Download Treating the Nonhealing Epithelial Defect

COMPREHENSIVE CLINICAL CARE BONUS FEATURE
Treating the Nonhealing
Epithelial Defect
An overview of standard and investigational therapies for persistent corneal epithelial defects.
BY BENNIE H. JENG, MD
T
he corneal epithelium, composed of nonkeratinized, stratified squamous epithelial cells, is essential to the normal functioning of the eye. In addition to providing a transparent conduit for visual
stimuli to pass to the retina, the cornea—and specifically
the corneal epithelium—provides one of the first lines of
immunologic defense for the eye. The epithelial cells are
connected by hemidesomsomes and gap junctions that
prevent infectious agents from penetrating the eye under
normal circumstances. The maintenance of a healthy functioning corneal epithelium is dependent on a healthy normal corneal nerve network.1 A breach in the integrity of the
corneal epithelium results in a wound-healing response.
Although most corneal epithelial defects heal quickly and
without incident, under certain conditions the epithelial
defect may be slow to heal, or it may not heal at all.2 When
these defects do not heal within the normal time frame
(usually defined in the literature as 2 weeks), they become
known as persistent epithelial defects (PED).3
Fortunately, PED of the cornea are uncommon, but in
addition to their immediate adverse effects on vision and
often on comfort, PED can have serious consequences for
the health of the eye that include infection, scarring, melting, and perforation. Etiologies for PED include dry eye,
exposure keratopathy, limbal stem cell deficiency, diabetic
keratopathy, neurotrophic keratopathy following corneal
transplant surgery (involving the anterior portion of the
cornea), and herpetic infections.3
Numerous standard therapies can be used in an attempt
to heal PED. Additionally, a number of new therapies have
recently been introduced, and there are promising alternatives in the pipeline. This article reviews these available and
potential treatment options for treatment of PED.
STANDARD THERAPIES
Listed below in order is a step-wise approach to standard
therapies for PED. Steps may sometimes be skipped based
on individual circumstances.
Aggressive lubrication. In general, traditional medical
therapy of PED starts with aggressive lubrication using
preservative-free artificial tears and ointments. In many
instances, the ocular surface fails to heal simply because the
surface is too dry.
Discontinuation of medications. On occasion, epithelial
defects fail to heal because the patient is using topical medications that contain preservatives toxic to the corneal
epithelium, such as benzalkonium chloride. Sometimes the
medications themselves are toxic and inhibit healing; these
include fortified vancomycin drops. Simply stopping these
medications, if appropriate based on the patient’s overall
ocular situation, can be curative for PED.
Punctal occlusion. If the ocular suface can be freed from
the toxic effect of unnecessary medications, then punctal
plugging can augment the beneficial effects of aggressive
lubrication by keeping the lubrication on the eye for a
longer time. It is not recommended to plug the puncta
when toxic medications are still being used because this will
keep the toxicity in contact with the ocular surface for even
longer.
Bandage soft contact lens. Bandage soft contact lenses
are effective devices for treating PED. They can protect the
fragile, healing epithlium from sloughing because of blinking. It is important, however, to keep the eye lubricated to
protect the lens from drying out and sticking to the ocular
surface. Therefore, it is recommended for all patients using
bandage soft contact lenses to apply preservative-free artificial tears every 1 to 2 hours. Furthermore, there is a
known risk of infectious keratitis with contact lens use, so
it is recommended to prescribe a broad-spectrum topical
antibiotic drop such as a fourth-generation fluoroquinolone or polymixin B-trimethoprim combination.
Even with antibiotic prophylaxis, infectious keratitis can
occur, so patients should be educated regarding the warning signs of infectious keratitis. However, because in many
instances PEDs are neurotrophic, patients may not notice
symptoms associated with infectious keratitis. Frequent
follow-up in these patients is of utmost importance.
Pressure patching. Pressure patching is an alternative to
bandage soft contact lenses. Although in routine corneal
epithelial defects (not PED) pressure patching is a popular
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COMPREHENSIVE CLINICAL CARE BONUS FEATURE
TAKE-HOME MESSAGE
• A step-wise approach to standard PED therapies may
include aggressive lubrication, discontinuation of
medications, punctal occlusion, bandage contact lenses,
pressure patching, debridement, and tarsorrhaphy.
• Alternative therapies include amniotic membrane grafting,
topical autologous serum, and limbal stem cell
transplantation.
• Thymosin beta 4, Nexagon, and scleral contact lenses are
currently being investigated for treatment of nonhealing
epithelial defects.
treatment method, it has been found in some studies to
actually inhibit the healing process.4,5 Additionally, as PEDs
often require exteneded time to heal, prolonged patching is
inconvenient and impractical. Patching for longer than 48
hours at a time is generally not recommended.6 It should also
be noted that infectious keratitis can occur with patching.
Debridement. On many occassions, the epithelial cells at
the leading edge of the PED become stagnant and thicken,
inhibiting further migration of the cells. When standard
medical therapies fail, debridement of the leading edges of
the PED can remove these stagnant cells and promote the
more peripheral epithelium to migrate and heal the defect.
Tarsorrhaphy. Although not used as frequently as it
probably should be, tarsorrhaphy is an excellent tried-andtrue methods to heal a PED. Closure of all or part of the eyelid fissure allows the ocular surface to heal itself even under
the most severe of circumstances. Short-term closure can be
achieved using tape, which lasts 1 to 2 days, or cyanoacrylate glue, which lasts 3 to 5 days. Temporary closure with
sutures and bolsters can last up to 6 weeks and can be performed in the office. Even permanent tarsorrhaphy, which
can last indefinitely, can be performed in a minor procedure
room in the office.
NEWER THERAPIES
In some cases, standard medical therapies for treating
PED do not work. The following therapies have recently
been popularized.
Amniotic membrane grafting. This approach has been
suggested for use in accelerating the corneal epithelial wound
healing process in PED.7,8 Additionally, it acts as a temporary
bandage on the ocular surface, as it is believed that amniotic
membrane contains growth factors and other substances
that are crucial to the proliferation and migration of the
corneal epithelial cells. Amniotic membrane, now available
commercially in fresh-frozen (Amnion; Bio-Tissue, Inc., Miami)
or freeze-dried (AmbioDry2; IOP Ophthalmics, Costa Mesa,
California) forms, can be sewn into place over the PED. More
recently, it has been suggested that the membrane can be
glued in place using fibrin glue.9 Amniotic membrane is also
available as a self-retaining device (ProKera; Bio-Tissue, Inc.)
that can be inserted in the office.
Autologous serum. Topical autologous serum has been
reported to be efficacious in treating persistent epithelial
defects.10-15 First described for this purpose in 1999 by
Tsubota and colleagues,9 this modality has become quite
popular. With use of autologous serum, 47% to 83% of PED
recalitrant to standard therapies healed within 4 weeks of
initiation of autologous serum therapy.10-15 A recent study
found that, for PED recalictrant to standard therapies, the
length of time a defect is left open prior to treatment is
directly related to the length of time required for healing.15
Thus, theoretically, the earlier in the course of the disease
treatment is initiated, the faster the PED will heal.
Unfortunately, the use of topical autologous serum is often
troublesome because there is no standardized protocol for
processing whole blood to be made into autologous serum
eyedrops. Therefore, few clinical laboratories and clinics are
equipped to prepare this product. Liu and colleagues16 have
recommended an optimized protocol for the processing of
whole blood for autologous serum, but this protocol has
not yet been validated.17 Additionally, at this time, regulatory
restrictions are still limiting the ability to produce autologous serum for therapeutic use in some areas.18 Umbilical
cord serum has been investigated as an alternative to autologous serum,19 given the potentially higher levels of nutrients in this product, but there are regulatory issues with
using this blood product as well.
Limbal stem cell transplantation. In the event that an
identifiable etiology can be established, specific treatments
can sometimes be instituted. For example, in PED secondary
to limbal stem cell deficiency, limbal stem cell transplantation can be employed.
IN THE PIPELINE
Several novel treatments are now being tested for use in
healing the nonhealing corneal epithelium.
Thymosin beta 4. Thymosin beta 4 (Tb4) is a synthetically
produced copy of a naturally occurring 43-amino acid peptide that is found in high concentrations in most tissue
types, with the highest concentrations in blood platelets
and white blood cells, and extracellularly in blood plasma
and wound fluid.20 It is one of a family of at least 16 highly
conserved peptides, collectively called beta-thymosins,
which are present in high concentrations in almost every cell
type. Tb4 has wound-healing and antiinflammatory properties, and it is thought to exert its therapeutic effect through
promotion of keratinocyte and endothelial cell migration,
increased collagen deposition, and stimulation of angiogenesis.21 Preclinical and animal models have suggested that this
compound has applications not only for dermal epithelial
26 CATARACT & REFRACTIVE SURGERY TODAY EUROPE SEPTEMBER 2011
COMPREHENSIVE CLINICAL CARE BONUS FEATURE
healing, but also for the corneal epithelium. A series of compassionate use studies, such as one conducted by Dunn and
colleagues, have demonstrated promising results for the use
of this compound for treating PED.22
Nexagon. Nexagon (connexin43 antisense gel; CoDa
Therapeutics, Inc., New Zealand) is a novel selective
inhibitor of connexin43 expression being developed for the
treatment of ocular and skin wounds. Connexin43 is one of
20 human connexins, the constituent proteins of gap junctions. Gap junctions serve as conductive channels that connect adjacent cells to allow the transmission of molecules
and ions, mostly small intracellular signaling molecules such
as triphosphoinositol and calcium. Previous research has
revealed that direct cell-to-cell communication through
connexin43 gap junction channels plays a major role in
wound healing; dying cells induce apoptosis in neighboring
cells in direct proportion to the number and density of gap
junctions within the dying cells.23 This process, known as
bystander death, leads to an increase in wound size referred
to as lesion spread. Topical administration of Nexagon to
wounds has been shown to bring about a transient downregulation of connexin43 protein levels, resulting in reduced
lesion spread and a dramatic increase in the rate of wound
closure.24 Nexagon has recently shown encouraging results
in compassionate use applications onto the corneas of eyes
with PED, all of which were caused by chemical burns (personal communication). A prospective clinical trial of using
this compound in the setting of nonhealing defects from
ocular burns is ongoing, and other trials are investigating the
use of this compound in healing PED from other causes.
Scleral contact lenses. The use of large fluid-ventilated
scleral contact lenses has recently gained popularity in treating severe ocular surface disease, including dry eye secondary
to graft-versus-host disease and chemical burns. These lenses have also been used successfully to treat ectasia when
standard contact lens therapies have been unsuccessful.
Formerly called the Boston Scleral Lens, this device is now
called the Prosthetic Replacement of the Ocular Surface
Ecosystem (PROSE; Boston Foundation for Sight, Needham,
Massachusetts). The distinguishing characteristic of this lens
is that it vaults over the entire cornea and limbus and
bathes the cornea in fluid. This device has been used to heal
PED, but, as with bandage soft contact lenses, infection is
still possibile.25 Placing an antibiotic drop in the reservoir
before insertion may mitigate the risk of corneal infection.
CONCLUSION
PED, while rare, can have devastating consequences. This
condition can be recalcitrant to standard treatment modalities, and many new modalities have been investigated.
Given that PED treated earlier in the course of the disease
may heal faster, we should consider prophylactically treating
eyes at risk for developing PED. Alternative approaches to
treating PED are currently being investigated, and it is hoped
that these will add to our armamentarium of treatment
modalities against PED. ■
Bennie H. Jeng, MD, is an Associate Professor of Clinical
Ophthalmology, Department of Ophthalmology and Francis I.
Proctor Foundation, University of California, San Francisco
(UCSF), and Chief of the Department of Ophthalmology at San
Francisco General Hospital. He is also Co-Director of the UCSF
Cornea Service, and he is the Director of the Francis I.
Proctor/UCSF Cornea Fellowship Program. Dr. Jeng states that
he has no financial interest in the products or companies mentioned. He may be reached at tel: +1 415 206 8304; fax: +1 415
206 6122; e-mail: [email protected].
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