Breaking Down CL Epitheliopathies
Practitioners should periodically review contact lens-related epitheliopathies and their treatment options to provide their patients with the best lens wear experience.
Release Date: MAY 2012
Expiration Date: MAY 1, 2015
This article will offer a review of contact lens-related epitheliopa-thies and provide an outline of their treatment options.
Mile Brujic, O.D.
Dr. Brujic is a
partner of Premier
Vision Group, a four-location optometric
practice in northwest
Ohio. He lectures extensively in
the areas of ocular disease management and contact lenses.
Crystal Brimer, O.D.
Dr. Brimer is a
graduate of UNC-Chapel Hill and
of Optometry. She
has practiced full-scope optometry in Wilmington, N.C. for 12
years and has special interest
in contact lenses and dry eye
management. She is also the
owner of Crystal Vision Services,
an ophthalmic equipment and
practice management consulting
This course is COPE-approved for 1 hour of CE credit. COPE ID is 34623-CL. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.
This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.
The authors have no financial relationships to disclose.
While advancements in
contact lenses and lens
care technology have
improved the wear experience,
several physiological effects of
lens wear continue to contribute
to secondary epitheliopathies.
There is decreased tear exchange
under the lens, which can create
a pooling effect of carbon dioxide, debris, antigens and bacteria.
The quality of the tear film, especially the mucin layer as it relates
to infection, can be negatively
affected with a reduction in lipid
layer integrity and increased tear
evaporation. Changes in the tear
film can then have a secondary
effect on the functionality of the
In addition to the concerns of conservative and compliant lens wear,
many patients are at even higher risk
due to external factors, such as overnight wear, protein and lipid build
up, hygiene issues, poorly fit lenses,
solution hypersensitivity and lid or
ocular surface disease.4,5
In this article, we will explore
several epitheliopathies associated
with contact lens wear and provide a
breakdown of treatment options.
Non-infectious infiltrates are
an immune-driven response of the cornea to antigens. Corneal
insult initiates chemotaxis of
leukocytes from the surrounding
limbal vasculature into the anterior stroma.6
An infiltrate presents as a
single (or multiple) round epithelial and sub-epithelial lesion
that often does not stain with
fluorescein, or may demonstrate
late-phase staining. Late-phase
staining often appears faintly
with poorly demarcated borders
several minutes after instillation
of fluorescein. When an infiltrate
stains, it is essential to pay close
attention to its pattern in order to
help differentiate it from an infectious ulcer.
The inflammatory cascade and
subsequent collection of white
blood cells can cause overlying
epithelial damage. Because the
damage is secondary, the overlying epithelial defect and staining
pattern will be smaller than the
underlying infiltrate. Typically,
there is sectoral injection, only
trace cells in the anterior chamber
(if any), and just moderate pain
and photophobia. Non-infectious
infiltrates are small in size (under
2mm) and usually are located
toward the peripheral cornea, but
may be scattered throughout the
This inflammatory response is
well controlled with a steroid.s And, because any overlying epithelial defect originates from the
inflammation, suppressing it with
a steroid actually aids the re-epithelialization process.
Using a combination antibiotic/
steroid will protect the compromised cornea from secondary
infection. The recommended
dosing is q2h while awake for
the first one to two days if
needed, then q.i.d. until resolution.8 Often, practitioners simply
will dose the combination agent
q.i.d., which seems to resolve
Infectious keratitis is a completely different entity that
requires meticulous care--both in
its diagnosis and treatment. It is
the direct result of an infectious
organism invading the corneal
tissue. A recent study showed
that contact lens wearers were 9.31 times more likely to experience microbial keratitis than non-contact lens wearers.9
Clinically, bacterial ulcers will
usually present as a single, more
centrally located infiltrate that
stains with fluorescein. They are
generally larger in size (greater
than 2mm). The staining pattern
closely outlines the footprint of
the infiltrate because an ulcer
originates in the epithelium
before penetrating into the stro-ma.10 There generally is an anterior chamber reaction, stromal
edema and significant conjunc-tival hyperemia. Often, there is
much more pain associated with
an infectious infiltrate than sterile
infiltrates, as well as decreased
vision and discharge.7
Differentiating infectious from
non-infectious infiltrates is critical, because the protocol is substantially different between the
two treatment regimens (figure 1). Bacterial ulcers are seen at a
considerably lower frequency than
|1a. Diffuse non-infectious infiltrative keratitis.
1b. Infectious keratitis with significant corneal staining representing the site of bacterial invasion.
1c. Cells in the anterior chamber, which can be seen with an infectious ulcer.
For an infective keratitis, the
treatment goal is to eradicate the
offending organism and promote
corneal healing. This is often
done with highly concentrated
topical fourth generation fluoro-quinolones.11 Typically, the newer
gatifloxacin or besifloxacin—are
first-line treatments; however,
none of these agents currently
are approved for use in microbial
Depending on the severity of
the infection, it is appropriate
to initiate treatment at an accelerated frequency over the first
several days to rapidly decrease
concentrations of offending
micoorganisms. Additionally, it
is reasonable to incorporate Polytrim (polymyxin b/trimethoprim,
Allergan) due to its efficacy
The standard of care for more
aggressive or centrally located
ulcers is to culture and treat with
the appropriate fortified antibiotics. Some doctors prescribe
30-minute dosing intervals in
those cases, alternating fluoroqui-nolones with the fortified antibiotics.8 However, some research
shows equivalent efficacy of
fourth-generation fluoroquino-lones to combination fortified
If the ulcer responds well after
48 hours, the drops can often
be decreased to q2h until re-epithelialization and then tapered
to q.i.d., according to the corneal
response. Cycloplegics can help
decrease the patient's pain significantly as the infectious infiltrate
Despite immediate treatment,
corneal scarring can threaten the
patient's visual outcome, and
concurrent steroid treatment has
been questioned as a means to
minimize the resultant scarring
from these infectious events.
A recent, large-scale study
established that there was no benefit to the patient's best-corrected
visual acuity or resultant scar size
when steroids were incorporated
into the treatment protocol.14 However, patients with central
ulcers greater than 4mm or those
with the worst entering acuities
did experience nearly a two-line
improvement in visual acuity
with adjunctive steroid treatment.
The study also illustrated the
safety of concurrent steroid use
after 48 hours of fluoroquino-lone treatment in culture positive
patients and confirmed that there
was no delay in re-epitheliali-zation time in the group using
Advancing wavelike epitheli-opathy is a rare condition that
consists of centripetally advancing wavelike epithelium that usually extends from the superior
limbus towards the visual axis.15 The individual's visual acuity
may be affected, depending on
how far the irregular epithelium
extends to the visual axis. This
can be seen during standard slit
lamp examination, but is significantly easier to identify after the
instillation of fluorescein dye
while viewing the cornea with a
cobalt blue light through a Wrat-ten filter (figure 2). Other signs
that may occur include ocular
irritation and redness, depending
on the severity of the clinical presentation.
|2. The appearance of advancing wavelike epitheliopathy while viewing the eye with a cobalt blue light through a wratten filter after the instillation of fluorescein dye.
In vivo confocal microscopy is
remarkable for the presence of
atypical, elongated and cetripe-tally oriented cells.16 Additionally,
these cells are remarkable for
relatively large, hyperreflective
nuclei and a loss of visible cellular borders in the basal epithelium.16,17
The pathophysiology of
advancing wavelike epithelium
is poorly understood, but is
believed to be multifactorial.
Risk factors for its development
include topical antiglaucoma
medications, contact lens solutions, contact lens wear, previous
ocular surgery and atopic dermatitis.15-17
There have been reports in
the literature that describe the
effectiveness of an application of
1% silver nitrate to the superior
limbus.15-17 Liquid nitrogen also
has been documented as an effective treatment for this condition.
During the treatment, the corneo-scleral limbus and surface corneal
epithelium are exposed to liquid
nitrogen through a double freeze-thaw procedure. The technique
is to apply liquid nitrogen to the
affected area for one to two seconds, wait 30 seconds, and then
reapply for another one to two
In 2005, Professors Patrick
Caroline and Mark Andre reported on a case in which advancing wavelike epitheliopathy was
included in the differential diagnosis. The recommended treatment called for removal of the
offending agents while having the
patient utilize non-preserved artificial tears.19
In our office, if visual acuity
is not affected, we follow the
same treatment plan of removing
the suspected offending agent.
Initially, we switch contact lens
patients who use a multipurpose
solution to a hydrogen peroxide
system (figure 3). We also look to
a daily disposable option, if one
is available for their prescription.
If the epitheliopathy either is not
improving or progressing, it is
reasonable to discontinue contact
lens wear and have the patient
use non-preserved artificial tears.
If it continues to progress and/
or visual acuity becomes affected,
more extreme measures may be
|3a. A patient using a store brand multipurpose solution presented with advancing wavelike epitheliopathy.
3b. Presentation of the same cornea, three months after switching the patient to a hydrogen peroxide system.
Corneal neovascularization is a
sign of tissue hypoxia. Normally
a transparent, avascular structure,
the cornea acquires its nutrients
from the aqueous, the tear film
and the atmosphere. Deeper vas-cularization is also possible and
signals a more serious condition.
Although the sclera and bulbar
conjunctiva are continuous with
the cornea, the rich vascular supply that typically nourishes these
structures usually abruptly stops
at the limbus. Under circumstances of low oxygen, the cornea
attempts to acquire more oxygen
to nourish itself. This will lead to
limbal vasculature signaling and
subsequent growth of new blood
vessels in a centripetal manner
to meet the increased oxygen
There still doesn't seem to be
a true consensus on the amount
of oxygen required by the cornea
under normal, open-eye conditions. Minimum oxygen permeability requirements range from 24 Dk/t to 90 Dk/t.24,25 Clinically,
most of the contemporary hydro-gel contact lenses utilized in the
last two decades seem to avoid
significant neovascular changes
under daily wear conditions.
Concern arises, however, when
patients sleep in these lenses for
extended periods of time. In the
face of such non-compliance, corneal neovascularization is more
likely to occur.
High-oxygen permeable contact lenses have alleviated much
of the breathability concerns for
patients who sleep in their contact lenses. The silicone hydrogel
lenses have offered significantly
lower rates of corneal neovascu-larization and are an ideal lens
option for those sleeping or suspected of sleeping in their lenses.
Be cautious because extended
wear will increases the risk for
other contact lens complications,
such as microbial keratitis.26,27
There are a number of epithelial conditions that can affect our
contact lens wearers. Through
understanding these conditions
and modifying risk factors, along
with accurately diagnosing and
treating these patients, we can
regain healthy corneal physiology and facilitate successful lens
- Villani E, Ceresara G, Beretta S, et al. In vivo confocal
microscopy of meibomian glands in contact lens wearers.
Invest Ophthalmol Vis Sci. 2011 Jul 13;52(8):5215-9.
- Alonso-Caneiro D, Iskander DR, Collins MJ. Tear film
surface quality with soft contact lenses using dynamic-area
high-speed videokeratoscopy. Eye Contact Lens. 2009
- Santodomingo-Rubido J, Wolffsohn JS, Gilmartin B.
Changes in ocular physiology, tear film characteristics, and
symptomatology with 18 months silicone hydrogel contact
lens wear. Optom Vis Sci. 2006 Feb;83(2):73-81.
- Michaud L, Giasson CJ. Overwear of contact lenses:
increased severity of clinical signs as a function of protein
adsorption. Optom Vis Sci. 2002 Mar;79(3):184-92.
- Nichols KK, Mitchell GL, Simon KM, et al. Corneal
staining in hydrogel lens wearers. Optom Vis Sci. 2002
- Baum J, Dabezies OH Jr. Pathogenesis and treatment of
"sterile" midperipheral corneal infiltrates associated with
soft contact lens use. Cornea. 2000 Nov;19(6):777-81.
- Stein RM, Clinch TE, Cohen EJ, et al. Infected vs sterile
corneal infiltrates in contact lens wearers. Am J Ophthal-mol. 1988 Jun 15;105(6):632-6.
- Bartlett J, Melton R, Karpecki P, Thomas R. Keratitis:
new paradigms in the understanding and management of
keratitis. Rev Optom. 2011 Nov;Suppl.
- Jeng BH, Gritz DC, Kumar AB, et al. Epidemiology of
ulcerative keratitis in Northern California. Arch Ophthalmol.
- Melton R, Thomas R. 2011 Clinical guide to ophthalmic drugs. Rev Optom. 2011 May;Suppl.
- Morlet N, Daniell M. Microbial keratitis: what's the
preferred initial therapy? View 2: Empirical fluoroquinolone
therapy is sufficient initial treatment. Br J Ophthalmol.
- Scoper SV. Review of third-and fourth-generation
fluoroquinolones in ophthalmology: in-vitro and in-vivo
efficacy. Adv Ther. 2008 Oct;25(10):979-94.
- Shah VM, Tandon R, Satpathy G, et al. Randomized
clinical study for comparative evaluation of fourth-generation fluoroquinolones with the combination of fortified
antibiotics in the treatment of bacterial corneal ulcers.
- Srinivasan M, Mascarenhas J, Rajamaran R, et al.
Corticosteroids for bacterial Keratitis: the Steroids for
Corneal Ulcers Trial (SCUT). Arch Ophthalmol. 2012
- D'Aversa G, Luchs JL, Fox MJ, et al. Advancing
wave-like epitheliopathy. Clinical features and treatment.
Ophthalmology. 1997 Jun;104(6):962-9.
- Chiou AG, Kaufman SC, Beuerman R, et al. A confocal
microscopic study of advancing wavelike epitheliopathy.
Arch Ophthalmol. 1999 Jan;117(1):126-7.
- Huang Y, Chu HS, Hu FR, et al. Recurrent advancing
wavelike epitheliopathy from the opposite side of the initial
presentation. Cornea. 2008 Jan;27(1):111-3.
- Fraunfelder FW. Liquid nitrogen cryotherapy of advancing wavelike epitheliopathy. Cornea. 2006 Feb;25(2):196- 8.
- Caroline P, André M. Analyzing unilateral complications. CL Spectrum. 2005 Jul. Available at: www.clspec-trum.com/articleviewer.aspx?articleid=12835 (accessed
- Binder PS. The physiologic effects of extended wear
soft contact lenses. Ophthalmology. 1980 Aug;87(8):745- 9.
- Efron N. Vascular response of the cornea to contact
lens wear. J Am Optom Assoc. 1987 Oct;58(10):836-46.
- Van Setten GB, Tervo T, Andersson R, et al. Plasmin
and epidermal growth factor in the tear fluid of contact-lens wearers: effect of wearing different types of contact
lenses and association with clinical findings. Ophthalmic
- Mastyugin V, Mosaed S, Bonazzi A, et al. Corneal
epithelial VEGF and cytochrome P450 4B1 expression in
a rabbit model of closed eye contact lens wear. Curr Eye
Res. 2001 Jul;23(1):1-10.
- Harvitt D, Bonanno J. Re-evaluation of the oxygen
diffusion model for predicting minimum contact lens Dk/t
values needed to avoid corneal anoxia. Optom Vis Sci.
- Ostrem E, Fink B, Hill R. A hypoxic response line model
for the human cornea. Br J Optom Disp. 1996;4:53-5.
- Dart JK, Radford CF, Minassian D, et al. Risk factors for microbial keratitis with contemporary contact
lenses: a case control study. Ophthalmology. 2008
- Stapleton F, Keay L, Edwards K, et al. The incidence of
contact lens-related microbial keratitis in Australia. Ophthalmology. 2008 Oct;115(10):1655-66.