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Corneal Collagen Crosslinking for Keratoconus
C-18113 O/D
45
Preeti Singla, MSc, MCOptom
Keratoconus is a non-inflammatory disease of the cornea also known as primary
corneal ectasia. It is characterised by biomechanical instability and thinning
have seen the introduction of exciting new treatments that aim to slow the
progression of the disease. One such treatment is corneal collagen cross-linking
It is interesting that young patients
(CXL). This article describes the treatment, results, and contraindications, so
with diabetes have never been reported
that patients with keratoconus can be educated about this new development.
to develop keratoconus unless its onset
was before the onset of diabetes, whilst
a
look to slow the progression of the disease
those patients already diagnosed with
stiffness of only 60% of that of a normal
too. Intra-corneal ring segments (Intacs)
keratoconus are not noted to have
cornea,1 which often leads to progressive
are one example, which involve the
progression of the disease following the
myopia, irregular astigmatism, higher
insertion of PMMA ring segments into the
onset of diabetes. It is the natural cross-
order aberrations and corneal scarring,
corneal stroma in order to delay the need
linking effect of glucose in the corneae
thus resulting in a potential decrease
for corneal transplant surgery (Figure 1).
of such patients that increases corneal
in visual acuity (VA). It affects 1 in
Less invasive than this is the cross-linking
resistance to deformation of shape.9
2000 of the general population and
of collagen fibres in the cornea, to provide
is
added strength, which is known as CXL.
A
cornea
with
generally
first
keratoconus
diagnosed
has
in
the
Cross-linking
a
well-established
technique used in synthetic polymer
chemistry
second and third decades of life.2 It is
is
and
the
manufacture
of
generally bilateral but often asymmetric
The principles of CXL
plastics
and is progressive in 20% of cases.
The cornea is made up of a regular matrix
orthopaedics.11 It works by increasing the
of collagen fibres of which the primary
mechanical strength of a material. Its use in
function
mechanical
the cornea was discovered at the Dresden
support. These are called the stromal
Technical University in 199812 and its
largely
lamellae. The individual collagen fibrils
use for keratoconus was first reported
disease
are strengthened by inter-molecular cross-
by Wollensak and colleagues in 2003.5
progression. Until recently, treatment of
links that develop as a natural part of
Corneal cross-linking has also been used
the condition centred on providing an
their maturation process. In conditions
successfully in the treatment of iatrogenic
improvement in VA, initially by spectacles
where the cornea is weak, such as in
ectasia after excimer laser ablation and
and then contact lenses, and finally,
keratoconus, there is an abnormality in
for
when refractive correction can no longer
the types and numbers of these links and
provide adequate levels of vision or when
as a result the corneal shape begins to
Technique
there is intolerance to contact lenses, by
bulge into a conic shape. CXL works by
CXL involves the use of riboflavin
penetrating and lamellar keratoplasty.
increasing these collagen cross-links and
(vitamin B2) and ultraviolet-A (UVA)
However, all of these techniques only
thereby strengthening the human cornea
light irradiation. Riboflavin has a two-
correct the refractive error associated
by up to 328.9%4 (Figure 2). A beneficial
fold role in the procedure. It acts as both
with keratoconus and do not address the
side effect of CXL in many patients is
a photo-sensitizer for the induction of
underlying ectasia. Recently-introduced
flattening and regularisation of the conic
cross-links between collagen fibrils, as
treatments however, no longer aim to
corneal shape, which in turn can cause a
well as shielding the underlying tissue
simply maintain good vision but actually
reduction in myopia and astigmatism.
from the effects of UVA (Figure 3).12
Traditional management
methods
Management
of
depends
the
on
keratoconus
extent
of
is
to
provide
10
as well as in dentistry and
pellucid
marginal
degeneration.
3
5-8
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Figure 1
Intra-corneal ring segments (Intacs) as a
treatment for keratoconus
of the corneal stroma as a result of weakened collagen fibres. Recent years
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Contraindications
Corneal opacities,17 ocular pathologies,17
corneal scarring,14 Vogt striae,14 dry eye,8
corneal infections,8 and previous surgery8
were all listed as contraindications for
CXL in the studies carried out to date. It
is not clearly indicated whether corneal
46
scarring or pathology causes an adverse
effect following treatment or whether the
24/02/12 CET
Figure 2
CXL works by increasing collagen cross-links thereby strengthening the human cornea
treatment would just be less effective.
The interaction of riboflavin and UVA
whilst improvement in best-corrected
produces a reactive oxygen species,
VA (BCVA) was on average 1-2 lines
which causes the formation of additional
of acuity.5-9,14 A reduction in myopia of
covalent
collagen
between 0.40D to 1.14D5-7 was noted
molecules, consequently producing a
and a reduction in astigmatism of
biomechanical stiffening of the cornea.
0.93D was also reported.8 The average
bonds
between
sterile
flattening of the corneal keratometry
conditions and is therefore generally
readings was by 1.42D to 2.00D.7,14,15
carried out in an operating theatre
Post-operative regression of keratoconus
(Figure 4). There are some variations to
has been noted in 70% of cases.5
The
treatment
requires
the treatment procedure but generally
Patient suitability
anaesthetic drops and then removal of the
Age
central 7mm diameter area of the corneal
Studies have included patients as young
epithelium. The exposed corneal surface
as 10 years of age,14 up to the age of 60
is then treated with the application of
years6 and as of yet, the National Institute
riboflavin 0.1% solution for a total of
for
30 minutes; 5 minutes into this process,
(NICE)
the cornea is irradiated with UVA of
there will be any age limitations on
370nm wavelength and irradiance of
the availability of the CXL treatment.16
has
and
not
Although no difference in pre- and postoperative corneal thickness has been
reported with CXL treatment,14 CXL in
corneas with thickness less than 400µm
after epithelial removal has been shown to
result in significant endothelial cell density
decrease
following
treatment.18
More
significantly in patients with thin corneas,
a permanent stromal scar tends to develop
after CXL.19 Most traditional studies use a
minimum thickness entry requirement of
it involves the instillation of topical
Health
Corneal thickness
400 µm.5,6,8,9,14,15 However a recent study
Clinical
Excellence
indicated
whether
3mW/cm2 at a distance of 1cm from the
has shown that the thickness of thinner
corneas can be increased by application
of
hypo-osmolar
riboflavin
solution
following epithelium removal. All corneas
in this study were found to be transparent
without any detectable scarring lesions
in the stroma at the 1-year follow-up.20
Complications
cornea. This too is applied for a period
Progression
of 30 minutes, delivering a total dose of
NICE
the
Failure of a treatment can be described in
5.4Jcm-1. Antibiotic eye drops are then
procedure should only be carried out on
a number of ways. Failure and retreatment
instilled, as a prophylaxis following
patients with progressive keratoconus.16
levels have been found to be low, with less
treatment, as well as a bandage contact
However, how this should be decided
than 2% of patients experiencing acute
lens, until the epithelium has healed.13
and over what time scale is not
exacerbation of neurodermatitis, which in
indicated. Studies to date have used
turn can cause progression of keratoconus
varying methods of analysis to establish
and
Studies on the outcome of CXL have
progression. These include (i) increase
Another indication of failure is an increase
only been conducted for approximately
in keratometry reading of greater than
rather than decrease in maximum corneal
a decade. These initial results, some
1.00D,7,8,15,17 (ii) increase in spherical
keratometry reading; an increase of more
of
refractive error by 0.50D,7 (iii) increase
than 1.00D was noted in 7.6% of patients.21
Results
which
have
conducted
long-
guidelines
Failure
indicate
that
may
require
repeat
treatment.8
8
in astigmatism by 1.00D, (iv) the need
in
for a new contact lens fitting in the space
Haze
uncorrected VA (UCVA) was found to
of 2 years,8,15 and (v) patient report of
Temporary haze is a very common
be between 1 to 3.6 lines of acuity6-8,14
decrease in VA over the past 2 years.8
occurrence after CXL treatment but this
term
are
analysis
very
of
positive.
up
to
6
years,
Improvement
7
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Figure 3
Appearance of the cornea after
absorption of riboflavin during
CXL. Courtesy of Mr Mohammed
Muhtaseb, Consultant Ophthalmic
Surgeon
is recognised and treated appropriately,
it may still cause corneal scarring and
decrease the BCVA. Therefore, although
rare, these cases emphasise the need for
all surgical procedures to be carried out
under sterile conditions, for post-operative
a grade of 0.06 noted at 12
months (grade 1 being total
corneal haze),21 or with use
of topical preservative-free
follow-up to include the use of topical
47
antibiotic agents, and for informed consent
to be obtained from patients who elect
to have this procedure for keratoconus.
Figure 4
Set-up of the CXL surgical technique
steroid therapy.14 Permanent
The future
corneal haze is more likely
The ability to achieve predictable cross-
progression. The weaker biomechanical
in patients with thinner corneas and
linking without epithelial removal would
effect is presumably due to insufficient
steeper corneal curvature.19 Persistent
be a desirable modification in order to
trans-epithelial
haze was found to reduce the BCVA by
lessen
and
into the stroma. Translated to a human
2 lines of acuity in 2.9% of patients.
shorten recovery time. However, it is likely
cornea, this will produce an increase in
A scar developed in 2.9% of eyes.
that complete removal of the epithelium is
Young’s modulus of only 64% with the
necessary to permit adequate and uniform
epithelium intact compared to 320%
saturation of the stroma with riboflavin.
found with standard CXL. Early studies
Removal of the corneal epithelium during
In 2004 Boxer Wachler proposed a
on human eyes have shown a limited
the process of CXL treatment will cause
slight modification of the existing CXL
but favourable effect of trans-epithelial
post-operative pain, often severe, for 24-72
treatment. He suggested the use of pre-
CXL
hours, as is noted with similar procedures
operative anaesthetic eye drops containing
However, based on these predictions
involving excimer surface ablation such as
benzalkonium chloride to loosen the
perhaps this method would best be
LASEK. It has been found that removing
tight junctions of corneal epithelial cells.
reserved for patients with thin corneas.24
the superficial epithelium by excimer
The use of benzalkonium chloride is
It would be reasonable to postulate
laser is significantly more painful than
thought to allow trans-epithelial cross-
that the risk for infection might be
full-thickness removal of the epithelium
linking treatment without removal of the
lower in trans-epithelial CXL where the
using the Amolis brush. Only removing
epithelium.
epithelium
the superficial epithelium also requires
the epithelium intact are absence of post-
almost 40% longer for full saturation of the
operative pain and better patient comfort.11
stroma with riboflavin.22 New treatments
This modification of the technique is
developed
21
21
Pain
post-operative
24
discomfort
The advantages of keeping
on
riboflavin
keratoconus
remains
diffusion
progression.25
intact.
However
further research is needed to confirm this.
Another new technique that has been
is
called
‘flash-linking’,
cross-linking
still in the early stages of human trials.
which uses a customised photoactive
however have been designed to reduce
However, the biomechanical effect of
cross-linking agent requiring only 30
levels of pain experienced (see later).
the trans-epithelial CXL procedure has
seconds of UVA exposure. In porcine
been successfully assessed in rabbit eyes.
eyes it has so far shown a similar
Young’s modulus measures the increase
efficacy in increasing the stiffness of
Microbial keratitis following CXL has been
in biomechanical rigidity and is the
the cornea as standard CXL. However,
observed infrequently with the majority
most reliable parameter for assessment
this is only through measurement with
of incidence reported as anecdotal case
of biomechanical properties. Studies on
surface wave elastometry and further
reports. The possibility of a secondary
rabbits have shown that standard cross-
studies are still awaited on human eyes.26
infection following CXL exists due to
linking increases Young’s modulus by
epithelial debridement as well as the
102.4%, whereas in trans-epithelial CXL
Summary
application of a soft contact lens. By 2010
there is only an increase of 21.3%. This
At present keratoconus is not curable.
a total of 5 incidents of keratitis following
is one-fifth of that found in CXL and
However, it has been shown that cross-
CXL had been reported with BCVA ranging
may not be adequate to increase corneal
linking can stop the progression of
from 6/6 to 6/60.
strength enough to prevent keratoconus
keratoconus. Taking into account both
such
as
trans-epithelial
Microbial Infection
23
Even if an infection
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rate of corneal flattening and failure rate,
the patient’s PCT. It is not known how
research shows that overall success rate
many of these requests will be funded
is best in corneas with a curvature of 54-
but hopefully an NHS referral pathway
58D.
will be established in the near future.
17
Where progression can be reliably
documented it is important to cross-link
corneas with progressive keratoconus as
24/02/12 CET
48
early as possible. Frequently patients are
Acknowledgements
The
author
would
like
to
thank
only referred to the Hospital Eye Service
Consultant Ophthalmologists Mr Bruce
once spectacles and contact lenses can
Allan (Moorfields Eye Hospital) and Mr
no longer provide adequate levels of
Andrew Coombes (Barts and The Royal
vision or the patient becomes intolerant to
London) for their help and support.
contact lenses. Often by this stage there is
Thanks to Consultant Ophthalmologists
evidence of significant disease progression
Mr Chad Rostron and Mr Mohammed
and they may have passed the stage where
Muhtaseb
for
use
of
the
images.
CXL is a suitable management option, for
example where the cornea has become
About the author
too thin or is no longer transparent.
Preeti Singla is a Specialist Optometrist
Cross-linking
is
mainly
indicated
with a keen interest in Paediatrics,
in young patients with clinical and
Contact Lenses and Low Vision. She holds
instrumental documented evidence of
keratoconus progression, a minimum
thickness of 400µm and biomicroscopic
evidence of a clear cornea. It can also be
suitable for older patients with progression
a Masters Degree in Clinical Optometry
or to improve VA in those intolerant to
rigid gas permeable contact lens wear.14
Although the risks of CXL have not yet
been fully quantified, the potential for some
risk would seem justified in the context of a
progressive disease that is otherwise likely
to result in further impairment of VA, or
even the need for lamellar or penetrating
keratoplasty. The decision to undergo
surgical treatment, such as lamellar or
penetrating keratoplasty, should always
be undertaken with careful consideration
to both risks and recovery period.
CXL has been shown to be a practical
outpatient service, which is minimally
invasive and cost-effective with minimal
stress for patients.8 So far it has been
used in research studies and is available
privately. Its use for keratoconus under
the NHS has been approved by NICE,16
although so far there is no routine
funding for CXL under the NHS. For
each individual deemed suitable for the
treatment, an Individual Funding Request
(IFR) must be completed and sent to
and works at Barts and The London
NHS Trust and Moorfields Eye Hospital.
References
1.Andreassan TT, Simonsen AH, Oxlund
H
(1980)
Biomechanical
properties
of
keratoconus
and
normal
corneas,
Experimental Eye Research 31:435-441.
2.National
Keratoconus
Website
www.
nkcf.org accessed on 28th October 2011
3.Cannon DJ and Foster CS (1978) Collagen
crosslinking in keratoconus. Investigative
Ophthalmology and Visual Science 17:63-64.
4.Wollensak G, Spoerl E, Seiler T (2003)
Stress-strain measurements of human and
porcine corneas after riboflavin-ultravioletA-induced cross-linking. Journal of Cataract
and
Refractive
Surgery.
29:1780-1785.
5.Wollensak G, Spoerl E, Seiler T
(2003)
Riboflavin/Ultraviolet-Ainduced Collagen Crosslinking for the
Treatment
of
Keratoconus.
American
Journal of Ophthalmology. 135:620-627.
6.Vinciguerra P, Albè E, Trazza s, Rosetta
P, Vinciguerra R, Seiler T, Epstein D (2009)
Refractive,
Topographic,
Tomographic,
and Aberrometric Analysis of Keratoconic
Eyes
Undergoing
Corneal
CrossLinking.
Ophthalmology
116:369-378.
7.Hersch PS, Greenstein SA; Fry KL (2011)
Corneal collagen crosslinking for keratoconus
and corneal ectasia: One-year results. Journal
of Cataract and Refractive Surgery. 37:149-160.
8.Raiskup-Wolf F, Hoyer A, Spoerl E,
Pillunat LE (2008) Collagen crosslinking
with riboflavin and ultraviolet-A light in
keratoconus: Long-term results. Journal of
Cataract and Refractive Surgery 34:796-801.
9.Caporossi A, Baiocchi S, Mazzotto C,
Traversi C, Caporossi T (2006) Parasurgical
therapy for keratoconus by riboflavinultraviolet type A rays induced cross-linking
of corneal collagen: Preliminary refractive
results in an Italian study. Journal of
Cataract and Refractive Surgery 32:837-845.
10. Snibson GR (2010) Collagen crosslinking: a new treatment paradigm in
corneal disease – a review. Clinical and
Experimental
Ophthalmology
38:141-153.
11. Pinelli R, El Beltagi T (2008) C3-R: the present
and the future. Ophthalmology Times Europe
4(8). Accessed online at: http://www.oteurope.
com/ophthalmologytimeseurope/Cornea/C3R-the-present-and-the-future/ArticleStandard/
Article/detail/556880
21st October 2011.
12. Spoerl E, Huhle M, Seiler T (1998)
Induction of cross-links in corneal tissue.
Experimental
Eye
Research.
66:97-103.
13. Ashwin PT and McDonnell PJ (2010)
Collagen
cross-linkage:
a
comprehensive
review and directions for future research.
British Journal of Ophthalmology. 94:965-970.
14. Caporossi A, Mazzotto C, Baiocchi S,
Caporossi T (2009) Long-term Results of
Riboflavin Ultraviolet A Corneal Collagen
Cross-linking
The
Siena
Journal
of
for
Eye
Keratoconus
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in
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Ophthalmology.
Italy:
American
149:585-592.
15. Grewal DS, Brar GS, Jain R, Sood V,
Singla
M,
Grewal
SPS
(2009)
Corneal
collagen crosslinking using riboflavin and
ultraviolet-A light for keratoconus: One year
analysis using Scheimpflug imaging. Journal
of Cataract and Refractive Surgery. 35:425-432.
16.
NICE
corneal
guidance
collagen
on
Photochemical
cross-linkage
using
riboflavin and ultraviolet A for keratoconus.
Issued
at
November
2009.
www.nice.org.uk,
27th
Accessed
October
online
2011
17. Koller T, Pajic B, Vinciguerra P, Seiler T
(2011) Flattening of the cornea after collagen
crosslinking for keratoconus. Journal of
Cataract and Refractive Surgery. 37:1488-1492.
18. Kymionis GD, Portaliou DM, Diakonis
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20. Raiskup F, Spoerl E (2011) Corneal CrossLinking with Hypo-osmolar Riboflavin
Solution in Thin Keratoconic Corneas.
American Journal of Ophthalmology 152: 28-32.
21. Koller T, Mrochen M, Seiler T (2009)
Complications and failure rates after
corneal crosslinking. Journal of Cataract
and
Refractive
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35:1358-1362.
22. Bakke EF, Stojanovic A, Chen X,
Droslum L (2009) Penetration of riboflavin
and postoperative pain in corneal collagen
crosslinking:
Excimer
laser
superficial
versus mechanical full-thickness epithelial
removal. J Cataract Refr Surg. 35:1363-1366.
23. Sharma N, Maharana P, Singh G,
Titiyal J (2010) Psedomonas keratitis after
collagen crosslinking for keratoconus: Case
report and review of literature. Journal of
Cataract and Refractive Surgery 36: 517-520.
24. Wollensak G, Iomdina E (2009)
Biomechanical and histological changes
after corneal crosslinking with and without
epithelial debridement. Journal of Cataract
and Refractive Surgery. 35: 540-546.
25. Leccisotti A, Islam T (2010) Transepithelial
corneal collagen cross-linking in keratoconus.
Journal of Refractive Surgery 26: 942-948.
26. Rocha KM, Ramos-Esteban JC, Qian Y, Herekar
S, Kruegar RR (2008) Comparative study of
riboflavin-UVA cross-linking and ‘flash-linking’
using surface wave elastometry. Journal of
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Module questions Course code: C-18113 O/D
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1) Keratoconus is a non-inflammatory disease of the cornea
which:
a) Affects 1 in 2000 people and is generally unilateral
b) Affects 2 in 1000 people and is generally bilateral
c) Affects 1 in 2000 people and is generally bilateral
d) Affects 2 in 1000 people and is generally unilateral
2) The primary function of corneal collagen fibres is to:
a) Provide nutrition
b) Provide mechanical support
c) Confer refractive power
d) Confer elasticity
3) The technique of CXL involves:
a) Removal of the central 7mm of corneal epithelium
b) Use of a bandage contact lens
c) Application of riboflavin 0.1% solution for 30 minutes
d) All of the above
4) Following CXL a reduction in myopia has been noted, in the order of:
a) 0.93D
b) 0.40D – 1.14D
c) 1.42D – 2.00D
d) 1.00D – 3.60D
5) At 1-year post treatment, corneal haze was found to be of grade:
a) 1.00
b) 0.06
c) 0.60
d) 6.00
6) In standard CXL there is an increase in Young’s Modulus, of the human
cornea, by:
a) 320%
b) 102.4%
c) 21.3%
d) 64%
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VF, Kounis GA, Panagopoulou SI, Grentzelos
MA (2011) Corneal Collagen Cross-Linking
With Riboflavin and Ultraviolet-A Irradiation
in Patients With Thin Corneas. American
Journal of Ophthalmology epub ahead of print
accessed at: http://www.sciencedirect.com/
science?_ob=MiamiImageURL&_cid=271967&_
user=7153203&_pii=S0002939411004636&_
check=y&_origin=&_coverDate=08-Sep2011&view=c&wchp=dGLbVlV-zSkzV&md
5=4a9f8e82c42953d8bcbdb6f2be263731/1s2.0-S0002939411004636-main.pdf
19. Raiskup F, Hoyer A, Spoerl E (2009)
Permanent corneal haze after riboflavin-UVAinduced cross-linking in keratoconus. Journal of
Refractive Surgery 25 (Supplement): S824-828.