Jurnal Mata

Clinical Science
PEDRAM HAMRAH, MD, EDITOR
Current and Upcoming Therapies

for Ocular Surface Chemical Injuries
ALIREZA BARADARAN-RAFII, MD, 1* MEDI ESLANI, MD, 2* ZEESHAN HAQ, BS, 2
EBRAHIM SHIRZADEH, MD, 1 MICHAEL J. HUVARD, MD, 2 AND ALI R. DJALILIAN, MD2
ABSTRACT Chemical injuries frequently result in vision loss, chemical injury is determined by several factors, including
disfigurement, and challenging ocular surface complications. the chemical and physical characteristics of the offending
Acute interventions are directed at decreasing the extent of agent (particularly the pH), the specific reactivity with tis-
the injury, suppressing inflammation, and promoting ocular sues (pK), concentration, volume, temperature, and impact
surface re-epithelialization. Chronically, management in- force.2,3 It is well known that alkaline substances, due to
volves controlling inflammation along with rehabilitation and their lipophilicity, penetrate the eye more readily and there-
reconstruction of the ocular surface. Future therapies aimed fore threaten both ocular surface tissues as well as intraoc-
at inhibiting neovascularization and promoting ocular surface ular structures such as the trabecular meshwork, ciliary
regeneration should provide more effective treatment op- body, and lens. In contrast, acidic substances cause protein
tions for the management of ocular chemical injuries. coagulation in the epithelium, a process that limits further
penetration into the eye.4-6 Nonetheless, acids may severely
KEY WORDS chemical burn, cornea, limbal stem cell
damage the ocular surface. With all ocular chemical injuries,
deficiency, ocular chemical burn, ocular surface, stem cell
swift intervention is crucial to improving the outcome and
prognosis.
I. INTRODUCTION The purpose of this review is to provide an update on
cular chemical injuries are true ophthalmic emer-
O gencies that require immediate and intensive inter-
vention to minimize severe complications and
profound visual loss.1 Such injuries, which are most preva-
the current medical and surgical management of ocular
chemical injuries and to describe future potential therapies.
lent among young males aged 20-40, can result in chronic II. CLASSIFICATION OF OCULAR SURFACE INJURIES
complications and life-long disability. The severity of There are several classification systems of ocular surface
injuries that predict prognosis and clinical outcome by
grading the severity of the injury.3,7,8 The Roper-Hall (R-
Accepted for publication September 2016. H) classification, first introduced by Ballen9 in the mid-
From the 1Ophthalmic Research Center, Shahid Beheshti University of 1960s and later modified by Roper-Hall,8 grades the severity
Medical Sciences, Tehran, Iran, and 2Department of Ophthalmology and
Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, USA.
of injury by the extent of corneal haze and perilimbal
ischemia (Table 1). A similar classification proposed by Pfis-
Supported in part by Clinical Scientist Development Program Award
K12EY021475 (ME), R01 EY024349-01A1 (ARD) and Core grant ter is based upon the same variables but categorizes the
EY01792 from NEI/NIH; MR130543 (ARD) from DoD; and unrestricted severity of injury as mild, mild-to-moderate, moderate-to-
grant to the department from RPB. severe, severe, or very severe based upon photographs.3 In
The authors have no commercial or proprietary interest in any concept or contrast, Dua proposed a classification based on both
product discussed in this article.
clock-hour limbal involvement as determined by fluorescein
Single-copy reprint requests to Ali R. Djalilian, MD (address below).
staining and percentage of bulbar conjunctival involvement
Corresponding author: Ali R. Djalilian, MD, Illinois Eye and Ear Infirmary, (Table 2).7 These clinical findings are then translated into an
Department of Ophthalmology and Visual Sciences, University of Illinois at
Chicago, 1855 W. Taylor St, EEI 3164, Chicago, IL 60612. Tel: 312-996- analog grading scale that should be calculated daily during
8936. Fax: 312-355-4248. E-mail address: [email protected] the acute stage as the extent of injury becomes evident.
*Drs. Baradaran-Rafii and Eslani contributed equally to this paper. The common element in all of these classification
schemes is the identification of the amount of limbal
Ó 2016 Elsevier Inc. All rights reserved. The Ocular Surface ISSN: 1542- involvement at the time of injury. Indeed, studies have
0124. Baradaran-Rafii A, Eslani M, Haq Z, Shirzadeh E, Huvard MJ, Djalilian shown that the relative proportion of surviving limbal tissue
AR. Current and upcoming therapies for ocular surface chemical injuries. is a major prognostic factor (Figure 1).4,10-14 However, the
2017;15(1):48-64.
Dua grade has been found to have better prognostic
48 THE OCULAR SURFACE / JANUARY 2017, VOL. 15 NO. 1 / www.theocularsurface.com

TREATMENT OF OCULAR SURFACE CHEMICAL INJURIES / Baradaran-Rafii, Eslani, et al
(e.g., DiphoterineÒ) have been proposed as a preferred op-

OUTLINE
tion for emergency neutralization.25-27 These novel neutral-
I. Introduction izers have been shown to correct the pH more rapidly than
II. Classification of Ocular Surface Injuries other irrigating solutions. Moreover, amphoteric solutions
III. Management of Immediate Phase are typically hypertonic and offer non-specific chelation of
IV. Management of Acute Phase acids and bases and less exothermic reactivity.28 However,
A. Anti-inflammatory Therapy the choice of aqueous solution is of less prognostic impor-
B. Prevention of Stromal Breakdown tance than the timing of treatment and any delay in irriga-
C. Promotion of Re-epithelialization and Repair tion should be avoided.
1. Bandage Contact Lens Once in the hospital setting, the most effective choice of
2. Amniotic Membrane Transplantation
irrigation solution remains undetermined. In a crossover
study of 12 eyes with acute chemical burns, Herr et al found
3. Autologous Serum
that patient comfort was statistically superior with balanced
4. Tenonplasty
saline solution plus (BSSP) compared to normal saline.29 Of
5. Treatment of High Intraocular Pressure note, all tested solutions produced comparable changes in
V. Management of Chronic Phase objective outcomes, including conjunctival pH and degree
A. Fornix and Eyelid Reconstruction of injection. However, the potential for bias as a result of
B. Management of Glaucoma accumulated benefit from inadequate washout in the acute
C. Management of Limbal Stem Cell Deficiency setting and the small number of studied patients must be
D. Corneal Transplantation considered. Accordingly, unless immediately available, the
E. Keratoprosthesis Surgery preferential use of BSSP should be limited to patients with
VI. Future Horizons severe discomfort that precludes appropriate irrigation
A. Anti-angiogenic Therapy with other solutions (Table 3).
B. Stem Cell-based Therapy
In a nonrandomized comparative case series of 66 pa-
tients, Merle et al found that the time to re-epithelialization
VII. Summary
was significantly shorter in R-H grade 1- or 2- patients who
received irrigation with DiphoterineÒ compared to normal
predictive value in severe ocular injuries than the R-H sys-
saline.30 However, in-hospital irrigation was delivered, on
tem.7,15 Accordingly, we prefer to use the Dua classification
average, more than 40 minutes later in the group receiving
for prognostication of ocular chemical injuries, particularly
normal saline. In addition, irrespective of injury severity, no
in the presence of significant limbal stem cell disease. Uni-
significant differences were detected in vision or corneal opa-
versal adoption of a single system should be considered, as
cification between the two groups. Given the intergroup
it will facilitate the comparison of published studies on
discordance in time-to-treatment and lack of difference in
outcomes.
functional outcomes, no definitive recommendations can be
McCulley10,16 has categorized the pathophysiology and
made on the basis of these findings.
course of the disease process into four distinct clinical
phases: immediate, acute (0 to 7 days), early repair (7 to
21 days), and late repair (after 21 days) phases. For IV. MANAGEMENT OF ACUTE PHASE
simplicity, we have chosen to classify the management of The main objectives during the acute phase are to
ocular chemical injuries chronologically into the immediate, decrease inflammation, avoid further epithelial and stromal
acute (<6 weeks), and chronic (>6 weeks) phases. breakdown, and foster re-epithelialization (Figure 2,
Table 4).31
III. MANAGEMENT OF IMMEDIATE PHASE A. Anti-inflammatory Therapy

The obvious first step in treating an ocular chemical Topical corticosteroids can be critical in controlling
injury is to immediately and thoroughly irrigate the surface acute inflammation and reducing the resulting inflamma-
to remove the offending agent.2,14,17-21 Given the correlation tory damage to the ocular surface after a chemical injury.
between time to irrigation and outcomes, swift irrigation is Corticosteroids reduce inflammatory cell infiltration and
usually performed at the site of the accident and prior to stabilize neutrophil cytoplasmic and lysosomal membranes,
completion of a thorough assessment of the injury.22 mitigating the release of matrix-degrading enzymes.32
Accordingly, tap water is appropriately employed as the Topical therapy is started immediately after the chemical
aqueous solution for irrigation in most pre-hospital settings injury and continued for at least 7 days.33,34 Published
due to its ubiquitous availability. However, some studies studies have described intense regimens including predniso-
have suggested that it may promote corneal edema due to lone 0.5% hourly or fluoromethalone 1% bihourly with sub-
its hypotonicity relative to the corneal stroma.4,20,23 For sequent tapering. Caution must be exercised after the first
this reason, some have suggested the use of purpose- week, as corticosteroids can inhibit epithelialization and
designed solutions such as lactated ringers (LR) or balanced collagen synthesis and potentially increase the risk of
salt solution (BSS).24 More recently, amphoteric solutions corneal perforation.35,36 Accordingly, in the setting of severe
THE OCULAR SURFACE / JANUARY 2017, VOL. 15 NO. 1 / www.theocularsurface.com 49

Table 1. Roper-Hall classification of the severity of ocular surface burns

Grade Prognosis Cornea Limbal ischemia
I Good Corneal epithelial damage None
II Good Corneal haze, iris details < 13
visible
III Guarded Total epithelial loss, stromal 1
3 to 1
2
haze, iris details obscured
IV Poor Cornea opaque, iris and pupil > 12
obscured
injury or a nonhealing epithelial defect, topical corticoste- inhibition of MMPs.11,41 Similarly, citrate has been shown
roid therapy should be tapered to a low dosage by 2 weeks. to prevent polymorphonuclear leukocyte migration into
Otherwise, if the injury site has epithelialized, topical corti- damaged tissue, thus reducing the release of free radicals
costeroids can be used safely beyond 2 weeks with adjunc- and proteolytic enzymes.42,43 However, studies of these treat-
tive ascorbic acid (topical and systemic) to minimize ments are limited to animal experiments and evidence of clin-
secondary inflammatory damage to the ocular surface.33,34 ical benefit from human reports remains lacking.38 While
If necessary, systemic corticosteroids can be considered to roles for systemic tetracycline and topical citrate as adjunctive
augment suppression of inflammation with fewer local treatments have been suggested,33,44 no well-controlled re-
side effects. Furthermore, in sufficiently severe injuries ports of either treatment in humans with ocular chemical in-
where prolonged inflammation is likely to be encountered, juries have been published to date.
a steroid-sparing agent such as mycophenolate mofetil In contrast to enzyme inhibition, ascorbic acid
may also be used (discussed in Section V below). supplementation directly promotes corneal stromal
repair.42,43,45 Ascorbate, an essential cofactor for wound
B. Prevention of Stromal Breakdown healing, has been shown in animal studies to acutely
Corneal ulceration and melting occur relatively decrease in concentration (by as much as two-thirds) in
frequently after severe chemical injuries (Figure 3). Reactive the aqueous following an alkali injury.46,47 This low level
inflammatory cells release enzymes such as collagenases and is sustained for 3 days in a moderate injury, but persists
matrix metalloproteinases (MMPs), which potentiate for at least 30 days in a severe injury. Collagen synthesis
corneal thinning.37 Collagenase inhibitors (e.g., tetracy- is impaired as a result of persistently lowered aqueous
clines, citrate, cysteine, acetylcysteine, sodium ethylenedi- concentrations of ascorbate. As mentioned above, ascor-
amine tetra acetic acid [EDTA], penicillamine) and bic acid may play a beneficial role as an adjunct by
proteinase inhibitors (e.g., aprotinin) have been found to restoring a favorable wound healing equilibrium in pa-
prevent corneal thinning experimentally and/or clinically af- tients with ocular chemical injuries that are receiving
ter chemical injuries.2,10,37-40 corticosteroid therapy.33,34
Tetracyclines are thought to suppress neutrophil-
mediated tissue damage through several mechanisms, C. Promotion of Re-epithelialization and Repair
including the inhibition of neutrophil migration and degran- In addition to standard therapy, which includes frequent
ulation, suppression of the synthesis of oxygen radicals, and preservative-free lubricants and prophylactic antibiotic
Table 2. Dua’s classification of the severity of ocular surface burns

Limbal involvement Conjunctival involve-
Grade Prognosis (clock hours) ment (%)* Analogue scaley
0
I Very good 0 0 0
0:1 to 3
II Good 3 30 1 to 29:9
3:1 to 6
III Good >3 to 6 >30 to 50 31 to 50
6:1 to 9
IV Good to guarded >6 to 9 >50 to 75 51 to 75
9:1 to 11:9
V Guarded to poor >9 to <12 >75 to <100 75:1 to 99:9
12
VI Very poor 12 (Total limbus) 100 (Total conjunctiva) 100
* Refers only to bulbar conjunctiva (up to and including conjunctival fornices).
y The analog scale is calculated through division of limbal involvement by conjunctival involvement.

Surface Ecosystem (PROSE; originally called the Boston

Scleral Lens) has been reported to be successful in multiple
studies examining its utility in patients with thermal burns
and a variety of other ocular surface diseases.11,50-53
2. Amniotic Membrane Transplantation

An amniotic membrane may be used as a permanent
surgical graft to provide a basement membrane for epitheli-
alization or as a patch where it acts as a biological bandage
contact lens.54-57 Both as a graft and as a patch, amniotic
membranes have been shown to promote epithelialization
and to reduce inflammation, scarring, and neovasculariza-
tion.55,56,58 It works in part by trapping and inducing
apoptosis of the post-injury inflammatory infiltrate, which
Figure 1. Eye after combined chemical and thermal injury to the lids
is primarily composed of neutrophils and macrophages.59
and ocular surface due to an explosion of a pyrotechnic device. There is
total corneal epithelial defect and 360 limbal ischemia (Roper-Hall Animal studies and noncomparative case series have sup-
grade IV and Dua’s grade VI). ported the effectiveness of amniotic membrane transplantation
(AMT) in ocular surface reconstruction after chemical in-
juries.60-62 For patients with acute ocular burns, multiple ran-
domized clinical trials have shown that AMT offers better
drops, a number of measures may be used to further acute pain reduction and earlier epithelialization in patients
enhance repair of ocular surface tissue in the acute setting. with mild to moderate grade injuries.63,64 However, no differ-
ences in long-term benefits were detected in these studies and
1. Bandage Contact Lens a systematic review of the literature found insufficient evidence
Therapeutic bandage contact lenses protect a compro- for the use of AMT in the setting of acute ocular burns.65
mised ocular surface and promote epithelialization through Nonetheless, AMT is most often employed as an adjunct to
improvement in the spreading of tear fluid over the ocular medical therapy in patients with severe ocular injuries.12,56,66-73
surface. Of note, silicone hydrogel contact lenses have been More recently, AMT has been applied to the cornea us-
found to confer improved corneal health and patient satisfac- ing a carrier with the amniotic membrane secured to a flex-
tion among frequent lens wearers and may be preferable.48 In ible plastic ring (ProKera, Bio-Tissue, Inc., Miami, FL). The
patients with relatively severe pain and photophobia, large- ring-amniotic membrane complex is placed onto the ocular
diameter gas-permeable scleral contact lenses can establish surface without any need for suturing or gluing in the office
a fluid-filled pre-corneal vault, providing even greater protec- or at the bedside. Using this technique, the amniotic mem-
tion to the cornea from desiccation and friction from the eye- brane usually lasts days to weeks (typically around 1 week)
lids during blinking.49 The Prosthetic Replacement of Ocular and its application can be repeated. In a series of chemical
Table 3. Irrigation solutions for the immediate phase management of ocular chemical injuries
Grade of available Evidence-based
Irrigation solution* Proposed advantages evidencey recommendations
Tap water (H2O) Ubiquitous availability C The choice of most effective
solution is equivocal. Pub-
Phosphate buffer Correction of pH D lished reports are limited to
Purpose-designed solutions Isotonic to stroma C in vivo experiments in animal
(e.g. NS, LR, BSSP) Patient comfort (BSSP) models and, at best, small
observational studies with
Amphoteric solutions (e.g. Hypertonic to stroma C significant limitations. Given
DiphoterineÒ) Rapid pH correction the importance of prompt
Non-specific chelation and continuous treatment,
Faster re-epithelialization the most immediately avail-
(mild injuries only) able and sufficiently abun-
dant solution should be
utilized.
* Rinsing with an aqueous solution should be initiated immediately and continued until confirmation of adequate neutralization of the tear film
pH by a health care professional.
y The grades of evidence are based upon the rating scale (A to D) put forth by the Oxford Centre for Evidence-based Medicine.
NS, normal saline; LR, lactated ringers; BSSP, balanced saline solution plus.

Figure 2. Algorithm for the management of acute phase after chemical burn.
injury patients, the use of Prokera appeared to facilitate procedure is to re-establish the limbal blood supply and to
rapid limbal stem cell recovery and promote epithelial heal- promote ocular surface repair.87 After debridement of
ing.68 However, future studies with adequate control groups necrotic tissue, tenonplasty involves the advancement of
are necessary to further elucidate its clinical benefit. viable vascular Tenon’s layer tissue up to the limbus that
is then secured to the sclera. Tenonplasty may be combined
3. Autologous Serum with AMT with or without lamellar corneal patch grafting.88
Human serum contains many soluble factors that pro- This intervention enables the reconstruction of the conjunc-
mote healing in various tissues including the cornea.47,74-79 tival matrix and limbal vascularity, which prevents anterior
Autologous serum has been shown to be effective in pro- segment necrosis, scleral ischemia, melting, and sterile ulcer-
moting wound healing in patients with persistent epithelial ation.4,89 Most recently, tenonplasty combined with buccal
defects due to a variety of etiologies, including chemical mucosal autograft has also demonstrated benefit for patients
injury.80 Umbilical cord serum has likewise been shown to with sclerocorneal melt after a chemical injury.90
be very effective in accelerating epithelial healing in acute
chemical injuries in both animal models and human studies; 5. Treatment of High Intraocular Pressure
however, difficulty associated with acquiring such serum is Chemical agents that reach the trabecular meshwork can
an important barrier to treatment.81,82 lead to an elevation in intraocular pressure (IOP), a compli-
More recent studies have reported the use of platelet rich cation that can be easily overlooked. Glaucoma after alkali
plasma (PRP) as a variation of autologous serum in patients injury may be immediate (less than a month) or delayed
with ocular chemical injuries.78,83-86 These reports include (months).91,92 Mechanistically, immediate injury may cause
both topical and subconjunctival injection of PRP and sug- tissue damage with subsequent impairment of aqueous hu-
gest it is a safe and effective adjunct to standard medical mor outflow channels. In the largest study to date, Kuckel-
treatments. The mechanism of action of autologous PRP is korn et al reviewed 66 cases (90 eyes) of severe chemical
likely the same as that of autologous serum. However, it injuries and found that early glaucoma occurred in 14
has a higher concentration of growth factors and platelets, (15.6%) eyes and late glaucoma occurred in 20 (22.2%)
which may lead to faster healing. eyes.93
4. Tenonplasty V. MANAGEMENT OF CHRONIC PHASE

Tenonplasty is an intervention that may be utilized in Management of chronic ocular disease after a chemical
severe injuries that cause loss of limbal vascularity and sub- injury can pose major therapeutic challenges and requires
sequent anterior segment necrosis. The intent of the a multidisciplinary approach involving cornea, oculoplastic,

Table 4. Therapies for the acute phase management of ocular chemical injuries
Therapeutic aim Treatment evidence* recommendations Suggested regimen
Reduction of Corticosteroids C Retrospective cohort Intense therapy
Inflammation studies suggest benefit 7 days with subse-
with topical treatment quent taper
in non-severe injuries.
Stromal Breakdown Tetracyclines D Literature is limited to Tetracycline 250 mg
Prophylaxis animal studies and PO QID. Doxycycline
expert opinion. 100mg PO bid
Citric acid C A single cohort study Topical Citrate 10%
suggests a role as an hourly or bihourly
adjunct in moderate
injuries.
Ascorbic acid C Retrospective cohort Ascorbate 0.5 to 2 g
studies suggest benefit QID PO þ topical
as an adjunct to Ascorbate 10% hourly
corticosteroids. or bihourly
Promotion of Epithelial Bandage contact lens C Retrospective cohort Daily wear of soft BCL
Repair (BCL) studies suggest benefit or PROSE scleral lens
but are limited to non- (in severe cases)
chemical injuries.
Amniotic membrane C Multiple case series Perform within 1 week
transplantation suggest benefit in se- of injury
vere injuries.
Autologous serum C A randomized Topical platelet-rich
controlled trial sug- plasma 10x QD
gested benefit in non-
mild injuries.
Tenonplasty C Observational studies As needed upon
suggest benefit in pa- recognition of scleral
tients with scleral pathology
ischemia or melt.
Treatment of high D Extrapolation from Topical
intraocular pressure cohort studies suggests agents procedural
benefit in all patients. intervention (e.g.
paracentesis)
* The grades of evidence are based upon the rating scale (A to D) put forth by the Oxford Centre for Evidence-based Medicine.
and glaucoma specialists. Much effort has been made to rule, all eyelid and fornix abnormalities should be corrected
develop more effective surgical interventions for the ocular before any limbal or corneal surgery is performed.
surface disorders in these patients. The goal of these surgical Symblepharon and ankyloblepharon are best classified as a
interventions is to restore normal ocular surface anatomy form of conjunctival deficiency (Figure 5). The surgical
and visual function. The typical order for surgical interven- approach depends on the severity of the symblepharon.68,88,94,95
tion is: correction of eyelid abnormalities, followed by man- In both mild and moderate symblephara, multiple obser-
agement of glaucoma, then ocular surface reconstruction/ vational studies have demonstrated that the fornix can be
transplantation, and finally keratoplasty (Figure 4, Table 5). reconstructed with the help of amniotic membrane trans-
plantation to the denuded surfaces.68,73,96 Amniotic mem-
A. Fornix and Eyelid Reconstruction brane can be sutured or glued to the surgical site. In
Ocular surface exposure due to loss of eyelid tissue, con- addition, antimetabolites such as mitomycin-C (MMC) or
tractures, and/or symblephara is a major contributing factor 5-fluorouracil can be simultaneously applied to the subcon-
to corneal complications including ulceration and perforation. junctival forniceal area to decrease the chance of recurrent
Significant exposure due to severe eyelid injury may occasion- forniceal shrinkage.96
ally necessitate corneal coverage by a mucous membrane graft In severe and extensive symblepharon or ankyloble-
or even skin graft to prevent corneal perforation. As a general pharon formation, new mucosal tissue must be transplanted.

for the use of nasal mucosa rather than buccal mucosa in or-
der to replenish the mucus-secreting capabilities of the
ocular surface.101
In addition to surgical intervention, the most important
element in the success of eyelid and fornix reconstruction is
the control of ocular surface inflammation, which drives the
cicatricial process. It is generally recommended that surgical
intervention be delayed as long as possible in order to avoid
surgery on “hot” eyes.102 In eyes with chronic inflammation,
treatment with systemic immunosuppression is advised in
preparation for surgery.103 Oral prednisone on a tapering
dose along with mycophenolate may be started several months
before surgery; however, severe inflammation may require
additional or stronger agents. Moreover, the use of systemic
steroids in the perioperative period helps to mitigate postoper-
Figure 3. Severe corneal thinning after severe chemical burn.
ative inflammation and improve surgical success rates.104
B. Management of Glaucoma
In cases of unilateral injury, an autologous conjunctival graft Ocular chemical injuries can lead to significant loss of
from the fellow eye can be used to replace destroyed con- vision not just from direct injury to the ocular surface
junctiva.97 In bilateral or extensive disease, mucosal mem- but also from glaucoma. Secondary chronic inflammation
brane grafts (MMGs) may be necessary for full fornix may lead to synechiae and angle closure. However, the
reconstruction and restoration of normal lid-globe relation- development of glaucoma may be partially counteracted
ships.98-100 Recently, cultivated oral mucosal epithelial by ciliary body necrosis in deeply penetrating alkali in-
transplantation (COMET) has been reported for ocular sur- juries.92 In addition, other factors such as damage to the
face reconstruction. The advantage of COMET is that the trabecular meshwork, severe uveitis, long-term steroid
transplanted epithelial sheet contains stem cells that help use, phacomorphic or phacolytic mechanisms, and
to reconstruct the corneal surface and maintain the integrity contraction of the sclera may also contribute to chronic
of the ocular surface.98 In addition, some authors advocate glaucoma in these patients.
Figure 4. Algorithm for the management of chronic phase after chemical burn.

Table 5. Therapies for the chronic phase management of ocular chemical injuries
Pathology Treatment evidence* recommendations
Fornix and Eyelid Disease AMT þ anti-metabolite (e.g. C Multiple interventional case
MMC, 5-FU) series suggest benefit in pa-
tients with mild to moderate
disease.
MMG C Small interventional case se-
ries suggest benefit in pa-
tients with severe disease.
Glaucoma Standard algorithm C Observational results suggest
benefit. CPC may be of
particular utility given the
complication profile associ-
ated with tube placement in
patients with chemical injury.
Limbal Stem Cell Deficiency Pharmacotherapy sectoral C Multiple case series suggest
surgical intervention reversibility of partial LSCD
with conservative measures.
In patients with involvement
of the central cornea, sectoral
procedures (e.g. partial LSCT)
have also demonstrated
benefit.
CLAU, CLET, SLET C Multiple interventional case
series demonstrate high rates
of visual recovery in patients
with unilateral total LSCD.
KLAL, lr-CLAL C Multiple interventional case
series suggest benefit in pa-
tients with bilateral total
LSCD. Long-term results are
favorable if adequate immu-
nosuppression is used.
Keratoprosthesis C Multiple interventional case
series suggest benefit as
salvage therapy after failed
LSCT.
Corneal Opacification PK, DALK C Multiple case series suggest
benefit for visual rehabilita-
tion. A staged approach with
antecedent LSCT is advised in
patients with total LSCD.
Keratoprosthesis C Multiple interventional case
series suggest benefit as
salvage therapy after failed
corneal transplantation.
* The grades of evidence are based upon the rating scale (A to D) put forth by the Oxford Centre for Evidence-based Medicine.
AMT, amniotic membrane transplantation; MMC, mitomycin-C; 5-FU, 5-fluorouracil; MMG, mucous membrane graft; CPC, cyclo-
photocoagulation; LSCD, limbal stem cell deficiency; LSCT, limbal stem cell transplantation; CLAU, conjunctival limbal autograft; CLET, cultivated
limbal epithelial transplantation; KLAL, keratolimbal allograft; lr-CLAL, living-related conjunctival limbal allograft; PK, penetrating keratoplasty;
DALK, deep anterior lamellar keratoplasty; SLET, simple limbal epithelial transplantation.
Secondary glaucoma is common following a severe chem- 50% of eyes in patients with severe ocular surface disease
ical injury, with an estimated incidence of over 20%; however caused by ocular chemical or thermal injuries.105 Lin et al iden-
it may go unrecognized since the focus of care is often on the tified an association between glaucoma and the severity of the
ocular surface.105 Tsai et al diagnosed glaucoma in more than ocular chemical injury: 84% of eyes with ocular chemical

Depending on the extent of the disease, LSCD is classified

as either partial or total (Figure 6A and B). Clinical findings
of LSCD include a loss of the palisades of Vogt, opaque
epithelium, whorl-like epithelial staining, recurrent and/or
persistent epithelial defects, superficial neovascularization,
and ultimately corneal melting (from non-healing defect)
or stromal scarring and neovascularization.108
Treatment depends on the extent of the injury and the
involvement of the central cornea. Many patients with cen-
tral cornea-sparing partial LSCD can be managed with con-
servative measures, such as nonpreserved lubrication and
autologous serum eye drops.77,109-111 Surgical management
of partial LSCD may be considered in cases with central
cornea involvement.111 Sectoral conjunctivalization of the
cornea may be effectively managed in select cases with
Figure 5. Symblepharon: Severe symblepharon formation.
sequential sector conjunctival epitheliectomy (SSCE) or
AMT that may mitigate or prevent recurrent conjunctival
ingrowth.61,62,68,112,113
injuries R-H grade III or higher required long-term glaucoma Limbal stem cell transplantation (LSCT) may be consid-
medication.92 In addition, glaucoma can occur after therapeu- ered for patients with more extensive corneal conjunctivali-
tic corneal procedures, with published incidences ranging from zation.103,112,114-120 LSCT is not recommended during active
10% to over 50%.92 inflammation and should be delayed until ocular surface
Management of glaucoma secondary to ocular chemical inflammation has subsided or is well controlled with medi-
injury is challenging.92,106,107 While medical therapy is the cations. In addition, all eyelid abnormalities (e.g., entropion,
standard initial treatment, the chronicity of the disease trichiasis, symblepharon) should be addressed before
and detrimental effects of eye drops on the ocular surface considering LSCT (Figure 7).103,115,116,121-124
are a cause for concern. Accordingly, procedural interven- Limbal stem cells can be harvested from autologous or
tions are generally considered earlier in these patients. nonautologous sources.103,125-129 A conjunctival limbal
Cyclophotocoagulation may also be indicated, particularly autograft (CLAU) taken from the healthy fellow eye is
in cases with advanced conjunctival shrinkage and scar for- considered the most effective surgical procedure in patients
mation. Despite the prognostic importance of glaucoma in with total unilateral LSCD. It produces excellent results,
these patients, no prospective studies evaluating the utility often with complete regression of corneal neovasculariza-
of various IOP treatment strategies have been performed tion such that successful re-epithelialization and functional
to date. vision is achieved in 80% to 90% of patients
(Figure 8).130,131 Cultivated limbal epithelial transplanta-
C. Management of Limbal Stem Cell Deficiency tion (CLET) is a suitable alternative in cases of total unilat-
Limbal stem cells deficiency (LSCD) is one of the most eral LSCD or in cases of bilateral LSCD when the damage
visually significant long-term sequelae of severe chemical is more severe in one eye.100,120,132-139 Pooling the results
injury. Healthy limbal stem cells act as a barrier against in- of previous studies, the overall success rate is estimated
vasion of the cornea by conjunctival tissue. In LSCD, to be 72% of 720 eyes while 63% had 2 lines of improve-
conjunctival tissue migrates toward the central cornea, a ment in visual acuity at last follow-up compared to
process called conjunctivalization, the hallmark of LSCD. baseline.140
Figure 6. A: Nasal and

temporal pseudopterigia in a
case with partial limbal stem
cell deficiency due to severe
alkaline chemical burn. B: Total
LSCD in a case with severe
chemical burn.

Figure 7. Upper lid entropion and trichiasis in a case with total LSCD Figure 9. Keratolimbal allograft surgery in a case with total limbal stem
due to severe alkaline chemical burn. cell deficiency due to acidic chemical burn.
Living-related conjunctival limbal allograft (lr-CLAL) a 2 2 mm strip of donor limbal tissue from the healthy eye
and keratolimbal allograft (KLAL) are surgical alternatives is divided into 8-10 small pieces and is evenly distributed
in patients with bilateral LSCD.103,125-129 Lr-CLAL utilizes over an amniotic membrane placed on the cornea.148
tissue from one eye (or occasionally both eyes) of a patient’s For patients receiving LSCT from an allogeneic source,
first-degree blood relative, a method that benefits from fresh systemic immunosuppression consisting of steroids (short-
tissue that has a strong genetic similarity to the patient. Lr- term), tacrolimus (or cyclosporine), and mycophenolate
CLAL also has the advantage of providing viable conjunc- (or azathioprine) is necessary to prevent limbal allograft
tival tissue, which may be used in patients with severe rejection.103,116,122,123 Close collaboration with an organ
conjunctival deficiency. In comparison, KLAL, which uti- transplant team is generally required for the optimal man-
lizes cadaveric tissue, is more accessible and offers more agement of the immunosuppression regimen and moni-
stem cells because of larger clock hours of available graft tis- toring of its associated side effects.149
sue (Figure 9). LSCT, with or without corneal transplantation, is an
There are many additional surgical options for bilateral effective procedure for anatomical and visual rehabilitation
LSCD, including the Cincinnati procedure, which is a com- of eyes with total LSCD. Complications primarily arise
bination of lr-CLAL with KLAL.141 COMET or allogeneic from immunologic rejection, chronic ocular surface expo-
CLET are other surgical options.142-146 Transplantation of sure, and graft-related complications (thickness, position,
autologous conjunctival epithelial cells cultivated ex vivo and alignment).121,124 These complications may ultimately
(EVCAU) on a denuded human amniotic membrane graft lead to ocular surface epithelial breakdown (including
has also been used in patients with total LSCD.147 In addi- persistent epithelial defect), thinning, and progressive
tion, another variation of LSCT has been described in which corneal conjunctivalization. Good tear film status, full
correction of adnexal abnormalities, proper handling and
dissection of limbal grafts, and adequate immunosuppres-
sion are the most important factors in preventing complica-
tions.124 Ocular surface reconstruction using different tissue
engineering methods is an emerging option that is currently
an active area of research.150-153
D. Corneal Transplantation
Conventional penetrating keratoplasty (PK) or deep
anterior lamellar keratoplasty (DALK) can be performed
for visual rehabilitation in patients with extensive stromal
scarring after chemical injury.154 In cases of partial LSCD
with opacification of the central cornea, primary PK or
DALK may be adequate; however, keratoplasty can aggra-
vate a compromised ocular surface with a borderline stem
cell reserve in some cases. In total LSCD with complete
Figure 8. Patient with total LSCD after chemical burn who was suc-
vascularization and opacification of the cornea, corneal
cessfully treated with CLAU (2 years after surgery).
transplantation should be preceded by LSCT; otherwise,

corneal transplantation will fail.155 Staged procedures are

preferred over a combined approach, and it is recommended
to wait at least 3 months for the surface to stabilize after
LSCT before proceeding with keratoplasty (Figure 10).156
Studies show that staged procedures offer significantly
greater transplant survival; approximately 80% of grafts per-
formed at least 6 weeks after LSCT survive past 1 year
compared to only 25% of nonstaged procedures. Long-
term outcomes similarly favor staged procedures; the
median graft survival time after a staged procedure has
been reported to be 4 years compared with 1 year for con-
current LSCT and PK. Given the risk of immunologic graft
rejection, DALK may be preferred over PK whenever
possible. The use of systemic immunosuppression can Figure 11. Boston Type I keratoprosthesis in a patient with LSCD due
reduce the risk of endothelial graft rejection in very high- to chemical injury. (Courtesy of Dr. Maria S. Cortina, University of Illinois
at Chicago).
risk cases.102,157,158
E. Keratoprosthesis Surgery
Surgical placement of an artificial cornea is an effective prevented or successfully treated with current postoperative
means of managing repeat corneal graft failure or corneal management practices. However, glaucoma is an irreversible
limbal stem cell failure in patients with unilateral or bilateral process and occurs with greater frequency in patients with
chemical injury.159-164 Currently, the Boston Type 1 kerato- chemical injuries. Accordingly, early detection and treat-
prosthesis (B1-KPro) is the most widely used device for ment of elevated IOP are of particular importance in this
restoring vision in patients who have failed previous corneal population. Coupling the baseline incidence of glaucoma
procedures.159,165 Placement of a keratoprosthesis with or in chemical burn patients with the high risk of progression
without a shunt may be considered 6 months after inflam- as a result of B1-KPro implantation, we recommend consid-
mation subsides (Figure 11).106,166 The B1-KPro study eration of a LSCT procedure prior to use of a keratoprosthe-
group found excellent anatomical retention in patients sis in appropriate patients.
with ocular chemical injuries: 94% after 1 year and 89% after The Boston Type 2 keratoprosthesis (B2-KPro) and
2 years.167 the osteo-odonto-keratoprosthesis (OOKP) are last resort
The ideal candidate for keratoprosthesis implantation options usually reserved for patients with bilateral
must be amenable to long-term risks, the need for life- corneal blindness in the setting of severe dryness and
long regular follow-up, adherence to daily antibiotic prophy- keratinization.172,173 Indications include severe chemical
laxis, and other chronic maintenance issues.160,162,163 or physical injury with loss of lids. In patients with a re-
Reported long-term complications include retroprosthetic sidual tear film, other surgical interventions (e.g., ocular
membrane formation, IOP elevation and/or glaucoma pro- surface reconstruction with stem cell transplant) should
gression, sterile corneal stromal necrosis or corneal thin- be considered prior to B2-KPro or OOKP
ning, infectious keratitis, persistent epithelial defect, retinal implantation.174
detachment, sterile uveitis/vitritis, and infectious endoph-
thalmitis.168-171 Most of these adverse events can be
VI. FUTURE HORIZONS
Most patients with mild-to-moderate chemical injuries
can achieve a stable ocular surface and functional visual
acuity with current management strategies. However,
most severe chemical injuries have an unfavorable prog-
nosis. A substantial number of patients with severe injuries
go on to develop significant corneal and limbal stem cell
disease, often complicated by neovascularization, melts,
and perforations. Furthermore, extensive conjunctival scar-
ring and symblepharon formation often progress in the
months following the injury, thus requiring major recon-
structive surgical procedures. Therefore, more effective
treatments are needed to prevent the most visually
disabling sequelae of chemical injuries. The two upcoming
Figure 10. Patient with total LSCD after chemical burn who underwent therapeutic strategies described below may potentially
KLAL and PKP with systemic immunosuppression (18 months after
improve the outcomes of our treatment in chemical
surgery).
injuries.

A. Anti-angiogenic Therapy limbus, and play an important role in tissue repair and
Corneal neovascularization (CNV) is one of the major maintenance. A number of clinical trials aimed at evaluating
complications of ocular chemical injuries. CNV leads to the safety and efficacy of MSCs in the promotion of cardiac
loss of corneal transparency and immune privilege.175-179 tissue regeneration, modulation of systemic immune dis-
Accordingly, the prevention and reversal of CNV is of eases, and healing of soft tissue injuries are currently under-
utmost importance for improving the visual outcome after way.211-217 In animal models of chemical injury, MSCs have
a chemical injury. The pathophysiologic mechanism of been shown to accelerate corneal wound healing, attenuate
corneal angiogenesis (hemangiogenesis and lymphangiogen- inflammation, and modulate corneal neovasculariza-
esis) after chemical injury is multifactorial, involving inflam- tion.209,218-227 These effects have been shown to be mediated
mation and production of angiogenic factors, as well as loss in part through secreted factors such as TSG-6.228 Overall,
of the natural anti-angiogenic milieu. A number of impor- MSC-based therapies are likely to be beneficial for manage-
tant angiogenic factors, such as basic fibroblast growth fac- ment in both the acute phase after chemical injury to help
tor, vascular endothelial growth factors (VEGFs), and control inflammation and chronically to help restore a
transforming growth factor-a and -b, placenta growth fac- more normal ocular surface environment.
tor, IL-1, TNF-a, IL-8, monocyte chemoattractant-1,
MMPs, and platelet activating factor have been
implicated in corneal neovascularization.175 In addition, VII. SUMMARY
loss of anti-angiogenic factors such as soluble fms-like tyro- Chemical injuries can have devastating consequences for
sine kinase-1, angiostatin, endostatin, restin, neostatin, the ocular surface and periocular structures. The overall goal
thrombospondins, pigment epithelium-derived factor, of treatment is restoration of normal ocular surface anat-
arrestin, canstatin, tumstatin, and angiopoetin-2 likely play omy, a process that begins with immediate treatment, fol-
an important role in the breakdown of corneal avascular lowed by measures to control inflammation, and
privilege.175,180 ultimately reconstructive procedures to restore a normal
Numerous agents with anti-angiogenic effects have shown ocular surface environment. With advancements in regener-
potential benefit in inhibiting corneal neovascularization in ative medicine, the clinical outcomes are expected to further
experimental models of chemical injury.181-204 In recent improve.
years, the availability of anti-VEGF agents (e.g., bevacizumab,
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Clinical Science

PEDRAM HAMRAH, MD, EDITOR

Current and Upcoming Therapies

48 THE OCULAR SURFACE / JANUARY 2017, VOL. 15 NO. 1 / www.theocularsurface.com

(e.g., DiphoterineÒ) have been proposed as a preferred op-

III. MANAGEMENT OF IMMEDIATE PHASE A. Anti-inﬂammatory Therapy

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Table 1. Roper-Hall classiﬁcation of the severity of ocular surface burns

Table 2. Dua’s classiﬁcation of the severity of ocular surface burns

50 THE OCULAR SURFACE / JANUARY 2017, VOL. 15 NO. 1 / www.theocularsurface.com

Surface Ecosystem (PROSE; originally called the Boston

2. Amniotic Membrane Transplantation

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4. Tenonplasty V. MANAGEMENT OF CHRONIC PHASE

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Depending on the extent of the disease, LSCD is classiﬁed

Figure 6. A: Nasal and

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corneal transplantation will fail.155 Staged procedures are

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