Combined collagen crosslinking treatments for keratoconus

Combined collagen crosslinking treatments for keratoconus

The landscape of keratoconus treatment has
changed profoundly since the introduction of corneal
collagen crosslinking (CXL). A decade ago, a newly diagnosed
keratoconus patient could expect a treatment
plan that involved gradual escalation from spectacle
correction to contact lens wear, perhaps followed by
an attempt to improve contact lens tolerance or spectacle
acuity with intrastromal corneal ring segments
(ICRS) and then, for some patients, keratoplasty.
This path is beset with frustrations for patients and clinicians
alike. Contact lens intolerance, multiple fitting
attempts, and temporal gaps in visual function while
waiting for special-order lenses are a few of the difficulties
faced by patients who would otherwise be enjoying
some of the healthiest and most productive
years of their lives. Keratoconus carries the additional
burden of significant medical expenses that are often
passed along as out-of-pocket expenses because of
inconsistent insurance coverage for ICRS and contact
lenses. When patients do reach the point of keratoplasty,
they are often disappointed by the discrepancy
between their post-transplant vision and the expectation
that transplantation will “cure” their disease
and reverse all the optical distortion that makes keratoconus
a leading cause of impaired vision-related
quality of life.1
Not long ago, disease progression was accepted as
an inevitability for predisposed patients, and one
that could be addressed only post facto. Crosslinking
has fundamentally altered this former truth. Originally
envisioned for stabilizing early disease, CXL is
increasingly used across the spectrum of keratoconus
severity and in combination with other therapies.
Questions about who to treat, when to treat, how to
treat, and why to treat are increasingly important
given the dizzying number of possible treatment
combinations.
In their prospective study of staged ICRS, CXL, and
toric phakic intraocular lens (pIOL) implantation,
Cos¸kunseven et al. (pages 722–729.) report impressive
refractive and visual results while providing a unique
opportunity to study the incremental effects of each
treatment not afforded in studies of simultaneous procedures.
The 14 eyes treated in the study demonstrated
very high myopia with a mean spherical equivalent
(SE) refractive error of 16.40 diopter (D) and a range
up to 22.50 D. Study eyes also had steeper corneas
(mean keratometry value was 60.57 D) than those in
most CXL studies, and progression of at least 0.75 D
was required prior to initiation of treatment. In such
eyes, CXL alonedeven with the associated benefit of
1 D to 2 D of keratometric flattening reported in
many studies2dmight promote stability but would
do little to rehabilitate vision.
With a mean delay of 7 months between ICRS and
CXL, Cos¸kunseven et al. demonstrated the effectiveness
of ICRS in reducing overall corneal curvature,
spherical refractive error, refractive astigmatism, and
keratometric astigmatism while improving corrected
distance visual acuity (CDVA) and uncorrected distance
visual acuity (UDVA). With another 8 months
between CXL and pIOL implantation, an additional
1.70 D of keratometric flattening was observed after
CXL without significant changes in refractive error
or keratometric astigmatism. One year after placement
of toric pIOLs, marked gains in UDVA and CDVA and
reductions of refractive error were achieved, with 86%
of eyes gaining 3 or more lines of CDVA. In the time
between the 6- and 12-month examinations after toric
pIOL implantation, no eye experienced a shift in SE
refractive error greater than 0.50 D.
These results reinforce the complementary functional
goals of each treatment modality in addressing
the different optical manifestations of keratoconus.
Intrastromal corneal ring segments are used to reduce
irregular corneal astigmatism. Corneal CXL is delayed
to allow some normalization of corneal shape after
ICRS before stabilizing an otherwise biomechanically
and optically unstable cornea. Finally, after another
delay to allow early resolution of post-CXL corneal
changes, a more refined intraocular correction of residual
spherocylindrical refractive error is performed with
a toric pIOL. A separate study by Cos¸kunseven
et al.3 of patients with lower levels of ametropia
and less severe keratoconus used transepithelial
topography-guided photorefractive keratectomy
(PRK) rather than a toric pIOL as the final step of
a staged 3-step approach to keratoconus treatment.
Compared with PRK, the advantages of a pIOL
include avoidance of tissue ablation, the capability to
correct higher degrees of spherical and astigmatic
refractive error, lower levels of surgically induced
aberrations, no risk of corneal haze, and a degree of
reversibility. Disadvantages of a posterior chamber
toric pIOL include a potentially higher lifetime risk
of cataract formation in a younger recipient group,
the potential for rotational instability (which might
bemitigated by an iris-fixated pIOL4), and the inability
to offer further correction of irregular astigmatism that
is not corrected by ICRS. This latter limitation, which

also applies to pseudophakic toric IOLs in keratoconus
patients, might explain why patients in the ICRS–
CXL–PRK study achieved UDVA and CDVA that
was on average 1 line better than the ICRS–CXL–toric
pIOL patients. However, a reasonable selection bias
toward pIOL in patients with high ametropia limits
the ability to compare these studies directly.
The worthy goal of these and other combined approaches
is to provide a comprehensive surgical
solution for the optical blur and instability that
drive visual symptoms in keratoconus. The costeffectiveness
of multiple procedures, long-term outcome
stability, patient-reported visual function, and
time required to achieve ultimate vision (which is
comparable to keratoplasty in the cited series) should
be explored in these cohorts and others to strengthen
the case for or against certain combination therapies.
In comparing approaches, it is essential to consider
the disease characteristics of the patients in each study,
particularly the degree of keratoconus severity and
evidence of disease progression prior to treatment.
To this point, judicious selection of patients for combination
treatments involving ICRS implantation is important
given evidence that patients with low-grade
keratoconus could be more prone to loss of CDVA5
because of induced irregularity.
The great promise of CXL for keratoconus is its potential
to prevent loss of vision that is only partially
reversible later with more expensive and invasive
treatments. For today’s patients who have already
experienced significant visual loss, it is increasingly
clear that carefully selected combinations of treatments
can provide both stability and meaningful
visual recovery.
William J. Dupps Jr, MD, PhD
REFERENCES
1. Kymes SM, Walline JJ, Zadnik K, Gordon MO; the Collaborative
Longitudinal Evaluation of Keratoconus (CLEK) Study Group.
Quality of life in keratoconus. Am J Ophthalmol 2004; 138:
527–535
2. Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-A-induced
collagen crosslinking for the treatment of keratoconus.
Am J Ophthalmol 2003; 135:620–627
3. Coskunseven E, Jankov MR II, Grentzelos MA, Plaka AD,
Limnopoulou AN, Kymionis GD. Topography-guided transepithelial
PRK after intracorneal ring segments implantation and
corneal collagen CXL in a three-step procedure for keratoconus.
J Refract Surg 2013; 29:54–58
4. G€uell JL, Morral M, Malecaze F, Gris O, Elies D, Manero F.
Collagen crosslinking and toric iris-claw phakic intraocular lens
for myopic astigmatism in progressive mild to moderate keratoconus.
J Cataract Refract Surg 2012; 38:475–484
5. Vega-Estrada A, Alio JL, Brenner LF, Javaloy J, Plaza
Puche AB, Barraquer RI, Teus MA, Murta J, Henriques J,
Uceda-Montanes A. Outcome analysis of intracorneal ring
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refractive, and aberrometric impairment.