FocalPoints

Clinical Modules for Ophthalmologists

VO L U ME X X X III NUMBER 11
N OV EMBER 2 01 5

Corneal Collagen Crosslinking

Aaron Chan, OD
Clara C. Chan MD, FRCSC, FACS

a
a

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REVIEWERS AND CONTRIBUTING EDITOR CONSULTANTS

Elmer Y. Tu, MD, Editor for Cornea and External Disease José L. Güell, MD, PhD
Stephen E. Orlin, MD, Basic and Clinical Science Course Faculty, Section 8 R. Doyle Stulting, MD, PhD
Dasa V. Gangadhar, MD, Practicing Ophthalmologists Advisory Committee for Education
 FocalPoints™ Editorial Review Board
Eric Paul Purdy, MD, Bluffton, IN
Editor in Chief; Oculoplastic, Lacrimal, and Orbital Surgery
CONTENTS
Lisa B. Arbisser, MD, Bettendorf, IA
Cataract Surgery Introduction 1
Syndee J. Givre, MD, PhD, Raleigh, NC Keratoconus and Other Ectatic Conditions 1
Neuro-Ophthalmology
Deeba Husain, MD, Boston, MA Corneal Collagen Crosslinking 3
Retina and Vitreous Safety Considerations in CXL 4
Katherine A. Lee, MD, PhD, Boise, ID Indications 4
Pediatric Ophthalmology and Strabismus
Contraindications 4
W. Barry Lee, MD, FACS, Atlanta, GA
Refractive Surgery; Optics and Refraction
Standard Surgical Technique 4
Ramana S. Moorthy, MD, FACS, Indianapolis, IN
Ocular Inflammation and Tumors Postoperative Management
Sarwat Salim, MD, FACS, Milwaukee, WI After Standard Crosslinking 6
Glaucoma
Elmer Y. Tu, MD, Chicago, IL Complications 7
Cornea and External Disease
Results of Major Clinical Trials 7
FocalPoints Staff
Surgical Technique Variations 7
Susan R. Keller, Acquisitions Editor
Epithelial-On Versus Epithelial-Off
Kim Torgerson, Publications Editor Crosslinking 7
D. Jean Ray, Production Manager
Techniques for the Thin Cornea 8
Debra Marchi, CCOA, Administrative Assistant
Techniques for Shorter Light Treatments 9
Clinical Education Secretaries and Staff Combining Crosslinking With
Louis B. Cantor, MD, Senior Secretary for Clinical Education, Other Modalities 9
Indianapolis, IN
Future Directions 11
Christopher J. Rapuano, MD, Secretary for Ophthalmic
Knowledge, Philadelphia, PA Conclusion 11
Dale Fajardo, Vice President for Education
Clinicians’ Corner 12

Suggested Reading 15

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ii FocalPoints Module 11, 2015

 LEARNING OBJECTIVES in many cases, halt the disease. Though many trials
have proven successful, the practicing ophthalmologist
should be mindful of the relatively nascent nature of this
Upon completion of this module, the reader
technology and the many controversies and questions,
should be able to:
such as the long-term effect of CXL, that remain to be
 Describe the common features of answered in this rapidly evolving procedure.
keratoconus and other corneal ectatic
KERATOCONUS AND OTHER ECTATIC
conditions CONDITIONS
 Describe the mechanism of collagen Keratoconus is a degenerative disorder that is character-
crosslinking as well as indications and ized by paracentral thinning and ectasia. It is the most
contraindications for its use common corneal dystrophy, affecting approximately
1 in 2000 in the general population with no conclusive
 Describe the surgical technique for predilection for gender or race. The condition is typi-
crosslinking and appreciate variations in cally bilateral but asymmetric. As the cornea thins, it
surgical technique protrudes anteriorly, forming a conical cross section that
most commonly decenters inferotemporally. The protru-
sion leads to a steepened curvature and scarring that may
manifest as striae at the level of Descemet membrane.
Introduction The resultant changes in shape cause significant irregu-
lar astigmatism, myopia, and reduced best-­ corrected
The concept of crosslinking as a means to stiffen tissue visual acuity (BCVA). Figure 1 shows a corneal topog-
and materials has been known for some time, but it was raphy that one might expect in a patient with keratoco-
not until 1998 when Eberhard Spoerl and Theo Seiler, nus. KC is initially managed with spectacle correction
researchers from the University of Dresden, began con- alone; however, as the disease progresses, the patient of-
sidering crosslinking as a therapeutic treatment for cor- ten requires rigid contact lenses to overcome the optical
neal diseases. The idea was based on the observation that aberrations. In its advanced stages, it is estimated that
the cornea naturally crosslinks itself to a more rigid and 10%–20% of patients require corneal transplantation.
stronger state with age, suggesting that simulated cross- The etiology of KC is not well understood as it in-
linking with ultraviolet‑A (UVA) light and riboflavin cludes genetic, biochemical, and physical factors. There
(vitamin B2) may have a similar effect. Since then, cor- is no sole theory elucidating its range of clinical pre-
neal collagen crosslinking (CXL) has become a widely sentation, and KC is likely the eventual manifestation
accepted treatment for keratoconus (KC) and related of several different conditions. The condition usually
ectatic conditions. While conventional management op- appears in isolation, but there have been reports of a
tions (contact lenses and glasses) for KC are effective number of systemic and ocular associations, including
in improving vision, they do not address the underlying connective tissue disorders and vernal disease. Ocular
weakness in the cornea. Corneal crosslinking, however, trauma associated with eye rubbing, contact lens wear,
is effective because of its ability to stiffen the cornea, and allergic eye disease also appears to be related. In-
which has been demonstrated to slow progression, and creased activity of protein enzymes has been identified

Financial Disclosures
The authors, reviewers, and consultants dis- OPHTEC (2015). (C, L) Alcon Laboratories C = Consultant fee, paid advisory boards or fees for at-
close the following financial relationships: (2014, 2015). (C, O) Cambium Medical Tech- tending a meeting (for the past 1 year)
Lisa  B. Arbisser, MD: (C) Bausch  + Lomb nologies, EyeYon, TearLab (2014, 2015). (L) E = Employed by a commercial entity
(2013, 2014). (C, L, S) OptiMedica (2013). Allergan (2014, 2015). Elmer  Y. Tu, MD: L = Lecture fees (honoraria), travel fees or reimburse-
(L) Abbott Medical Optics (2014). Clara (C) Bausch  + Lomb (2013), Seattle Genetics ments when speaking at the invitation of a com-
C. Chan, MD, FRCSC, FACS: (C) Bausch  + (2014, 2015). mercial sponsor (for the past 1 year)
Lomb (2013–2015), Tearscience (2015). (C, The following contributors state that they O = Equity ownership/stock options (publicly or pri-
L) Allergan (2013–2015). (L) Alcon Laborato- have no financial interest or other relation- vately traded firms, excluding mutual funds)
ries (2013–2015). (S) Allergan (2015). José L. ship with the manufacturer of any commer- P = Patents and/or royalties that might be viewed as
Güell, MD, PhD: (C) Alcon Laboratories, Carl cial product discussed in their contributions creating a potential conflict of interest
Zeiss, OPHTEC BV, RVO Raindrop, Thea to this module or with the manufacturer of S = Grant support for the past year (all sources) and all
(2015). (O) Calhoun Vision, Orca Surgical any competing commercial product: Syn- sources used for this project if this form is an up-
(2014, 2015). W.  Barry Lee, MD, FACS: (C) dee  J. Givre, MD, PhD; Deeba Husain, MD; date for a specific talk or manuscript with no time
Shire (2015). (L) Allergan, Bausch  + Lomb Susan R. Keller; Katherine A. Lee, MD, PhD; limitation
(2013–2015). Eric Paul Purdy, MD: (L) Al- Ramana S. Moorthy, MD, FACS; Kim Torger-
con Laboratories (2014). Sarwat Salim, MD, son (2013–2015). Eric Paul Purdy, MD (2013,
FACS: (L) Alcon Laboratories (2013, 2014), 2015). Dasa Gangadhar, MD; Stephen  E.
Merck & Co (2013). R. Doyle Stulting, MD, Orlin, MD (2014). Aaron Chan, OD (2014,
PhD: (C) Abbott Medical Optics, Calhoun Vi- 2015). Lisa  B. Arbisser, MD; Sarwat Salim,
sion, Hoya, NuLens, Optovue (2014, 2015); MD, FACS (2015).

FocalPoints Module 11, 2015 1

 Figure 1  Topographic image showing inferior steepening in the right eye, worse than the left eye in a patient with
keratoconus.

Figure 2  Topographic image showing high against-the-rule astigmatism from pellucid marginal degeneration in the
right eye.

in keratoconic corneas, resulting in weakened biome- peripheral cornea rather than the paracentral cornea
chanical stability. Growing evidence suggests that tissue (Figure  2). PMD is characterized by a peripheral band
degradation and corneal thinning involve the expression of thinning from approximately the 4  o’clock to the
of inflammatory mediators. The pathogenesis and pro- 8 o’clock position, which gives a classic “crab-claw” ap-
gression of keratoconus is a very active area of research pearance on topography. Consequently, managing PMD
that warrants a separate discussion, one that is beyond with penetrating keratoplasty is more difficult, as larger
the scope of this module. It is, however, important to be and more eccentric grafts are required, raising the risk for
aware of some of the ongoing debate about theories of postoperative astigmatism and graft rejection. Crosslink-
inflammation and progression in keratoconus. ing for PMD is performed in the same fashion as with
Pellucid marginal degeneration (PMD) is less com- KC. Although the area of steepening is more peripheral
mon than keratoconus and usually affects the inferior in PMD, the central 8–9 mm treatment zone appears to

2 FocalPoints Module 11, 2015

 Figure 3  Topographic image showing irregular astigmatism and inferior steepening in a patient with post-laser
keratoectasia in the left eye.

be adequate in coverage. Along with keratoglobus, there riboflavin then reacts with oxygen, creating reactive
seems to be overlap between PMD and keratoconus. oxygen species and radicals. These reactive species theo-
Progressive post-laser keratoectasia (PPLK) is a con- retically induce covalent crosslink bonding between the
dition of gradual corneal thinning and steepening fol- protein molecules within the stroma including collagen
lowing LASIK or photorefractive keratectomy (PRK) and proteoglycans.
surgery (Figure  3). It generally occurs within 2  years Considerable evidence supports the creation of
after refractive surgery and is estimated to occur in 1 in these crosslink formations following CXL. In a seminal
2500 to 1 in 5000 cases. The underlying cause of PPLK study, Spoerl and Seiler irradiated porcine and rabbit
is not well understood but is thought to be from the corneas presoaked in photosensitizing agents, and re-
weakening of the anterior stroma from flap creation, sultant corneas were stiffer and more resistant to en-
insufficient residual stromal bed thickness after tissue zymatic degradation. Subsequent in vivo studies have
ablation, or from the uncovering of a previously undi- confirmed increases in corneal rigidity, with an original
agnosed ectasia such as forme fruste keratoconus. Risk study by Wollensak supporting a >320% gain in corneal
factors for PPLK include thin corneas, repeated en- biomechanical strength. Later reports claimed that cor-
hancement treatments, irregular preoperative topogra- neal stiffening was dependent on depth, with the effect
phies, and deep ablations. confined mostly to the anterior 200 µm of the stroma.
In regard to the crosslinked cornea being more resistant
to enzymatic degradation, it is postulated that changes
Corneal Collagen to the tertiary structure of the collagen fibers prevent en-
zymes (eg, collagenases) from accessing specific cleavage
Crosslinking sites. This may be helpful in understanding in part the
pathogenesis of keratoconus, as some studies indicate a
CXL specifically involves the activation of riboflavin disruption in the balance between proteolytic enzymes
(vitamin B2) with UVA light to enhance covalent bond and their endogenous inhibitors in KC corneas, imply-
formations (or “crosslinks”) between collagen fibers in ing more proteolytic activity and fewer protein compo-
the stroma. The process begins with the activation of the nents when compared to normal controls.
photosensitive riboflavin to an excited state. The excited

FocalPoints Module 11, 2015 3

SAFETY CONSIDERATIONS IN CXL unknown, a part of its stabilization is explained by the
The use of UVA light in CXL warrants a discussion on cornea’s inherent ability to stiffen with age. Therefore,
potential negative effects on ocular structures. Exposure the newly diagnosed and/or rapidly progressing young
to UVA radiation is cytotoxic to structures that lie deep patient has the most potential benefit from CXL. Con-
to the intended stromal tissue including the endothe- versely, the treatment may be unnecessary for a 40‑year
lium, lens, and retina. In fact, several case series have old keratoconic patient with no evidence of progression.
reported endothelial and iris damage from UVA irra- To date, applicable treatment age and progression crite-
diation in CXL. Standard parameters in thickness, ir- ria are still being studied and remain controversial.
radiance, wavelength, and exposure time have thus been
CONTRAINDICATIONS
chosen to maximize safety while ensuring efficacy.
The current recommendation is that any patient CXL should be avoided in a number of situations; how-
treated with CXL should have a corneal thickness of ever, since there are no official criteria, treatment is de-
at least 400  µm at the thinnest point after the epithe- pendent on the surgeon’s discretion and management of
lium has been removed. Treatment is not safe below this patient expectations. Patients very advanced in their dis-
400 µm threshold and an alternative technique should ease tend not to make good candidates. These patients
be considered if such is the case (see “Techniques for the typically have thin corneas and steep maximal corneal
Thin Cornea” later in this module). This recommenda- curvatures. One study indicates that patients with pre-
tion is based on the observation that the standard irra- operative keratometry readings of greater than 58.00 D
diance of 3 mW/cm2 is effectively 0.18 mW/cm2 at the have a greater risk of treatment failure and postopera-
level of the endothelium of a 400 µm riboflavin-­imbibed tive haze formation. Additionally, this study suggests
stroma, which is two-fold lower than the irradiance that patients who are older than 35  years of age and
considered cytotoxic to endothelial cells. The chosen present with better than 20/25 preoperative corrected
wavelength of 365–370 nm is outside the range that can distance visual acuity are at a higher risk for vision
cause photokeratitis (270–315 nm) and cataract forma- loss from stromal scarring. Finally, eyes with preopera-
tion (290–360 nm), and the standard treatment time of tive corneal thicknesses of less than 400 µm should be
30 minutes delivers a total dose of 5.4 J/cm2. avoided for the concern of damage to deeper structures.
The very nascent nature of this technology has re- As a result of these findings, the authors recommend
sulted in a number of groups modifying the standard that patients be treated with the requirements of being
parameters by changing irradiance, duration of UVA less than 35  years old, having greater than 400  µm of
exposure, and riboflavin concentration in order to ca- corneal thickness at the thinnest point after epithelial
ter for thinner corneas and more rapid treatments (see debridement, and measuring less than 58.00 D on maxi-
“Techniques for Shorter Light Treatments” later in this mal keratometry readings.
module). The variety of these new protocols has raised Factors that can potentiate postoperative complica-
some controversies as to the safest and most efficacious tions, such as delayed healing or infection, also need to
way to perform CXL. be seriously considered prior to treatment. Severe dry
eye, vernal/atopic inflammatory disease, and concurrent
INDICATIONS infections, such as herpetic keratitis, should be managed
The primary indication for CXL is progressive kerato- or treated appropriately before considering CXL. There
conus. However, it is critical to emphasize the challenge is also a case study suggesting that pregnancy limits
in defining “progression” as it relates to indications the effects of CXL and may exacerbate corneal ectasia.
for treatment and analysing outcomes. The prevailing Though the evidence is limited, it is probably prudent
goal of CXL is to stop progression; however, the term to avoid CXL during and immediately after pregnancy.
is not standardized and can be arbitrarily set for each Lastly, severe central scarring with associated decreased
study. Previous studies have defined the progression of visual acuity is unlikely to be improved after CXL, so
keratoconus with diverse parameters, from the clinical alternate treatment options such as corneal transplanta-
progression that necessitates transplantation to several tion should be considered.
topographic indices (eg, +1.0 D change from baseline in
Kmax). As such, there is little uniformity in the litera-
ture, and this has caused much confusion in comparing
data and interpreting successful outcomes.
Standard Surgical
Regardless, there is general consensus in the ability
of CXL to stiffen the cornea, and it is thus often rec-
Technique
The most accepted treatment protocol is based on
ommended as a first-line treatment option. Despite this, the original Dresden protocol, an epithelium-­ off ap-
CXL may not be suitable for every keratoconic patient. proach first described by Wollensak et al (2003). It in-
KC typically manifests at around puberty and progresses volves 0.1% riboflavin combined with UVA-­irradiation
at variable rates until the age of 30–40, after which it (370 nm; @ 3mW/cm2), providing 5.4 J/cm2 of energy to
often stabilizes. Though the etiology of KC is largely

4 FocalPoints Module 11, 2015

the cornea. The following are the step-by-step instruc-
tions for the Dresden protocol:
1. Under sterile operating conditions, the patient is
draped and the cornea is anaesthetised topically
with 2–3 applications of 0.5% proparacaine or
0.5% tetracaine ophthalmic solution.
2. The orbital area is cleaned with 10% povidone-­
iodine solution (Betadine) and a lid speculum is
applied (Figure 4).
3. The central 7–9 mm of the corneal epithelium is
debrided (Figure 5).
4. A baseline corneal thickness measurement is Figure 5  Removal of corneal epithelium using a
taken with an ultrasound pachymeter to ensure Beaver blade and dry Weck-Cel ophthalmic sponge.
thickness of 400 µm (Figure 6).
5. 0.1% iso-­osmolar riboflavin in 20% dextran
solution is instilled on the corneal surface every
2–3 minutes for 30 minutes (Figure 7).
6. The patient is examined under slit lamp with
blue light to ensure riboflavin has fully infused
the cornea. (Check for riboflavin in the anterior
chamber by presence of a yellow coloration.)
7. Corneal pachymetry is remeasured before UVA
irradiation.
8. If it is safe to continue, a sponge ring is placed
around the limbus of the cornea to protect the
limbal stem cells (Figure 8a).
9. UVA light is focused directly on the area
of absent epithelium to photoactivate the
riboflavin-­imbibed stroma.

Figure 6  Measurement of corneal pachymetry to

ensure 400 µm thickness prior to UVA irradiation.

Figure 4  After application of povidone iodine to the

periorbital region and insertion of a lid speculum, an
8 mm corneal optic zone marker is filled with alcohol
for 10 seconds. (Bores Optic Zone Marker, Katena, Figure 7  Application of 0.1% riboflavin in 20% dextran
Denville, New Jersey.) onto the cornea every 2–3 minutes for 30 minutes.

FocalPoints Module 11, 2015 5

 a

Figure 9  Application of bandage contact lens after

UVA treatment.

This lens is left until the cornea is fully re-­

epithelized, which usually occurs in 4–7 days.
14. The patient is discharged with a course of
antibiotics and topical steroids. Regular
follow‑up should occur until the epithelium has
fully healed and the contact lens can be removed.

b
Postoperative
Figure 8  UVA treatment of riboflavin-­imbibed
Management After
cornea. a. Limbal stem cells are protected with
a Kerocel Chayet Drainage Ring (Beaver Visitec,
Standard Crosslinking
Waltham, Massachusetts). b. Irradiation commences The postoperative management of crosslinking is a simi-
for 30 minutes with continued riboflavin instillation. lar experience to postoperative management after PRK.
The early healing stage is most symptomatic, and pa-
tients may experience symptoms of pain, tearing, foreign
10. Irradiation commences for 30 minutes, with body sensation, and photophobia that are consistent
continued riboflavin instillation every 3 minutes with having a corneal abrasion. A bandage contact lens
(Figure 8b). is used to support re-­epithelialization and reduce pain.
11. Alternating applications of balanced saline Topical antibiotics and preservative-­free lubricants are
solution (BSS) and topical anaesthetic are given given until re-­epithelialization and pain can be man-
intermittently to prevent desiccation and to aged with oral opioids and analgesics. The epithelium
maintain corneal anesthesia. typically heals by day 4–7, at which point the bandage
contact lens is removed and a regimen of topical ste-
12. Corneal pachymetry is measured at 10, 20, and roids is given to reduce scarring and promote further
30 minutes after riboflavin drops have started healing. (The author uses dexamethasone 4 times daily
to ensure that the stromal thickness remains for 2–4  weeks, tapering to twice daily for 2–4  weeks
greater than 400 µm. Should the pachymetry depending on the presence or absence of any haze, but
measurement fall below 400 µm, hypotonic there is much variation in the literature.) Patients are
riboflavin drops are used instead of the routine followed up at 1 day, 4–7 days for bandage contact lens
isotonic riboflavin drops. removal, 1 month to monitor for haze, then further fol-
13. Upon completion of the UVA irradiation low‑up at 3 months, 6 months, and 1 year. Thereafter,
treatment, a broad-­spectrum antibiotic, such as patients are seen every 6–12 months to monitor for pro-
moxifloxacin, is instilled and a bandage contact gression via serial manifest refraction and topography
lens is positioned onto the cornea (Figure 9). with their optometrist or ophthalmologist.

6 FocalPoints Module 11, 2015

Complications outcomes. Though studies indicate stability for up to
5 years, the exact duration of CXL’s effect on the cornea
CXL, like any surgical procedure, involves potential is unknown, and longer-­term data remains to be seen.
risks. Intraoperatively, improper UVA delivery from In examining the data presented in the studies, one
excessive energy, incorrect wavelength, or insufficient should be aware that there are significant inconsisten-
amount of riboflavin in the stroma can lead to possible cies in evaluating the literature. As each study is inde-
corneal, iris, lens, and retinal damage. Corneas with a pendently conducted, there is variability in the way
thickness less than 400 µm after de-­epithelization have Kmax and other parameters are measured. The study
a greater chance for endothelial cell and permanent vi- of the disease in itself is confounded by variability from
sion loss. It has been demonstrated that extreme cor- patient to patient or even between the 2  eyes of a pa-
neal dehydration following debridement can exacerbate tient. As aforementioned, factors such as defining the
thinning, thus extra care is warranted to ensure appro- rate of progression, time of onset, natural course of
priate corneal thickness and hydration throughout the disease, genetic components, and physical environment
duration of the treatment. Sterile infiltrates have been vary dramatically between patients diagnosed with this
reported. In rare cases, severe inflammatory responses same condition. In this rapidly evolving field, one should
have occurred within 24 hours of UVA treatment, with be cognisant of the variability and confounding factors
patients developing iritis, keratic precipitates, and cor- that have a made it difficult to study this chronic and
neal edema. Research suggests that UVA light induces progressive disease with relatively small and short-term
apoptosis in keratocytes, which may be linked to an ini- studies.
tial inflammatory response. However, keratocyte dam-
age is of lesser concern as a normal cell population is
typically regained 6 months after treatment.
Postoperatively, there is added risk for haze, scar-
Surgical Technique
ring, delayed wound healing, corneal melt, and infectious
keratitis, especially when the epithelium is removed.
Variations
Though permanent scarring is rare, stromal haze is fre- EPITHELIAL-ON VERSUS EPITHELIAL-OFF
quently noted after CXL and usually responds well to CROSSLINKING
topical steroids, resolving within 6 months to a year. A The discussion between epithelial-­ on (epi‑on) versus
transient decrease in corneal sensitivity and innervation the standard epithelial-­off (epi‑off) CXL is arguably the
can also be observed up to 6 months postoperatively, most contentious topic in crosslinking research today. As
although this has minimal effect on tear film stability the name suggests, epithelial‑on or transepithelial CXL
or basic tear secretion. Close observation during the leaves the epithelium intact as riboflavin penetrates to
epithelial healing phase is important to monitor for in- the stroma. Riboflavin, a large molecule, is impermeable
fection and delayed wound healing, the latter of which to the intact epithelium, thus necessitating its removal in
has been linked to limbal stem cell damage or poor epi- standard crosslinking. However, the theoretical benefits
thelial cell migration over a steepened cone. In spite of of leaving the epithelium on include less risk of infec-
this, potential chronic complications such as late lim- tion, reduced haze, reduced pain, and improved healing
bal stem cell deficiency or relationship to ocular surface times. Accordingly, various approaches have been tried
malignancy have yet to be demonstrated in literature. clinically and in the laboratory to enhance epithelial
Finally, it is worthwhile to mention that many of the permeability. Riboflavin preparations with trometamol,
earlier studies reporting adverse events lacked explicit benzalkonium chloride (BAC), and/or EDTA, among
inclusion and exclusion criteria, thus potentially treat- other drugs have demonstrated an ability to loosen epi-
ing at-risk patients who would be otherwise excluded thelial tight junctions. “Mechanical disruption” to cre-
today. Regardless, the incidence of complications from ate pockmarks or grid patterns in the epithelium have
CXL represents an extremely small proportion of eyes, been utilized to facilitate diffusion. Unfortunately, at the
and patients should be counselled accordingly. expense of leaving the epithelium on, treatments may
take significantly longer than epi‑off CXL to ensure the
riboflavin has adequately infused the stroma. The drugs
Results of Major used are also toxic to the epithelium, which can be espe-

Clinical Trials
cially uncomfortable for the patient.
There is much debate to epi‑on CXL’s effectiveness
The results of major clinical trials are listed in Table 1. as it compares to the “gold-­standard” of epi‑off CXL.
Of the many peer-­reviewed clinical trials, nearly all re- Experimental support for epi‑on CXL is controver-
port halting moderate to advance progressive kerato- sial. Wollensak experimented with epi‑on in a labora-
conus, often with some regression of corneal steepness tory and found it to be 20% as effective as epi‑off. A
(Kmax). On average, studies report a Kmax reduction number of subsequent reports have concluded similar
of approximately 2.00  D, resulting in improved visual decreases in efficacy. On the contrary, there are a few

FocalPoints Module 11, 2015 7

 Table 1. Results of Major Clinical Studies for Standard CXL

MAXIMUM NO. OF EYES % HALTED OR

AUTHORa FOLLOW-UP START/END IMPROVED IMPROVEMENT
Wollensak, et al (2003) 4 years 23/2 95.5 (70) Kmax 2.01 D,
BCVA 1.26 lines
SE –1.14 D
Caporossi, et al (2006) 3 months 10/10 — Kmax 1.90 D
BCVA 1.66 lines, UCVA 3.6 lines
Raiskup-Wolf, et al (2008) 6 years 241/5 81 (57) Kmax 2.44 D
BCVA –0.18 LogMAR
Jankov, et al (2008) 6 months 25/25 100 (52) Kmax 2.14 D
UVCA –0.11 LogMAR
Wittig-Silva, et al (2008) 12 months 33/9 (>50) Kmax 1.45 D
BCVA–0.12 LogMAR
Vinciguerra, et al (2009) 2 years 28/28 — Kmax 1.35 D
BCVA –0.15 LogMAR, UCVA –0.24 LogMAR
Agrawal (2009) 1 year 37/37 92 (54) Kmax 2.47D
BCVA improved >1 line
Coskunseven, et al (2009) 1 year 19/19 — Kmax 1.57D
BCVA –0.10 LogMAR, UCVA –0.06 LogMAR
Koller, et al (2009) 1 year 192/155 98 (37.7) Kmax 0.89D
BCVA –0.55 LogMAR
Derakhshan, et al (2011) 6 months 31/31 90.3 (77) Kmax 0.65 D
BCVA 1.7 lines, UCVA 2 lines
Hersh, et al (2011) 1 year 49/49 89.8 (51.0) Kmax 2.00 D
BCVA –0.14 LogMAR, UCVA –0.05 LogMAR
Viswanathan, et al (2013) 4 years 51/? — Kmax 0.96 D
BCVA –0.05 LogMAR
Goldich, et al (2012) 2 years 14/14 92.8 Kmax 2.40 D
BCVA –0.07 LogMAR
Vinciguerra, et al (2012) 2 years 40/40 — Kmax 1.27 D
(<18-year-olds studied) BCVA –0.19 LogMAR, UCVA –0.21 logMAR
SE –1.57 D
Vinciguerra, et al (2013) 4 years 400/? — BCVA:
–0.11 LogMAR (<18 years old @ 12 months)
–0.31 LogMAR (18–29 years old @ 36 months)
–0.33 LogMAR (30–39 years old @ 36 months)
–0.25 LogMAR (>40 years old @ 36 months)
a
Refer to Suggested Reading for citations.
Kmax = keratometry value in the steepest meridian, BCVA = best-corrected visual acuity, UCVA = uncorrected visual acuity, SE = spherical equivalent refraction

small, published studies that suggest epi‑on is at least as that the group’s UV light source and riboflavin formula-
efficacious as epi‑off. The results of these epi‑on CXL tion are proprietary and much of their data is yet to be
studies are listed in Table 2. There is also a very large, published. At present, all published long-term data have
multicenter, nonrandom, prospective, research effort un- been performed with epi‑off procedures. Further clinical
derway in the United States that cites excellent initial re- studies with longer follow-­up and randomized controls
sults. The CXL‑USA Study Group supports that epi‑on are required to ascertain the efficacy of epi‑on CXL as it
CXL provides patients with equivalent or superior out- compares to the current standard of epi‑off CXL.
comes to epi‑off CXL while causing significantly less
pain and healing time. The study group has treated pa- TECHNIQUES FOR THE THIN CORNEA
tients as young as 9 and has even found benefit in treat- Many patients with advanced keratoconus have corneas
ing patients more than 35. Readers should be mindful that are under the threshold for treatment (<400  µm

8 FocalPoints Module 11, 2015

 research needs to be conducted to confirm the safety of
Table 2. Results of Clinical Studies for
such newer techniques.
Epi-On CXL
NO. OF EYES COMBINING CROSSLINKING WITH OTHER
AUTHORa FOLLOW-UP START/END IMPROVEMENT MODALITIES
Filippello, 18 months 20/20 Kmax: 2.97D Although in most cases, CXL halts the ectatic process
et al (2012) UCVA –0.66 and can result in mild to modest gains in vision, the
LogMAR, BCVA:
–0.11 LogMAR procedure alone typically does not provide significant
visual recovery, and patients should be counselled ap-
Koppen, Up to 18 53/18 Sphere, Cyl, Kmax
et al (2012) months and refractive propriately. Investigators therefore, have experimented
power remained with combining CXL with various refractive techniques
stable from with the goal of stabilizing the cornea as well as improv-
baseline without
statistically ing vision. The results for some of these clinical trials are
significant listed in Table 3.
improvements at
18 months. CXL IN COMBINATION WITH INTRASTROMAL
Lessicotti, 12 months 63/51 BCVA: –0.036 RINGS. Intrastromal corneal ring segments (ICRS) are
et al (2012) LogMAR
an effective treatment option for keratoconic patients
SE: 0.35D
who are contact lens intolerant. Intacs (AJL Ophthamic,
(overall favorable
but limited effect)
Vitoria-­Gasteiz, Spain) and the Ferrara Ring/Keraring
(Mediphacos, Belo Horizonte, Brazil) are specific ex-
a
Refer to Suggested Reading for citations.
amples of ICRS that consist of semicircular polymethyl-
methacrylate (PMMA) segments which can be implanted
into a channel deep in the stroma. The segments flatten
after epithelial debridement). Hypo-­ osmolar ribofla- the central cornea and, with strategic positioning, move
vin solutions have been used to swell corneal stromas the decentered cone to a more central position, reduc-
to >400 µm, allowing for the treatment of thin corneas ing optical aberrations such as coma and improving vi-
that would otherwise be excluded. It appears that the sion and/or contact lens fit. Figure 10 depicts an Intacs
effect is transient, so surgeons must carefully monitor segment properly positioned in the stroma. Studies have
pachymetry throughout the entire CXL treatment, in- indicated good visual recovery with more than a 2‑line
stilling additional hypo-­osmotic riboflavin on a regular improvement in BCVA. Though the exact mechanism is
basis. There is good evidence that subsequent CXL treat- unknown, it is believed that the remodelled cornea re-
ment stabilizes the progression of keratoconus with no distributes and dampens the biomechanical strain on the
side effects or damage to the endothelium with results cone to slow progression of the disease. As such, there
up to a year post-­treatment. As with other techniques, are trials, including those of Joseph Colin, that have
additional research is required to see if corneas treated demonstrated significant stability in visual outcomes
with hypo-­osmolar riboflavin have lasting effects. and in halting keratoconus progression over many
years. With the establishment of CXL, a few investiga-
TECHNIQUES FOR SHORTER LIGHT
tors have begun looking at ways to combine the 2 treat-
TREATMENTS
ments in order to synergize their effects. Initial reports
Recent modifications have been made to reduce CXL suggest that it is safe and effective to combine CXL with
surgery time. The current standard protocol takes ap- Intacs insertion.
proximately an hour, which can be considerably uncom-
fortable for the patient. Furthermore, longer exposure CXL IN COMBINATION WITH PRK. Patients with
time puts corneas at risk for desiccation, which can de- keratoconus often suffer from significant irregular astig-
crease corneal thickness during surgery and increase the matism. In healthy corneas with adequate thickness, la-
risk for infection afterwards. By decreasing the exposure ser refractive surgery can be an option. However, KC
time of UVA delivered, the same total energy on the cor- is traditionally a contraindication for such procedures
nea can be maintained if the power is increased. Avedro because of the obvious dangers of exacerbating an al-
(Waltham, Massachusetts), a private medical device ready weakened cornea. Recently, the favorable effects
company, was the first to take advantage of this concept of CXL have allowed some ophthalmologists to recon-
in 2011 with their accelerated KXL system. The device sider limited refractive surgery on ectatic corneas. The
provided up to 30 mW/cm2 of power over 3 minutes of controversial concept was first introduced by Kanello-
exposure, providing the equivalent 5.4 J/cm2 of energy poulos, where he simultaneously combined CXL with
while drastically truncating surgery time. Theoretically, topographically guided photorefractive keratectomy
increasing the power of UVA to the cornea may increase (PRK) in what is now known as the Athens Protocol.
the risk for cytotoxic damage, and therefore more The procedure does not treat the whole refractive error

FocalPoints Module 11, 2015 9

 Table 3. Results of Clinical Studies on CXL in Combination With Other Modalities

AUTHORa MEAN FOLLOW-UP NO. OF EYES IMPROVEMENT

CXL COMBINED SIMULTANEOUSLY WITH PRK
Kanellopoulos (2009) 36 months 198 Kmax: 3.50 D
(simultaneous group) BCVA –0.28 logMAR, UCVA –0.66 LogMAR
SE: 3.20 D
Kymionis, et al (2009) 10.6 months 17 Kmax: 3.07D
BCVA –0.10 LogMAR, UCVA: –0.83 LogMAR
SE: 1.74 D
Stojanovic, et al (2010) 12 months 12 Astigmatism: 2.7D
BCVA: 20/57 to 20/35
UCVA: 20/1000 to 20/100
Kanellopoulos, et al 24 months 32 UCVA & BCVA: –2.25 LogMAR
(2011) Mean RE: 2.50D
CXL COMBINED WITH INTACS/ICRS
Kılıç, et al (2012) 7.07 months 131 Kmax: 4.47D
UCVA –0.26 LogMAR, BCVA: –0.24 LogMAR
Mean Sph Refraction: 2.62D
Mean Cyl: 1.62D
Legare, et al (2013) 9.8 months 27 BCVA –0.20 logMAR, UCVA –0.79 LogMAR
(ICRS + CXL group) Mean Sphere: 1.59D
Mean Cyl: 3.55D
Yeung, et al (2013) 12 months 38/47 (single/paired ICRS) Single ICRS:
UCVA: 3.4 Lines
Mean Cyl: 1.65D
Paired ICRS:
UCVA: 2.7 Lines
Mean Cyl: 0.95D
CXL Combined With PTK
Kymionis, et al (2012) 12 months 19 UCVA –0.36 LogMAR, BCVA: –0.12 LogMAR
Mean Cyl: 1.53D
Kapasi (2012) 12 months 17 Mean Sphere: 1.68D
Mean Cyl: 0.53D
Lines of Improvement: 0.33 lines
a
Refer to Suggested Reading for citations.

but rather, uses minimal laser ablation to resurface and CXL IN COMBINATION WITH PTK. In another tech-
normalize the irregular cornea by removing no more nique variation, laser phototherapeutic keratectomy
than 50 µm of tissue. The goal is to improve BCVA with (PTK) has been used to remove the epithelium prior
a flatter and more regular corneal surface while halt- to CXL. By using the patient’s epithelium as a mask-
ing the ectasia with CXL. A number of case series have ing agent and with the understanding that the epithe-
repeated the Athens protocol with encouraging results lium is thinnest above the steepest point of the cornea,
and demonstrated safety (see Table 3); however, the un- the premise is to take advantage of the smoothing and
orthodox procedure remains quite contentious amongst normalizing effect of PTK to achieve better visual out-
leading experts. Larger, longer, prospective, randomized comes. An excimer laser is used to remove the anterior
studies establishing safety and efficacy are needed to 50 µm of surface tissue, including the epithelium. At a
validate the results of these studies. For now, extra cau- depth of 50  µm in a keratoconic eye, a small amount
tion and explicit informed consent is warranted when of the stroma and anterior cone is ablated, effectively
considering this procedure for patients. flattening and levelling out the cone. Initial studies have

10 FocalPoints Module 11, 2015

 Future Directions
Corneal collagen crosslinking remains a heavily re-
searched field. One novel consideration involves using
other agents in lieu of the riboflavin/UVA combination,
essentially eliminating the risks that arise from exposure
altogether. Aliphatic beta nitro-­alcohols without UVA
have shown potential in crosslinking porcine corneas;
however, studies documenting efficacy and safety in vivo
remain to be seen. There is also a favorable trend toward
using CXL in nonectatic conditions such as for corneal
edema in cases of pseudophakic bullous keratopathy
and Fuchs endothelial dystrophy. It is hypothesized that
CXL increases intracellular attachments, thereby reduc-
ing space for fluid accumulation. Reported cases have
had mixed results, ranging from some with only tempo-
rary reduction in swelling to others with limited effect.
Figure 10  Patient with intrastromal corneal ring
Studies with longer follow-­up and greater patient num-
segment (Intacs, Addition Technology Inc, Lombard, bers are necessary to assess the efficacy and limitations
Illinois) inserted into a femtosecond laser-created of CXL in the treatment of corneal edema.
channel prior to same-day CXL treatment.

Conclusion
reported lowered mean refractive spherical equivalent Corneal collagen crosslinking has ushered fundamen-
(MRSE) and better visual outcomes but longer term, tal changes in the treatment of keratoconus and kera-
follow‑up studies with larger patient series are necessary tectatic conditions. CXL treatment can stabilize these
to properly evaluate outcomes of this combination. diseases, allowing patients to preserve or improve their
vision and possibly delay or obviate the need for cor-
CXL TO TREAT INFECTIOUS KERATITIS. As we enter
neal transplantation. Long-term studies continue to be
an era of antimicrobial resistance, there has been added
carried out to confirm the lasting effects of CXL and
emphasis in finding agents that can eradicate microbes
combined treatment modalities such as with PRK, PTK
with limited side effects. The known antimicrobial prop-
or intrastromal corneal ring segments. Questions about
erties of activated riboflavin have been widely leveraged
rates of re-treatment and definitions of progression in
in the past to disinfect blood products and inactivate
patients treated for 10 years and beyond still need to be
viruses. In vitro experiments have also demonstrated
addressed. Further modifications to the treatment pro-
the bactericidal effect of CXL. Subsequently, a num-
tocol with epithelial-­on techniques and adjustments in
ber of reports have surfaced in which CXL is used to
UVA light delivery will lead to increased patient com-
treat multi-­ drug resistant infectious keratitis. Of the
fort and decreased surgical risks associated with the
published data, nearly all report a reduction in pain,
procedure.
ulceration, and healing time in a wide array of bacte-
rial, fungal and Acanthamoeba organisms. Moreover,
the stiffening effect of CXL increases resistance to en- Aaron Chan, OD, is an MD candidate at the University
zymatic degradation, which has been demonstrated to of Toronto Medical School and is a Doctor of Optom-
halt corneal melt. Worth noting is that the majority of etry at Downtown Eye Associates, Toronto, Canada.
these cases are severe, and many eventually require cor-
Clara C. Chan MD, FRCSC, FACS, is an assistant pro-
neal transplant from significant scarring. Though this
fessor in the Department of Ophthalmology and Vision
potential application is exciting, published literature
Sciences, University of Toronto, Toronto, Canada.
is mostly anecdotal and randomized clinical trials are
needed to define appropriate criteria. Until more data is
established, CXL for infectious keratitis should be ap-
proached with caution.

FocalPoints Module 11, 2015 11

Clinicians’ Corner

Clinicians’Corner
Clinicians’ Corner provides additional viewpoints on the subject covered
in this issue of Focal Points. Consultants have been invited by the
Editorial Review Board to respond to questions posed by the Academy’s
Practicing Ophthalmologists Advisory Committee for Education. While
the advisory committee reviews the modules, consultants respond
without reading the module or one another’s response. –Ed.

1. Do you prefer epithelial-­on or epithelial-­off treat- stiffening effect that occurs. Remember, it is always pos-
ment for corneal collagen crosslinking (CXL)? sible to offer epi‑off treatment if there is progression af-
ter epi‑on treatment.
>>>Dr. Güell: Today, despite the obvious advantages
of leaving the epithelium untouched (postoperative risk
and subjective complaints), I still prefer an epithelial-­
off procedure with the classical protocol in my stan- 2. Can patients with thinner corneas (<400 µm) re-
dard CXL treatments. The available data of riboflavin ceive CXL safely? How do you modify your tech-
stromal distribution through an intact epithelium is still nique for a thinner cornea?
quite debatable and inconsistent. On the other hand,
and together with other investigators, we are exploring >>>Dr. Güell: Again, available data on this item is
the epithelial‑on iontophoresis technique (particularly quite confusing. I still recommend CXL with the stan-
in our older patients) because it looks like that, although dard epithelium-­ off protocol in cases with central
slightly reduced, the penetration of riboflavin through pachymetry between 375–400 µm using hyposmotic ri-
this approach is quite homogeneous throughout the cor- boflavin preparations. We should take into account that
neal stroma. these unstable thin corneas would only have, as a sec-
ondary option, a keratoplasty approach. Thus, it makes
>>>Dr. Stulting: We have been performing CXL for sense to test a not-so-­invasive procedure first.
7  years as investigators for 3  different clinical trials,
treating over 400 eyes using both epi‑off and epi‑on pro- >>>Dr. Stulting: For the past 1  1/2  years, we have
tocols. Although we have not had any cases of severe, been performing epi‑on CXL under a protocol that al-
significant visual loss, we have seen sterile infiltrates lows treatment of corneas as thin as 250 µm. We have
and subepithelial scarring due to persistent epithelial de- actually treated corneas with a thickness in the low
fects with epi‑off treatments. Epi‑off protocols result in 300 µm range without complications. During our early
greater discomfort, lengthier visual recovery, and more years of performing CXL, we instilled artificial tears
frequent follow-­up examinations than epi‑on protocols. and asked patients to sit with their eyes closed when the
On the other hand, epi‑on treatments probably do not corneal thickness was less than 400 µm after saturation
stiffen the cornea as much as epi‑off treatments do. with riboflavin. This method causes rapid swelling of
The key to obtaining good results with epi‑on treat- the cornea so that treatment can be begun on a cornea
ment, I believe, is to obtain good saturation by effective thicker than 400 µm typically in only a few minutes.
enhancers in the riboflavin solution, mild mechanical
epithelial disruption during saturation, slit lamp verifi-
cation of adequate riboflavin penetration, not applying
3. What age limits are recommended for CXL? Do
riboflavin during light treatment, and greater fluence.
Nobody knows how much stiffening is “enough” for these limits change depending on the reason for
any given patient, but I believe the increased safety of treatment (eg, keratoconus, postrefractive ectasia)?
epi‑on CXL more than compensates for any reduced

12 FocalPoints Module 11, 2015

Clinicians’ Corner

>>>Dr. Güell: I do not consider any age limit nor dif- >>>Dr. Güell: My limited experience using CXL in
ferences between primary or secondary ectasia for my severe cases of infectious keratitis unresponsive to the
CXL indication. I only consider refractive-­topographic conventional topical treatment has been extremely sat-
instability or progression in primary and secondary isfactory. There were 3 cases of infectious keratitis, sev-
cases. Age might be an issue when recommending CXL eral months apart, 2 caused by Pseudomonas and 1 by
without demonstrating this instability or progression. Acanthamoeba. In 1 of the pseudomonas cases, amni-
In these very young patients, I recommend CXL before otic membrane transplantation was applied immediately
these signs are topographically obvious if I consider the after the CXL treatment. All cases responded very well,
risk of progression to be high. stopping the active process in less than 1 week. Several
groups are investigating the effect of CXL early in the
>>>Dr. Stulting: Having seen the results of CXL in management of infectious keratitis. Although the results
my own hands and reading the international literature, have not yet been published, preliminary results look
I now believe that CXL is the procedure of choice for quite promising.
keratoconus at the time of diagnosis for young patients,
regardless of patient age. Because CXL is a relatively >>>Dr. Stulting: I have no experience in treating in-
safe treatment, particularly with epithelium on, and fectious keratitis with CXL.
progression of keratoconus so likely, I do not believe
it is in the best interest of a young patient to wait for
demonstrated progression before offering CXL. On the
other end of the spectrum is the older patient, whom we 6. What is your experience with CXL in combina-
initially believed might not benefit from CXL because tion with photorefractive keratectomy (PRK) and
of the natural stiffening of the cornea that occurs with intrastromal corneal ring segments (ICRS)?
age. We have now seen not only stabilization of disease,
but improvement in vision in older patients. Based on >>>Dr. Güell: I started relatively late with the combi-
these observations and the safety of epi‑on CXL, I be- nation of PRK and CXL because I needed to see long-
lieve the upper age limit for CXL treatment should be term results from other groups first. Finally, during
up to 60 years of age. the last 3 years, I have been using such a combination
in 2  groups of patients with very good results: forme
fruste keratoconus with low ametropia (<3.00 D of SE)
in those patients seeking or refractive surgery and in
4. What major contraindications exist for CXL? those progressive keratoconic eyes with low ametropia
(<3.00 D of SE). I recommend doing both procedures at
>>>Dr. Güell: From a clinical point of view and beside the same time, starting with the PRK, and my favorite
the corneal thickness limitation, the only major contra- approach is the topography-­guided transepithelial tech-
indications are a history of recent active ocular surface nique for PRK, in order to precisely try to correct the
herpetic disease or allergy to riboflavin. irregular component of the topography.
Regarding the combination with ICRS, I am recom-
>>>Dr. Stulting: Patients with very thin corneas that mending CXL after ICRS implantation only in kerato-
might receive endothelial damage from CXL and corneal
conic eyes that show progression, accepting the practical
scarring that would prevent the patient from obtaining
limitations in evaluating progression in these cases.
acceptable vision are contraindications to CXL. I believe
that the original recommendation that CXL with the >>>Dr. Stulting: I have no experience with CXL in
Dresden protocol should not be performed on corneas combination with PRK and ICRS.
less than 400 µm in thickness may be overly conserva-
tive. It is certainly overly conservative for epi‑on treat-
ments as we are now performing. We are not certain,
however, what the minimum safe limit of corneal thick- 7. What is the re-treatment rate for CXL? Is the ef-
ness for epi‑on CXL might be. This question will only fect of the surgery stable?
be answered when we gain more experience with CXL.
>>>Dr. Güell: After 7  years of standard protocol
epithelium-­off CXL and with more than 300 eyes oper-
ated on, I have re‑treated only because of progression of
5. What is your experience with CXL in treating the ectasia in one case. In most series, the r­e‑treatment
infectious keratitis? What other future indications rate is very low, although I presume that groups us-
might apply for the CXL modality? ing transepithelial techniques and shorter treatment

FocalPoints Module 11, 2015 13

Clinicians’ Corner
protocols will probably observe a higher incidence when this indication but only to improve irregularity indexes
using them in their young progressive keratoconic cases. and to correct low ametropia. For obvious reasons, pen-
etrating and lamellar keratoplasty techniques will sta-
>>>Dr. Stulting: After performing CXL for 7  years, bilize the situation for a number of years but the late
we finally saw 1 patient who had progressed. We realize progression of the disease has been described after all
our follow-­up time is not as long as it is internationally, these keratoplasty techniques. Consequently, some of
but we believe the need for re‑treatment will be minimal. us are considering the use of CXL several months after
keratoplasty in order to ensure a longer stability. Un-
fortunately, as with most approaches directed toward
long-term stabilization of the disease, only long-term,
8. How do you define progression of keratoconus?
well-­designed studies would provide the answer of our
>>>Dr. Güell: There is not yet an accepted consensus questions.
worldwide about the definition of progression in ker-
ataconus (Gomes et al, 2015). From a practical point >>>Dr. Stulting: Traditionally, we have treated kera-
toconus with glasses, rigid contact lenses, and corneal
of view, I consider that an already diagnosed primary
transplantation, in that order, as the disease progresses.
or secondary ectasia is progressing if its mean K read-
None of these modalities addresses the underlying pa-
ings increase >1.00  D, refractive astigmatism increases
thology. They just aid in improving vision. CXL is unique
>1.00  D, best spectacle-­corrected visual acuity dimin-
because it stiffens the cornea, halting progression of the
ishes >1  Snellen line while best-­corrected visual acuity
disease and affecting the underlying pathology. Other
with rigid gas permeable contact lenses remains the same
modalities are now being used internationally in con-
and/or central corneal thickness diminishes >20 µm.
junction with CXL to improve vision—such as ICRS,
>>>Dr. Stulting: Progression is difficult to determine thermokeratoplasty, and topography-­guided PRK. Based
because measurements of disease severity are not very on the extremely favorable risk-­benefit analysis of CXL,
precise in eyes with ectatic corneal disease. Fortunately, I believe it should be considered as soon as the diagnosis
as our experience with CXL has increased and as we of ectatic corneal disease is made. Properly administered
have migrated from epi‑off treatment to epi‑on treat- at the time of diagnosis, along with early disease detec-
ment, proof of progression has become less important to tion, CXL can virtually eliminate loss of vision from
us in deciding whether to recommend treatment or not. ectatic corneal disease and other pathology. It has the
potential to reduce the number of corneal transplants
we perform in this country by up to 50%.

9. What are the alternatives to treat progressive José L. Güell, MD, is director of the Cornea and Re-
keratoconus, and when should crosslinking be fractive Surgery Unit at the “Instituto de Microcirugia
considered? Ocular de Barcelona” and an associate professor of oph-
thalmology at the Autonomous University of Barcelona
>>>Dr. Güell: There is today no other treatment but in Barcelona, Spain.
CXL to treat progression in keratoconic eyes. It has
been described in several published series, including R. Doyle Stulting, MD, PhD, is cofounder of the Stult-
ours, that ICRS might stabilize in a significant number ing Research Center at Woolfson Eye Institute and a
of cases of progression but they should not be used for practicing ophthalmologist in Atlanta, Georgia.

14 FocalPoints Module 11, 2015

SUGGESTED READING
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