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December 2011
CORNEA
Cornea editor's corner of the world
Anxiously awaiting corneal crosslinking
by Enette Ngoei EyeWorld Contributing Editor
With the treatment closer to FDA approval in the U.S., EyeWorld looks at the details of corneal
crosslinking in practice
Corneal collagen crosslinking as the standard of care treatment for progressive keratoconus and
Corneal collagen
crosslinking
(CCL) has been
utilized for the
treatment of
corneal ectasia
throughout the
world. Studies
have
demonstrated
the benefits of
this technique as
a treatment to
stabilize corneas
that are
demonstrating
progressive
ectasia. CCL has
been used in
patients with
keratoconus to
prevent further
thinning and
steeping of the
cornea, thus
preventing the
need for a
keratoplasty. In
addition, CCL has
been utilized as
the first-line
therapy for
patients with
post-corneal
refractive ectasia
to prevent
further corneal
changes and in
some cases
achieve a slight
reversal of the
corneal
steepening. The
largest potential
clinical
application of
CCL may be in
prophylaxis
rather than
treatment of
ectasia. Some
clinicians are
advocating the
use of this
treatment for all
patients who are
diagnosed with
keratoconus or
pellucid marginal
degeneration
before the cornea
has developed
significant
steepening and
irregular
astigmatism.
Another
prophylaxis
possibility is the
corneal refractive
patient at a
higher risk for
ectasia with the
CCL treatment
given
pre-operatively
or
intraoperatively.
Finally, the use
of CCL is being
explored in
patients with
established
keratoconus to
allow for the
possibility of
subsequent
corneal refractive
surgery.
Unfortunately,
CCL does not
have FDA
approval in the
U.S. at this time.
Therefore U.S.
patients are not
receiving what
appears to be a
safe and effective
in-office
procedure that in
many cases will
prevent the
progression of
ectasia and the
need for a
keratoplasty. I
have asked Drs.
Donnenfeld and
Stulting, U.S.
refractive
surgeons who
have been active
in CCL research,
to give their
views. In
addition, Dr.
Stein, a very
experienced CCL
clinician in
Canada, shares
his insights.
Edward J.
Holland, M.D.,
cornea editor
post-LASIK ectasia has been available in Canada for more than 4 years and in Europe for even
longer. In the U.S., there are several clinical trials being conducted, and the one that's closest to
resolution is one sponsored by Avedro Inc. (Waltham, Mass.), said Eric D. Donnenfeld, M.D.,
co-chairman, Cornea, Nassau University Medical Center, East Meadow, N.Y.
"That data has been submitted to the FDA, and we're looking forward to seeing that approved,"
he said.
An effective treatment
Keratoconus is the second most common cause of corneal transplants in the United States, and
with crosslinking, it can virtually be eliminated, Dr. Donnenfeld said.
The document of literature shows that corneal crosslinking overwhelmingly stops the progression
of keratoconus or ectasia and that there's a mean of approximately 1.0-2.0 D of flattening of the
cornea as well, he said.
While the data on post-LASIK ectasia patients is not quite as good as with keratoconic patients,
it's still good, Dr. Donnenfeld said.
R. Doyle Stulting, M.D., Woolfson Eye Institute, Atlanta, who is involved with clinical trials
sponsored by Topcon Medical Systems (Oakland, N.J.), also said the treatment is very effective,
based on international data. Raymond Stein, M.D., medical director, Bochner Eye Institute,
Toronto, whose practice was the first in Canada to become involved with corneal crosslinking,
said, "We've been doing it for 4-and-a-half years, and we've treated approximately 2,500 eyes in
that period. We haven't seen any patient who's shown progression, and we've treated patients as
young as 10 years of age."
The majority of his patients are between 18 and 30, but he has also treated patients whose ages
range from 10 all the way up to 60.
"It's an extremely effective procedure at preventing progression," Dr. Stein said.
Who should be treated and when
Dr. Donnenfeld said that any patient who has progressive disease should be treated. "Any patient
who is showing worsening ectasia by keratometry often verified by refraction should be treated,
and the earlier you treat patients, the better the prognosis," he explained.
He added that patients who have advanced disease generally aren't as eligible for treatment
because these are patients who have very steep corneas, over 60 D, patients with apical thinning
with corneas thinner than 400 microns, and patients with apical scarring. Dr. Stulting is of the
same opinion: "Anyone who has keratoconus or corneal ectasia should be treated at the time of
diagnosis. Perhaps some of those people will not progress, but I think the risk/benefit ratio for
the treatment favors a decision to treat everyone once a diagnosis is made."
There's also no age limit on how young patients can be treated, Dr. Donnenfeld said. "I've
treated patients as young as 14 years of age and as old as 60. The real key is whether the
disease is progressing and if we can stop it from progressing safely. The same goes for refractive
surgery patients," he said.
In Europe, the general guideline is to wait for progression before treating, Dr. Stein said. "But
our thought in Canada is that if someone develops keratoconus at an early age, the chance [of
progression] is close to 100%, and the earlier you do the treatment, the better the visual
prognosis because it basically locks everything in place and prevents deterioration of best
corrected visual acuity."
In Canada, patients between the ages of 10 and 28 are recommended treatment even without
evidence of progressive disease, he said. However, in patients over 28, some progression is
usually documented, with follow-ups every 3-6 months. Topographic analysis is performed and if
there is some further thinning or progressive steepening, crosslinking will be performed, Dr.
Stein said.
As for post-LASIK patients, Dr. Stein said they tend to respond or progress a little differently
than the keratoconus patients. They tend to progress over time even if they're older, whereas
when keratoconus patients get to about 35 or 40 years of age, their corneas are usually fairly
stable. So for these patients, intervention treatment is recommended at any age without having
to have a second instrument showing progression, Dr. Stein said.
Crosslinking as prophylactic treatment
With very little hard data to show the safety and efficacy of the prophylactic treatment of patients
at risk of ectasia using corneal crosslinking, the jury is out right now, Dr. Donnenfeld said.
"I'm convinced that if you crosslink patients who are at risk of developing ectasia, they won't
develop ectasia. My concern is that crosslinking, which is known to flatten the cornea, will change
the visual results of LASIK or PRK, and the results will not be as good with crosslinking as they
are without," he explained.
A prospective trial needs to be conducted, he said. But at present, he is not crosslinking patients
who have come in for LASIK because of the lack of knowledge in this area and the fact that
crosslinking is not approved in the United States, he said. He added: "I think it's very reasonable
in the United States to treat patients who have a therapeutic need for visual rehabilitation and
the prevention of ectasia progression, but prophylaxis is a different level of treatment and one
that I'm not comfortable performing today until we have more knowledge about the outcomes."
According to Dr. Stulting, prophylaxis for ectasia in refractive surgery may have a role in selected
cases where there is an increased risk for ectasia. However, he would not do it across the board,
he said.
For Dr. Stein, while the concept is interesting, he said the question is whether it is right to do
crosslinking when the incidence is about 1 in 3,000. "Surgeons certainly could make a case for
crosslinking patients, whether they crosslink all patients or they crosslink patients who are at
higher risk or patients with thinner corneas, slightly irregular topographies, family history of
keratoconus, and higher refractive corrections. We have not done this yet," he said.
He wants to make sure from the data that there isn't an increase in complications from the laser
portion. "For example, if there is a delay from putting the flap back down because surgeons have
irrigated riboflavin under the flap and waited awhile and then irrigated again, is there a higher
incidence of micro-striae?"
While he hasn't heard of any reports that there is, it would certainly be concerning, he said.
"We're waiting for published clinical studies before getting involved with that."
While clinicians wait for FDA approval, Dr. Donnenfeld said: "In the meantime, I don't think it's
fair to our patients to allow them to develop progressive keratoconus and ectasia. Any patient
who comes in to a clinician's office with progressive corneal thinning and ectasia should be
directed to a doctor who is performing this treatment or sent abroad to another country where
it's approved. We can't wait any longer and allow our patients to be needlessly harmed by the
lack of approval of riboflavin UV crosslinking."
Editors' note: Drs. Donnenfeld, Stein, and Stulting have no financial interests related to this
article.
Contact information
Donnenfeld: 516-766-2519, [email protected]
Stein: 416-960-2020, [email protected]
Stulting: 770-255-3330, [email protected]
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