranes, peripheral anterior synechiae, cataract, glaucoma, hypotony, and phthisis
bulbi may develop.2*5 Under no circumstances can
a satisfactory result be anticipated in the absence
of aggressive

surgical

intervention,

and

withhold-

ing therapy while awaiting a satisfactory outcome

is not justified. Even with aggressive management,
the final visual prognosis in Grade IV injuries is
poor.217

IV. Medical Therapy

A modification
of the Kenyon
proach
to sterile corneal
ulceration
to the severely chemically-injured

three-step
apis applicable

eye.1g6p4o6
Man-

CHEMICALINJURIESOFTHEEYE
agement of the extreme chemical injury must attempt to 1) promote ocular surface epithelial recovery with proper cornea1 phenotypic transdifferentiation, 2) augment corneal repair by supporting
keratocyte
collagen production
and minimize ulceration related to collagenase activity, and 3) control inflammation.
k PROMOTE
TRANSD-TION

RON/

The recovery of an intact and phenotypically

normal cornea1 epithelium is the most important
determinant of a favorable outcome following
chemical injury. Initially, aggressive medical management is indicated to facilitate re-epithelialization. This is especially important in presumed
Grade I or II injuries where the prognosis is excellent for re-epithelialization and the major concern is with secondary complications (e.g., microbial keratitis)
that may occur prior to re-epithelialization. In presumed Grade III injuries, aggressive medical therapy is warranted in the
fortunate event that the severity of the injury has
been overestimated and some residual limbal stem
populations (actual Grade II) still persist which will
allow some re-epithelialization. Nonetheless, confirmation of a grade III healing pattern by evidence of no re-epithelialization
at three weeks
mandates consideration of surgical intervention
(see below). In presumed Grade IV injuries, medical therapy alone is doomed to failure and prompt
surgical intervention is warranted.

in the setting of an acute chemical injury and may

actually be harmful.414
3. Fibronectiu

Fibronectin is a multimeric glycoprotein present

in the extracellular matrix that promotes cell-cell
and cell-matrix adhesion, but has no effect on cell
mitosis or migration .22~271~272
Fibronectin produced
by epithelial cells and keratocytes is detectable
within eight hours after cornea1 epithelial injury.
It is distributed on the bare basement membrane
ahead of and under the advancing epithelium
where it persists until re-epithelialization is complete.7,67J08J09
Plasminogen produced by basal epithelial cells after chemical injury may degrade fibrin and fibronectin and interfere with adhesion
of migrating epithelium .**JS5Although topical fibronectin has shown some favorable effect on promoting re-epithelialization following experimental
chemical injury,3,67,271,319,514,360,374
it is currently an
investigational medication and is not available for
clinical use, where there has been no conclusive
evidence that it is of significant value.
4. Epidermal Growth Factor
Epidermal growth factor (EGF) is a polypeptide
originally isolated from the mouse submaxillary
gland.lj3 It stimulates the uptake of DNA, RNA,
and protein precursors by cornea1 epithelium101J02and enhances the rate of epithelial migration

1. Tear Substitutes
Most chemical injuries occur in young, healthy
individuals with the ability to produce copious teating, so tear substitution is not needed. In rare
cases,where chemical injury occurs in the setting
of preexisting keratoconjunctivitis sicca, preservative-free tear substitutes may be useful. Temporary
or permanent punctal occlusion may facilitate the
function of tear substitutes. Tear substitutes are of
greater value following re-epithelialization, where
they ameliorate persistent epitheliopathy, reduce
the risk of recurrent erosion, and accelerate visual
rehabilitation.
2. Bandage Soft Contact Lens

Bandage soft contact lenses promote epithelial

migration, basement membrane regeneration, and
epithelial-stromal adhesion by protecting the ocular surface from the windshield-wiper effect of
the lids. Unfortunately, they tend to be poorly toierated by the acutely chemically-injured eye. Similarly, collagen shields tend to be poorly tolerated

by

inducing

hyperplasia.7*,130~163,~~~~~39.~51.3~7

Its action is not dose-dependent, with maximal

stimulation occurring within a very narrow range
of dosage. 130It does not promote adherence of
the migrating epithelium to the damaged basement membrane.351 In theory, its benefit in Grade
I or II injuries is obvious. Its benefit in Grade III
injuries should be confined to enhancing the rate
of conjunctival epithelial recovery of the cornea1
surface, and there should be little or no effect for
Grade IV injuries.
Epidermal growth factor has been shown to be
beneficial in promoting epithelial migration in
experimental alkali injury.25J03J63~286~328~33g~351
It has
also been reported to favorably influence epitheha1 migration in human studies of alkali injury,109.328,343,351
a1 th ough recurrent epithelial defects
have been seen following its discontinuation.351
Like fibronectin, EGF remains investigational and
is not available for clinical use. The combined use
of EGF-fibronectin
to facilitate migration-adhesion is theoretically promising, but awaits clinical
trials.

290

Surv Ophthalmol41

5. Retinoic

(4) January-February 1997

WAGONER

TABLE 2

Acid

Retinoic acid stimulates conversion of limbal stem

cells to transient amplifying cells, inhibits the prolif
eration of corneal and limbal transient amplifying
cells, and prevents abnormal terminal epithelial differentiation.*13 It promotes transdifferentiation of
conjunctival epithelium into corneal epithelium following severe chemical injury.213,3*3g51thas shown
promise in the treatment of ocular surface disorders
associatedwith goblet cell dysfunction and abnormal
keratinization.358 Theoretically, it may be useful following severe chemical injury in promoting goblet
cell recovery, tear film stabilization, and improved
ocular surface wetting. The clinical use of retinoic
acid remains investigational, and it is not available
for general clinical use.
6. Sodium

Hyaluronate

(Healon)

Reirn?*j has reported clinical successin the use

of topically applied sodium hyaluronate (Healon)
in facilitating epithelial migration in severe chemical injuries, especially when used in conjunction
with tenoplasty (see below). In addition, he feels
that it may beneficial in reducing the amount of
conjunctival scarring and symblepharon formation.
B. SUPPORT BBPAIR AND MINIMIZE
ULCERATION

Relative Potency of CollagenaseInhibitors

Inhibitor
Acetylcysteine
Sodiumcitrate
Cysteine
Tetracycline
Doxycycline
Carboxyl synthetic peptide
Thiol synthetic peptide

SDS-page* HPLC
Assay 48
Assay 48
1
1
3
13
33
100
10,000

7
8
180
122
27,000

and is probably due to chelation of zinc at the

active site of the enzyme.27This accounts for the
fact that doxycycline, which binds zinc more effectively than other tetracycline derivatives, is
also a more potent in vitro inhibitor of collagenase than tetracycline or minocycline.4s
Tetracycline derivatives also inhibit PMN leukocyte activity.111,225,*36
They can indirectly reduce ulceration by scavenging PMN-generated reactive oxygen compounds such as hypochlorous acid and
superoxide dismutase, thereby preventing it from
converting inactive procollagenase to actively destructive collagenase.225PMN leukocyte inhibition
may also account for the efficacy of tetracyclines in
facilitating re-epithelialization
in experimental
chemical injury.284

1. Ascorbate

Ascorbate is an essential water-soluble vitamin

which must be taken daily to maintain sufficient body
stores~8,2sy

Pfister

md

o&,e~97,233,300,305,307-309,312.315

have

demonstrated the benefits of supplemental ascorbate

in restoring depleted aqueous ascorbate levels and reducing the incidence of corneal thinning and ulceration following experimental alkali injuries. In severe
injuries, topical application is superior to systemicadministration,5** presumably due to damage to the ciliary body epithelium with reduction in active ciliary
transport and concentration of anterior chamber
ascorbate. While both topical and systemic ascorbate
reduce the incidence of ulceration, they do not halt
the progression of established ulceration,s7-309~312
emphasizing the importance of early supplementation.
Double-masked clinical trials are being conducted on
the efficacy of topical and systemicascorbate on alkali
injury, but results are not yet available.
2. Tetracycline

Tetracycline
be efficacious
27.48.125-12A.175.236.283

ty
experimental
independent

derivatives have been shown to

in reducing collagenase activiand

cornea1

ulceration

in

alkali injuries.2s4.345 The effect is

of its antimicrobial properties4,L25

3. Collagenase

Inhibitors

Some of the earliest pharmacological tools used

to treat severe chemical injuries were collagenase
inhibitors.17g Early work with a number of collagenase inhibitors, including cysteine,31,34,35,3g~~~352-354
acetylcysteine
(Mucomyst),34,3g,352-354 sodium
EDTA 34,39,ss4
calcium EDTA,40 and penicillamine,gg
proved favorable in experimental and clinical studies. Unfortunately, only acetylcysteine (Mucomyst
10% and 20%) has been available for clinical use.
It must be refrigerated, is unstable, must be replaced weekly, penetrates poorly into the cornea1
stroma, must be applied frequently, and is relatively toxic. 307Recent experimental results fail to demonstrate any favorable effect with acetylcysteine for
severe experimental alkali injuries.07 Its effect is
relatively weak, comparable to citrate, but markedly inferior to tetracycline and newer synthetic inhibitors (Table 2) .47.48
Although the early collagenase inhibitors have
largely fallen into disfavor, recent discovery of the
potent inhibition of collagenase by tetracycline derivatives and promising new synthetic inhibitors
have reopened this area of therapy. Synthetic thiol
and carboxyl peptide collagenase inhibitors, which

CHEMICAL

INJURIES

OF THE

are lo5 times more potent inhibitors of collagenase

than acetylcysteine,47,48,74J36J37,280,344,413
are effective
in experimental chemical injury in reducing the
incidence of cornea1 thinning, ulceration, and perforation.47,48.280,344,413
Recombinant tissue inhibitors
of metalloproteinases (TIMP) have similar anti-collagenolytic properties and have in vitro inhibition
of cornea1 ulceration similar to that of synthetic
thiol inhibitors.280 To date, no clinical trials are
available with synthetic thiol or recombinant collagenase inhibitors.
C. CONTROL

291

EYE

INFLAMMATION

1. Corticosteroids

Corticosteroids have traditionally been the mainstay of therapy for the reduction of tissue injury
related to acute or chronic inflammatory conditions, including those of the eye.1g7s232
Corticosteroids reduce inflammatory cell infiltration and stabilize polymorphonuclear
leukocyte cytoplasmic
and lysosomal membranes9 Unfortunately, there
has been an unfounded reluctance on the part of
many clinicians to use corticosteroids in the severely inflamed, acutely chemically-injured
eye.
This may be due to unfavorable experiences that
often result from the injudicious use of corticosteroids in this setting. This error is compounded by
the extrapolation that such poor outcomes automatically exclude this potentially beneficial family
of substances from the management of severe
chemical injuries.
It is well recognized among clinicians that there
is little risk of sterile ulceration in the first week
after severe chemical injury whether or not corticosteroids are used. This finding is confirmed in
experimental models, where there is no adverse
effect on outcome when corticosteroids are used
in the first 10 days. Corticosteroids interfere with
stromal wound repair by impairing both keratocyte
migration into the area of injury and collagen synthesis.0~0,114~17,~1~
The deleterious side effects of
corticosteroids do not become apparent until corneal repair processes begin, since a balance between collagen synthesis and proteolytic debridement must be maintained to avoid cornea1 thinning and perforation .looDuring this phase, which
usually peaks after lo-14 days, suppression of keratocyte collagen production by corticosteroids may
offset the advantages of their effect on inflammatory cell suppression and collagenase inhibition 42,210.317
resulting in a net shift of cornea1 repairtoward ulceration.
The key to successful use of corticosteroids is to
maximize their anti-inflammatory effect during the
first 7-10 days when the risk-benefit ratio is favor-

able. Later the therapy can be modified by tapering the corticosteroids while monitoring for evidence of cornea1 thinning or by substituting progestational steroids or substituting non-steroidal
anti-inflammatory drugs (NSAID) .
2. Progestational

Steroids

Progestational steroids have less anti-inflammatory potency than corticosteroids, but have only a
minimal effect on stromal repair and collagen synthesis.317They are effective in reducing cornea1 ulceration in experimental chemical injuries.141,224,27
They may be substituted for corticosteroids at lo14 days when suppression of inflammation is needed but interference with cornea1 stromal repair is
undesirable. Topical, subconjunctival, or systemic
medroxyprogesterone
(Provera) has potent anticollagenolytic activity in experimental animal models 141.270
The ability of medroxyprogesterone to inhibit neovascularization141 may be helpful in promoting ocular surface epithelial transdifferentiation in the early stagesafter chemical injury3g1 and
for visual rehabilitation in the late stages.
3. Non-steroidal

Anti-inflammatory

Drugs

WSm)

NSAID, such as diclofenac sodium, ketorolac tromethamine, and experimental lipogenase and leukotriene inhibitors, are effective inhibitors of PMN
leukocytes. 363They reduce inflammation at least as
effectively as corticosteroids following routine cataract surgery54.s~g2,371
and in experimental lens-induced uveitis.54
Early experimental trials on the efficacy of
NSAID in reducing ocular inflammation after
chemical injuries have been promising. Struck
reported that leukotriene antagonist S 872419, a
specific antagonist of peptide leukotrienes, reduced clinical evidence of inflammation following
experimental alkali injuries in rabbit eyes by inhib
iting lipoxygenase-mediated reactions. He also reported37 that BN 52 021, a specific antagonist of
PAF receptors led to a visible anti-inflammatory effect of the chemically burned anterior segment of
rabbit eyes by reducing the anticipated increase in
PGF2 alpha. Preliminary clinical trials379suggest a
possible additive effect of topical indomethacin, an
inhibitor of cyclooxygenase, to dexamethasone in
the early treatment of moderate and severe chemical injuries.
The effect of NSAID on stromal wound repair
and collagen synthesis, collagenolytic activity, and
inhibition of neovascularization has not been adequately addressed, * It is hoped that NSAID will
prove to be an effective substitute or an additive
for corticosteroids in the first week and for pro-

SUIV Ophthalmol41

(4) January-February

1997

WAGONER

Fig 8. (A) Grade IV chemical injury: schematic. There is loss of all corneal epithelial, limbal stem cells, and proximal
conjunctival epithelium. (B) Type IV healing pattern: schematic. Little or no re-epitbelialization is expected from the
distal conjunctival epithelium. Interactions between inflammatory cells and keratocytes, in the absence of modulation
by migrating epithelium result in excessive collagenolysis instead of appropriate repair. (C) Grade IV chemical injury:
clinical appearance. Complete corneal epithelium defect with limbal ischemia remains unchanged four months after
original injury. (D) Type IV healing pattern: clinical appearance. Sterile cornea1 ulceration with perforation and iris
prolapse in the inferior cornea. A mature cataract is also present. (C and D reprinted by permission from Mandel
ER, Wagoner MD: Atlas af Cornea1 Disease. Philadelphia, WB Saunders,1989,p 72.)

gestational steroids after the first week following

severe chemical injury if similar efficacy or an additive effect in the control of inflammation can be
demonstrated in this setting.

ical administration is superior to systemic administration.501*307

The effect is reversed by application
of calcium.48s295
Double-masked human clinical trials are currently being conducted, but final results
are not available.

4. Citrate

Citrate, a natural food ingredient with physical

properties similar to ascorbate, is a calcium-chelator which decreases the membrane and intracellular calcium levels of PMN leukocytes, with resultant impaired chemotaxis, phagocytosis, adherence, and release of lysosomal enzymes.2g5~298~302
It
has a potency comparable to that of acetylcysteine
in the inhibition of collagenase.48
In experimental chemical injuries, early administration of citrate144 reduces early-phase and latephase PMN infiltration by 63% and 92%, respec~ve~y,281,2S2.294,295,298,502,303
and significantly reduces
the incidence of corneal ulceration.g1~301*305*307
Top-

V. Surgical Therapy
A. PROMOTE
TRANSD-TION

REFaP-TION/

Over the past two decades important advances

in the management of chemical injury have occurred based on the application of theories on ocular surface and limbal stem cells in conjunction
with the development of a number of ocular surface transplantation techniques which may address
specific anatomic abnormalities during the immediate, early, and late stages of management of
chemical injuries of the eye. 330,385,38g
Ocular sur-

Fig. 9. Technique
of limbal stem cell transplantation.
(early intervention).
(A-D) Technique
of donor eye preparation. Superior and inferior limbal grafts are delineated with focal applications
of cautery approximately
2 mm posterior
to the limbus. The initial incision is made superficially within clear cornea using a disposable scarifier. The bulbar
conjunctival portion of the graft is undermined
and thinly dissected free from its limbal attachment. (E/F) Technique
of recipient eye preparation.
The limbal grafts are transferred
to their corresponding
sites in tbe recipient eye and
are secured with interrupted
sutures, 10-O nylon at the corneal edge and 8-O vicryl at the conjunctival
margin.
Superficial keratectomy is not required.
(A-F reprinted
from Kenyon KR and Tseng SCG1wwith permission from the
authors and JB Lippincott.)

face transplantation
techniques
that are useful inelude
conjunctival/Tenons
advancement
(tenoplasty)
for immediate
t-e-establishment
of hmbal
vascularity
and a proximate
source of epithelium
for the denuded
corneal
surface,330 limbal
stem

cell transplantation
for early or late re-establishment of limbal stem cell populations
in the hope
of producing
a phenotypically
normal
corneal
ep
ithelial
surface,199,*v408
and conjunctivaP
or mucous membrane
transplantation220~267~34g
for the late

294

Surv Ophthalmol41

(4) January-February 1997

reestablishment of the conjunctival fornices and

normal lid-globe apposition.

WAGONER

juries in an effort to prevent a Type III or IV healing pattern and the need for more complicated
late rehabilitation.
1. Conjunctival/Tenons
advancement
The technique, as described by Kenyon and
(Tenoplasty)
Tseng lgg (Fig. 9), involves harvesting two crescents
In Grade IV injuries, the most immediate conof peripheral cornea1 limbal epithelium with a corcern is the development of anterior segment neresponding section of conjunctiva from the limbus
crosis due to loss of the limbal vascular blood supof the patients uninjured or less injured contraply, as well as the certainty of failure to re-epithelateral eye (autograft) or from a close relative (allialize. There is extensive evidence to suggest that
lograft). When performed early in the clinical
prompt reestablishment of the limbal vascularity
course, the graft can be transferred to the recipimay greatly reduce the subsequent development of
ent eye without preparatory superficial keratectothe disastrous Type IV healing pattern.21g~326~330~375
my. In such cases, successful transplantation deThe use of conjunctival/Tenons
advancement,
pends upon having controlled ocular inflammaor tenoplasty, is based upon the principle of using
tion with appropriate medical therapy, and insurvital connective tissue within the orbit to re-estaing that the graft is properly
attached to
blish limbal vascularity and to facilitate re-epithewell-vascularized conjunctiva. In Grade IV injuries
lialization.375 As described by Teping and Reim,375 prior extension of an appropriate vascular supply
all necrotic conjunctival and episcleral tissue is exto the limbal region by tenoplasty, either before or
cised, followed by blunt separation of Tenons tisat the same time as limbal stem cell transplantation
sue from the equatorial region of the globe and
is mandatory to insure graft survival.
from the extraocular muscles. The Tenon sheet
In the past, the evolution of a Type III healing
must be prepared with a smooth surface to allow
pattern (fibrovascular pannus) following a Grade
conjunctival epithelium to slide on this layer. The
III injury was allowed to proceed without intervention with the intention of attempting rehabilitation
Tenons flap, with its carefully preserved vascular
supply, is then advanced to the limbus and sutured
after six months with superficial keratectomy, contightly to the sclera.
junctival or limbal stem cell transplantation, and
possibly penetrating keratoplasty. This healing patReim330reported 24 severely chemically-burned
eyes in 21 patients in which conjunctival tissue was
tern can be anticipated after a Grade III injury or
not available for advancement and for which Tenafter a Grade IV injury in which successful tenoon flaps alone were employed. In all cases,sterile
plasty has been performed early in the course. It
cornea1 ulceration was either prevented or arrestis now known that the use of limbal stem cell transplantation asearly as three weeks after injury offers
ed. Although this technique has been almost unithe theoretical potential of a phenotypically norformly successful in preventing anterior segment
mal ocular surface by upgrading the healing patnecrosis and/or sterile cornea1 ulceration, it has
tern to that normally associated with a Grade II
been lesssuccessful in insuring adequate or approinjury. Such therapy may produce a satisfactory
priately differentiated
cornea1 epithelial recovclinical outcome (Fig. lOA-D), without the comery. 21g,326,330,375
This technique may be very effective
plication of fibrovascular pannus (Fig. iD) and
in insuring initial stablization of a Grade IV injury,
complicated rehabilitation.1gg~3g6~408
providing the eye with the possibility of a Type III
In the past, Type IV healing patterns were treatrather than a Type IV healing pattern. This teched with either tissue adhesive or with keratoplasty
nique may have prevented the sterile cornea1 ulas the need arose (see below). As discussed above,
ceration which occurred in the case depicted in
early tenoplasty offers the opportunity to reduce
Fig. SC and D.
the risk of sterile ulceration and perforation asso2. Limbal
Stem Cell Transplantation
ciated with Grade IV injuries. Still, the best outcome that can be anticipated is an upgrade to a
Limbal stem cell transplantation was proposed
Type III healing pattern with delayed re-epithelialby Kenyon and Tsenglgg as a modification of the
ization and eventual development of fibrovascular
original conjunctival transplantation technique of
pannus of the ocular surface. In these cases,there
Thoft.381,388Limbal stem cell transplantation, but
are also theoretical advantages to attempting early
not transplantation of conjunctival bulbar epithelimbal stem cell transplantation in an effort to
lium, restores the normal cornea1 epithelial phereestablish a phenotypically normal cornea1 surnotype after chemical injury. Limbal stem cell
face. Unfortunately, the severe spectrum of antetransplantation is the only currently available techrior segment injury often precludes a satisfactory
nique to reestablish a normal cornea1 phenotype
outcome.
earlv in the clinical course for Grade III or IV in-

CHEhfKAL

INJURIES

OF THE

EYE

While limbal stem cell transplantation has proven extremely useful in the management of unilateral chemical injury, it has not been extensively
applied to the management of the bilateral chemical injury due to the lack of an alternative source
of limbal stem cells. Recent innovations which may
prove useful in such cases are limbal allograft
transplantation or the use of cultured limbal stem
cells.
Weise and colleagues410first reported the use of
limbal allografts on 12 primates. In 12 allograft
limbal transplants, there was successful transfer
and re-epithelialization in all 12 eyes. The transplanted tissue showed marked injection, hemorrhage, and chemosis, which subsided after 28-150
days. The donor tissue survived in all 12 cases,despite immune reactions. Pfister described two cases
in humans in which limbal allograft transplantation was obtained from donor globes.287The first
patient had an asymmetric injury with a type III
healing pattern in one eye at 11 months and a visual acuity of counting fingers at one foot. The
other eye had 20/20 acuity, but due to extensive
limbal epithelial injury, it was not considered to be
a suitable donor site. Five months after limbal allograft transplantation, successful penetrating keratoplasty was performed and it was still clear 15
months later. The second patient had a bilateral
severe chemical injury, in which one eye had been
lost following multiple failed penetrating keratoplasties and a keratoprosthesis. The other eye had
two failed penetrating keratoplasties. Five months
following limbal allograft transplantation
(with
transient, steroid-responsive immune reaction), a
penetrating keratoplasty was performed. It was still
clear with 20/80 visual acuity 18 months later.*s
Although these anecdotal casesseem promising,
there are concerns of eventual rejection of the limbal allograft stem cells followed by subsequent replacement of the cornea1 epithelial cells with a
conjunctival epithelium and incomplete transdifferentation. Williams4Ls recently investigated the
survival of non-related, donor-derived epithelial
cells after limbal stem cell allotransplantation in a
patient with bilateral limbal stem cell failure, using
short tandem-repeated DNA polymorphisms to distinguish between donor and recipient cells. He
demonstrated that cells of the donor genotype
were not detected in the central cornea until 12
weeks postoperatively, indicating that repopulation
of cornea1 surface with transplanted cells from the
donor is slow. In addition, only recipient-type cells,
and not donor cells, were detected in the central
cornea by the 20th week, despite systemic immunosuppression of the recipient with azathioprine
and cyclosporine. This single case of rejection of

allograft limbal transplantation from a nonrelated

donor should not discourage the continued investigation of limbal allograft transplantation from related donors with appropriate immunosuppressive
therapy. Long-term results from several clinical trials are still awaited before the potential value of
limbal allograft transplantation can be confirmed.
In the future, the development of monoclonal
antibodies to human limbal stem cells may make
it possible to localize, isolate, and culture these
cells in preparation for limbal stem cell transplantation.s5 This technology has been mastered recently for the culture of stem cells from the mouse
bone marrow, where transplantation of as few as
50 stem cells may be life-saving for lethally-irradiated mice.35g The remarkable proliferation and
pluripotential
differentiation
characteristics of
such cells may mean that transplantation of only a
few cells of the human limbus might make possible
the renewal of the entire ocular surface. As Yang
has observed, one potential problem is that rabbit
cornea1 stem cells may not retain their stem cell
properties in vitro and perform as limbal stem cells
only in their limbal niche, suggesting that it might
be necessary to use animals as temporary vehicles
for limbal stem cell transfer.4ZSLindberg et aPS5
have shown that human limbal stem cells can survive in a subdermal mouse model, producing cells
that are immunologically of a stem cell type. Still,
concerns about allograft transplantation of cultured limbal stem cells still exist, particularly in
view of the study of Williams et al.ll Potentially,
however, this technology may offer the opportunity
to harvest small numbers of limbal stem cells in
eyes with significant, but incomplete depletion,
and use cell culture and intermediate animal transfer before reintroduction to the original eye. Much
additional work will be required before this technology will be available for human clinical trials.
3. Conjunctival

Transplantation

Conjunctival transplantation has largely been

relegated to ocular surface disorders, such as occur
with pterygium excision, where t-e-establishment of
normal anatomic and Functional relationships of
the ocular surface is needed but restoration of normal cornea1 epithelial
function
is not required.~.201.2.74.36~,403
Following an acute chemical
injury, the role of conjunctival transplantation is
largely confined to advancement with Tenons capsule to re-establish limbal vascularity in conjunction with limbal autograft transplantation.7
4. Keratoepithelioplasty

Keratoepithelioplasty was originally advocated by

Theft as an alternative to conjunctival transplan-

296

Surv Ophthalmol41

(4) January-February

1997

WAGONER

Fig. 10. Limbal autograft, early intervention.

(A/B) Preoperative appearance. Four weeks following an alkali injury,
there is extensive limbal ischemia and no evidence of corneal epithelial recovery. (C) Postoperative appearance, one
month. Cornea1 epitheliahzation
was complete in one week. At one month, the cornea1 epithelium
is clear and the
stroma is clear with visual acuity of 20/50. (D) Postoperative appearance, two years. The corneal epithelial appearance
remains normal, the stroma is clear and free of neovascularization,
and the visual acuity is 20/25. (A-D reprinted
from Wagoner MD, Kenyon KR, Shore JS408 with permission of Churchill Livingstone.)

tation
in the bilaterally
chemically-injured
and not uncommon in neglected or poorly treated
eye.378,381The
first attempt to restore ocular surface
Grade III injuries. Traditional treatment such as
epithelial function with limbal stem cell transplanthe application of cyanoacrylate glue for impendtation used allogenic corneal donor limbal epitheing or small perforations
and tectonic keratoplasty
for perforations > 1 mm offer a means of preservlium taken on thin crescents of stroma. Unfortuing the integrity of the globe. They do not, hownately, keratoepithelioplasty is technically difficult
and has failed to produce convincing results.377~sg7 ever, rectify the ocular surface deficiency or the
aberrant stromal repair mechanisms responsible
Interestingly, large diameter penetrating kerafor the corneal ulceration (in Grade III and IV intoplasty (see below),21s,323may solve the technical
juries) or the complications of an avascular limbal
problems of transfer of limbal stem cell allografts
zone (in Grade IV injuries). Even if adequate tecfrom donor
tissue and, at the same time, provide
tonic support
is achieved,
there is inevitably
proa more favorable substrate for migration and visual
gressive vascularization
and scarring,
loss of visual
recovery than either keratoepithelioplasty or limacuity, and a worsened prognosis for subsequent
bal stem cell allograft transplantation alone. Still,
penetrating keratoplasty.
limbal stem cells transferred by this method, while
Although tenoplasty214~21g~326*330~375
and limbal
initially successful, may have problems with evenstem
cell
transplantation
have
been
discussed
tual stem cell rejection.21s~323~418
B. SUPPORT REPAIR AND MDNJMIZE
ULCERATION
Progression
to cornea1 thinning
and perforation
is quite common
after Grade IV chemical
injuries

above in the context

of proper
promotion
of re-epithelialization
and transdifferentiation
of the OCUlar surface, they must also be considered
with respect to their role in the support of repair and
minimization
of sterile ulceration.

CHEhflCAL

INJURIES

OF THE EYE

Fig. II.
Technique
of limbal stem cell transplantation
(late intervention,
donor eye preparation).
(A) Using Castroviejo calipers and disposable cautery, the area to be resected is marked approximately
2 mm posterior to the limbus.
(B) After conjunctival
resection, abnormal corneal epithelium
and fibrovascular pannus are stripped by blunt dissection using cellulose sponges and tissue forceps and/or
superficially
dissected with Martinez
spatula or disposable
scarifier. (C/D) Additional
surface polishing smoothes the stromal surface and improves clarity. Donor limbal autografts are obtained in the same manner shown in Fig. 9 A/B and sutured in place as shown in Fig. 9 C/D. (A-D
reprinted from Kenyon KR and Tseng SCG* with permission from the authors and JB Lippincott.)

Fig. 12. Limbal autograft, late intervention.

(A) Preoperative appearance. One year after acid injury there is extensive
symblepharon
of the superior fornix to the superior cornea, with associated cornea vasculature, poor cosmetic appearance, and count fingers (CF) vision. (B) Postoperative appearance,
one year. There is dramatic improvement
in
cosmetic appearance,
elimination
of symblepharon
and superficial vascular pannus, and improved visual acuity to
20/50. Mild superficial cornea1 vascularization
persists. (A and B reprinted
by permission from Brightbill
FS (ed),
Curneal Surgery, St Louis, CV Mosby, 1986, p.412. Courtesy of Kenneth Kenyon, MD, Massachusetts Eye and Ear Infirmary, Harvard Medical School.)

298

Surv Ophthalmol41

(4) January-February

1997

1. Tenoplasty
Tenoplasty has already been discussed for its role
in reestablishment of the limbal vascular blood
supply.21g~926~350~375
The access of vascularly derived
collagenase inhibitors may be of clinical significance in the prevention of collagenolytic-related
ulceration of the cornea1 stroma prior to the re-establishment of an intact epithelium.

WAGONER

problems of the cornea. This suggests that preventing rejection of limbal stem cell allografts is
much more difficult than preventing endothelial
cell rejection, even with the use of systemic immunosuppression.
4. Tissue

Adhesive

Tissue adhesives are an effective tool for management of impending or actual perforation related to sterile ulceration of the cornea1 stroma fol2. Limbal
Stem Cell Transplantation
lowing chemical injury. g3Jg8,406
While the use of tisIrrespective of its source, an intact epithelium
sue adhesive was originally described in conjunceffectively arrests further sterile cornea1 ulceration with the application of a glued-on hard
tion1g6,405
by producing cytokines which inhibit corcontact lens, this has not been adopted in common
neal fibroblast collagenase production1sG184s70and
clinical practice. lg8 The application of tissue adby excluding PMN-leukocytes from the cornea1
hesive is best reserved for impending perforations
stroma.rgs Thus, successful limbal stem cell transor actual perforations of 1 mm or less. Using the
plantation early in the clinical course is not only a
slit-lamp or operating microscope, cyanoacrylate
means of encouraging re-epithelialization and esglue can be applied easily to the area of ulceration
tablishing an appropriate cornea1 epithelial pheor perforation, after which a durable bandage soft
notype, but the reestablishment of an intact epicontact lens is usually applied to provide comfort
thelium is also an effective means of supporting
and reduce the chances of dislodgement of the
repair and minimizing ulceration.1sO-1a4,196,370,405 glue. g3,406
The adhesive can be left in place until it
loosens spontaneously as re-epithelialization oc3. Large Diameter
Therapeutic
Penetrating
curs. It can be removed with jewelers forceps after
Keratoplasty
six to eight weeks when the inflammation has subKuckelkorn218 and Redbrake
have reported
sided and neovascularization of the area has eliminated the risk of recurrent ulceration.406
encouraging results with the use of large (11-12
mm) diameter penetrating keratoplasty in the
In addition to providing immediate tectonic
management of both acute and chronic severe
support, tissue adhesive arrests further ulceration
chemical injury. By transferring not only cornea1
by excluding PMN leukocytes from the site and
inducing fibrovascular scarring.lg8 Unfortunately,
tissue for tectonic support, but also limbal stem
this fibrovascular scar results in poor visual acuity
cells of the donor globe, this procedure, used in
conjunction with tenoplasty (when indicated), adand worsens the prognosis for penetrating keradresses not only the issuesof tectonic support and
toplasty. If possible, it is best to take precautions
visual rehabilitation, but the problems of ocular
to prevent or reduce the likelihood of requiring
tissue adhesive. Repair with tissue adhesive, howsurface epithelial abnormalities and vascular defiever, remains vastly preferable to emergency tecciency as well. This addresses the major problems
which usually lead to failure of conventional tectonic keratoplasty, where the potential complications of recurrent ulceration and perforation,
tonic keratoplasty (see below).
graft opacification, and immunological stimulaKuckelkorn218 successfully managed six eyes with
tion make subsequent rehabilitation even more
sterile cornea1 ulceration with large diameter pen&fficult.93,194*196
etrating keratoplasty, arresting ulceration and
maintaining an intact epithelium during a period
5. Tectonic
Keratoplasty
of follow-up exceeding one year, although two
grafts did experience rejection 2-3 months postTectonic keratoplasty may be required in the uroperatively. Redbrake
reported the treatment of
gent setting of acute perforation not amenable to
tissue adhesive.1v32s35*36
Unlike tissue adhesive,
nine severely chemically-injured eyes in seven patients with cornea1 ulceration and perforation with
which tends to arrest further ulceration, tectonic
keratoplasty may be the preferred approach for ac12 large diameter penetrating keratoplasty (three
tual perforation, especially if the defect is greater
repeated for graft failure). All nine eyes were prethan 1 mm in diameter. This technique is used to
served tectonically, but only two of 12 grafts rebuy time in caseswhere the perforation is relamained clear throughout the entire period of foltively small and can be addressed with a small teclow-up, despite the fact that only four endothelial
tonic keratoplasty, until vascularization of the graft
graft rejection episodes were documented. Among
bed arrests further cornea1 ulceration. Until this
the 10 failures, eight were attributed to epithelial

CHEMICAL

INJURIES

occurs, it is occasionally necessary to use tissue adhesive for leaks at the graft-host junction
or progressive thinning and impending perforation
within the graft itself.
As with tissue adhesive, it is best to take every
preventative
measure to minimize the necessity of
tectonic keratoplasty,
including prompt use of conjunctival advancement
or tenoplasty in Grade IV
injuries. If a tectonic keratoplasty
does become
necessary, there is some merit to consideration
of
large diameter grafts to provide tectonic stability
while transferring
an adequate (albeit, potentially
short-lived)
limbal stem cell population.218.32s.48
C. LATE

299

OF THE EYE

REHAJ3ILITATION

In the event that early intervention with limbal

stem cell replacement has not adequately prevented the development of conjunctivalization
of the
ocular surface, it is still possible to proceed with
late rehabilitation using a superficial keratectomy
in conjunction with ocular surface transplantation
techniques.
1. Limbal Stem Cell Transplantation
Limbal stem cell transplantation was originally
described for the late rehabilitation
following
chemical injury of the scarred, vascularized cornea
with complete limbal stem cell 10~s.~~~
Following
superficial keratectomy, transfer of donor limbal
stem cells is performed (Fig. ll).lgg In caseswhere
most or all of the scarring and opacification was
superficial, this procedure often provides dramatic
improvement in visual acuity (Fig. 12).lgg In cases
where deeper cornea1 scarring and opacification
are present, lamellar or penetrating keratoplasty
may be performed. iggThere appears to be an improved prognosis for graft survival after ocular surface rehabilitation.*g9,3g6
2. Conjunctival Transplantation
Bulbar conjunctival transplantation can be used
in the late management of a chemically injured eye
to improve the mechanical functions of the ocular
surface. It may be used to relieve mechanical extraocular movement restrictive
abnormalities
caused by conjunctival/Tenons
scarring, and to
restore an obliterated fornix when conjunctival fibrosis and cicatrization leads to fornix foreshortening, symblepharon formation, cicatricial entropion, trichiasis, distichiasis, ocular surface keratinization, and vascularization.4054s Its use is largely
limited to unilateral or asymmetric chemical injuY.
For the late rehabilitation of unilateral or bilateral injury, Kuckelkorn 214has described tarsoconjunctival advancement to correct cicatricial entro-

pion and eyelid malposition. While experience

with this procedure is limited, it does offer the potential of avoiding more complicated procedures,
such as mucosal membrane grafts (see below), in
some cases of late conjunctival scarring and symblepharon.
With the development of the more phenotypitally correct limbal stem cell transplantation, the
use of bulbar conjunctiva for late rehabilitation of
cornea1 epithelial function381 has largely fallen into
disfavor.lgg
3. Mucosal Membrane Grafts
Like conjunctival transplantation, mucosal membrane grafts may be useful in the reconstruction of
fornix obliteration and the restoration of normal
lid-globe relationships. 220,267,34g
Mucosal tissue mechanically restores ocular surface anatomical relationships and reduces or eliminates the problems
associated with mechanical disturbance of the forniceal conjunctiva. It will not provide a source of
phenotypically normal cornea1 epithelium. While
this procedure has been used principally for autoimmune cicatricial conjunctival disorders such as
Stevens-Johnson syndrome and ocular cicatricial
pemphigoid, g5-g8,220,255,256
it has also been useful for
bilateral chemical injury where contralateral conjunctiva is not available (Fig. 13). Some authors
advocate the use of nasal mucosa,220.267
with its gob
let cell population, rather than buccal mucosa,94g
to restore some of the mucus-secretion capabilities
of the ocular surface. It is possible that the improved ocular surface wetting due to improved
goblet cell function following transfer of nasal mucosa may be beneficial in improving the prognosis
of subsequent penetrating keratoplasty.220
4. Penetrating Keratoplasty (Fig. 14)
The prognosis for successful penetrating keratoplasty is related to the original severity and sequelae of a chemical injury.212,240The prognosis is
virtually hopeless if there are intraocular abnormalities such as glaucoma, hypotony, anterior
chamber membrane formation, and retinal detachment.i,32*.36 If intraocular abnormalities themselves do not preclude an attempt at visual rehabilitation, the success of penetrating keratoplasty
still remains poor if it is performed in the setting
of limbal stem cell dysfunction, conjunctival cicatrization, fornix foreshortening, entropion, trichiasis, and mechanical trauma or exposure of the
cornea.
If the severity of intraocular abnormalities does
not preclude penetrating keratoplasty, it is now
possible to improve the prognosis for penetrating
keratoplasty if rehabilitation of the ocular surface

300

Surv Ophthalmol41

(4) January-February

1997

WAGONER

Fig. 13. Severe alkali injury, late sequelae. (A) Extensive symblepharon
between the right lower lid and temporal
bulbar conjunctiva and cornea. Corneal epithelium
is intact and relatively clear due to preservation
of superior and
nasal limbal stem cells. (B) Similar findings are present laterally in the left eye.

Fig. 14. Failed penetrating

keratoplasty for severe chemical injury. (A) Status/post two failed penetrating
keratoplasties with a scarred, vascularized graft due to persistent depletion
of limbal stem cells. (B) Status/post repeat
penetrating
keratoplasty, one year. The graft remains relatively clear with a reasonable ocular surface. Conjunctival
phenotypic characteristics
are not obvious yet. (C) Postoperative appearance, two years. Recurrent epithelial defects
are present in the central graft. Encroachment
of peripheral
superficial vascular pannus suggests the cornea1 epithelial
phenotype
is conjunctival.
(D) Postoperative appearance,
four years. Recurrent
cornea1 epithelial
erosions and replacement of ocular surface with conjunctival-like
epithelium
has resulted in scarred, opacified graft. (Courtesy of
Claes Dohlman, MD, Massachusetts Eye and Ear Infirmary, Harvard Medical School.)

CHEMICALINJURIESOFIHEEYE

Successfulkeratoprosthesisfor severe chemical injury. (A) Preoperative appearance. Severely vascularized

and scarred cornea with extremely poor ocular surface and prognosisfor penetrating keratoplasty. (B) Postoperative
appearance, one year. Keratoprosthesisis secure and visual acuity is 20/60. (Courtesy of ClaesDohlman, MD, MassachusettsEye and Ear Infirmary, Harvard Medical School.)

Fig. 15.

can be achieved with the appropriate combination

of limbal stem cell, conjunctival, and/or mucosal
membrane transplantation. In the event of bilateral injury where it is not possible to correct limbal
stem cell abnormalities due to lack of a suitable
donor or due to previous unsuccessful limbal allograft transfer, large diameter penetrating keratoplasty, with transfer of attached donor limbal
stem cells, may be attempted.
5. Keratoprosthesis

Keratoprosthesis may be useful for bilateral, severe chemical injury where the prognosis is hopeless for penetrating keratoplasty due to irreparable
damage to the ocular surface or repeated immunological rejection (Fig. 15). Although the success
rate has been variable in the past,51,76,211,322
improved keratoprosthesis design and postoperative
management may offer an improved prognosis in
the future.

VI. Specific Therapy

The most common therapeutic mistakes in the
management of severe chemical injuries of the eye
are the failure to institute immediate debridement
of necrotic conjunctival tissue and restore adequate limbal vascular supply, to address persistent
limbal stem cell dysfunction at an early stage, and
to properly control cornea1 stromal inflammation.
The early management of chemical injuries should
maximize medical therapy, with the exception of
Grade lV injuries where appropriate debridement
of necrotic tissue and advancement of an adequate
blood supply to the limbus is mandatory. Persistent
evidence of complete limbal stem cell dysfunction
after the end of the third week, however, warrants

strong consideration of limbal stem cell replacement, whenever possible.

A, IMMEDIATEPHASE
Immediate therapy is directed toward alleviating
continued contact between the chemical agent and
the eye. While the use of irrigation is the cornerstone of immediate therapy, the value of paracentesis and lavage of the anterior chamber is less
clear.
1. Irligation
One of the main determinants of ultimate outcome following chemical injury is the duration of
contact between the chemical agent and the eye.
Because of the deep location and relatively protected site of the limbal stem cells, it is possible
that injury may be averted with prompt irrigation.
When the patient arrives in the ophthalmologists
office, it must be assumed that any previous irrigation applied at the time of the injury was inadequate. Prompt irrigation should be initiated immediately. Manual irrigation directly onto the
globe and into the conjunctival cul-de-sac may be
performed while the eye is held open with a speculum. Conversely, some authors have found continuous irrigation systems a suitable alternative.424
No therapeutic differences have been identified
between normal saline, normal saline with bicarbonate, lactated Ringers, and balanced salt solution (BSS), or BSS~~US.*~
Adhering to the principle that it is impossible to
overirrigate a chemically injured eye, irrigation for
15-30 minutes is recommended. If the pH of tears
in the conjunctival fornices does not return to normal, irrigation must be continued. If the pH re-

SW-V Ophthalmol

302

41 (4) January-February

1997

WAGONER

mains elevated despite continued irrigation, the lid

should be everted (doubly, if necessary) to search
for and remove any retained particulate matter
with jewelers forceps. It may be necessary to use
chelation with EDTA to facilitate removal.

9. cycloplegic of choice as needed.

2. Debridement

C. EARLY

REPAIR

Debridement of necrotic cornea1 epithelium is

necessary to allow proper re-epithelialization, irrespective of the degree of the chemical injury. In
severe injuries, where there is associated necrosis
of conjunctival and subconjunctival tissue, debridement is essential to remove a nidus of continued
inflammation from retained caustic materials, a
site of accumulation of PMN and mononuclear
leukocytes, and the sustained release of detrimental proteolytic enyzymes.32~3z~3

1. Grade

3. Paracentesis

The benefit of paracentesis and irrigation of the

anterior chamber following a severe chemical inIn
animal
studies,
jury is uncertain. 12.49,133,279,289
Grant13 showed the value of anterior chamber irrigation within one minute of injury. Bennett et
alI2 showed that irrigating within 15 minutes, but
not after 30 minutes, had a beneficial effect on
outcome. Limited published studies have not demonstrated conclusively the value of paracentesis
and lavage during the first two hours after injuY.

12.49.

289

B. ACUTE

1. Grade

PHASE

Adequate therapy consists of topical corticosteroids to reduce inflammation, appropriate glaucoma medications for elevation of intraocular pressure, prophylactic antibiotics while awaiting re-epithelialization, and cycloplegics as needed for comfort.
2. Grades

II/III

For chemical injuries of this severity, initial therapy which addresses all of the pathophysiological
abnormalities includes:
1. topical corticosteroids every four hours to four
times a day;
2. sodium ascorbate 10% topically every two
hours;
3. sodium citrate 10% topically every two hours;
4. tetracycline ointment four times a day;
5. sodium ascorbate two grams orally, four times a

day;
6. doxycycline 100 mg orally, twice a day;
7. P-blocker of choice twice a day as needed;
8. diamox sequels 500 mg orally, twice a day;

3. Grade

IV

Grade IV injury requires all the therapies recommended for Grades II/III, plus tenoplasty.
PHASE

Following complete re-epithelialization, topical

cycloplegics may be discontinued if there are no
signs of anterior uveitis, glaucoma medications
may be tapered or discontinued depending upon
the intraocular pressure, and antibiotic/steroid
therapy may be tapered and discontinued. Lubrication may be used as needed for comfort and persistent epitheliopathy.
2. Grade

II

If re-epithelialization
progresses, but fails to
reach completion during this phase, adjustments
to the initial therapy may include tapering of topical corticosteroids, topical/systemic sodium ascorbate, topical sodium citrate, and topical/systemic
tetracycline.
3. Grades

III/IV

As little or no re-epithelialization occurs in this

phase, it is necessary to discontinue or taper (with
careful observation) topical corticosteroids, begin
topical Medroxyprogesterone or NSAID, continue
topical/systemic sodium ascorbate, continue topical sodium citrate, and continue topical/systemic
tetracycline.
D.

LATE

REPAIR

PHASE

1. Type1

Lubrication with preservative-free artificial tears

may be continued or tapered, depending upon patient comfort and status of the epithelium.
2. Type II
Even with complete re-epithelialization, persistent epitheliopathy requires the use of prolonged
lubrication. Goblet cell dysfunction may be treated
with bedtime retinoic acid O.Ol%, if available. Medroxyprogesterone 1% may be used for persistent
inflammation and/or vascularization.
3. Types

III/IV

Continued absence of epithelialization by the

beginning of this phase mandates consideration of
surgical intervention. This includes limbal stem
cell transplantation (limbal autograft for unilateral
or asymmetric injury or limbal allograft [bilateral
injury], if possible). Large diameter penetrating

CHEMICAL

INJURIES

303

OF THE EYE

keratoplasty
(1 l-12 mm) may be performed
if limbal stem cell transplantation
is not possible (especially applicable in bilateral cases).
Pending completion
of re-epithelialization
following limbal stem cell transplantation,
it is necessary to continue the following
medical therapy:
Medoxyprogesterone
1% or NSAID;
topical/systemic sodium ascorbate;
topical sodium citrate;
topical/systemic
tetracycline.

8.
9.

10.

11.
12.

VII.

Conclusion

For many years, the main focus of investigation

and therapy for severe chemical injury was on control of inflammation
and regulation of the delicate
balance between collagen synthesis and collagenolytic activity in the cornea by carefully selected
medical intervention.
In the last two decades, improved understanding
of the importance
of the ocular surface has added several surgical options for
the management
of severe chemical injury. The
development
of ocular surface
transplantation
techniques which may help restore depleted limbal
stem cell populations
(limbal autograft and allograft transplantation),
restore limbal vascularity
(conjunctival
advancement/tenoplasty),
and correct mechanical and anatomical disturbance
of the
bulbar and palpebral
conjunctiva
(conjunctival
and mucous membrane transplantation)
offer the
opportunity
for improving
both the early and late
management
of severe injuries.
The therapy of severe chemical injuries of the
eye depends upon a thorough understanding
of all
of the pathophysiological
changes which occur as
a result of and in response to the injury. An approach that addresses the three major pathophysiological processes of chemical injury (ocular surface injury, repair, and differentiation;
cornea1
stromal injury and repair; inflammation)
will improve the prognosis of severe chemical injury.

13.
14.
15.

16.

17.

18.

19.

20.

21.
22.

23.

24.

25.

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32.

33.

34.

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37.
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39.

40.

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Surv Ophthalmol

41 (4) January-February

1997

tion of the major matrix

degrading
metalloproteinase
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CHEMICAL

INJURIES

313

OF THE EYE
Outliie

I. Etiology
A. Alkali
B. Acid
II. Pathophysiology
A. Epithelial
injury, repair, and differentiation
1. The ocular surface
2. Limbal stem cell hypothesis
3. Limbal stem cell/ocular
surface injury
B. Cornea1 stromal matrix injury, repair, and
ulceration
1. Collagen
2. Collagenase
C. Inflammation
III. Clinical course and evaluation
A. Immediate
B. Acute phase
C. Early repair phase
1. Grade II
2. Grades III/IV
D. Late repair phase
1. Type I: Normal epithelial recovery
2. Type II: Delayed differentiation
3. Type III: Fibrovascular pannus
4. Type nT: Sterile cornea1 ulceration
IV. Medical therapy
A. Promote re-epithelialization/transdifferentiation
1. Tear substitutes
2. Bandage soft contact lens
3. Fibronectin
4. Epidermal
growth factor
5. Retinoic acid
6. Sodium hyalouronate
B. Support repair and minimize ulceration
1. Ascorbate
2. Tetracycline
3. Collagenase inhibitors
C. Control inflammation
1. Corticosteroids
2. Progestational
steroids
3. Non-steroidal
anti-inflammatory
drugs
4. Citrate

V. Surgical therapy
A. Promote re-epithelialization/transdifferentiation
1. Conjunctival/Tenons
advancement
(tenoplasty)
2. Limbal stem cell transplantation
3. Conjunctival
transplantation
4. Keratoepithelioplasty
B. Support repair and minimize ulceration
1. Tenoplasty
2. Limbal stem cell transplantation
3. Large diamater therapeutic
penetrating keratoplasty
4. Tissue adhesive
5. Tectonic keratoplasty
C. Late rehabilitation
1. Limbal stem cell transplantation
2. Conjunctival
transplantation
3. Mucosal membrane grafts
4. Penetrating
keratoplasty
5. Keratoprosthesis
VI. Specific therapy
A. Immediate phase
1. Irrigation
2. Debridement
3. Paracentesis
B. Acute phase
1. Grade I
2. Grades II/III
3. Grade IV
C. Early repair phase
1. Grade I
2. Grade II
3. Grade III/IV
D. Late repair phase
1. TypeI
2. Type II
3. Types III/IV
VII. Conclusion

Reprint
Address: Michael
D. Wagoner,
MD, c/o Medical
Library, Ring Khaled Eye Specialist
Hospital,
PO Box 7191, Riyadh 11462, Kingdom
of Saudi Arabia.