Surface Ablation Prophylactic: Vitamin C or Mitomycin C?
A benign nutrient and a controversial cytostatic share a common effect.
BY ROCHELLE NATALONI, CONTRIBUTING EDITOR
With surface ablation's growing use comes increasing debate about the use of mitomycin C (MMC) or vitamin C to prevent postoperative corneal haze. The stromal changes induced by wound healing that cause haze are more often seen in surface ablation than in LASIK, and MMC effectively prevents or reduces corneal haze, according to numerous reports in the literature. However, its use remains controversial because it is a powerful cytostatic agent with less than a decade of outcomes associated with its use on human corneas.
Meanwhile, the use of prophylactic oral vitamin C also to prevent or minimize corneal haze is on the fast track to "standard of care." Aleksandar Stojanovic, M.D., in charge of refractive surgery at the University Hospital of North Norway, and medical director of the SynsLaser Clinic, in Tromsoe and Oslo, Norway, reported on his use of vitamin C and PRK-related haze in 2003, and word of mouth has promoted it to a starring role in the formulary of virtually all surface ablators.
Mitomycin C blocks the replication of fibroblast cells, which is how it prevents or reduces corneal haze. Proponents say when MMC is used in very limited amounts, for a controlled amount of time, the chemotherapeutic agent is safe. The literature supports their anecdotal observations, albeit in most instances with the provision that additional studies are needed to evaluate long-term effects.
A literature review by researchers Ulrike Kottler, M.D., and H. Burkhard Dick, M.D., of Augenklinik mit Poliklinik der Johannes Gutenberg-Universitaet, in Mainz Germany, showed that it was safe and efficacious. "The local use of MMC 0.02% for 2 minutes is safe and enables one to treat and prevent stromal haze and myopic regression and allows a reduction of the postoperative topical pharmacotherapy. Results are still limited due to small case numbers and short follow-up periods."
A study done by Massimo Camellin M.D., of Rovigo, Italy, showed that while the use of MMC 0.01% with LASEK significantly decreased subepithelial haze, the refractive outcome was less predictable.
"High-order aberrations increased after laser-assisted epithelium keratamileusis (LASEK) with MMC," says Dr. Camellin. "Additional studies with longer follow-up are necessary to evaluate long-term effects, and ideal MMC concentration and exposure time."
Rudolph's Secret Weapon
How did a study on
the amount of ascorbic acid in the eyes of reindeer and other animals lead to the
use of vitamin C in surface ablation patients? Norwegian ophthalmologist Amund Ringvold,
M.D., Ph.D., and fellow researchers from the University of Oslo found that diurnal
animals have higher levels of vitamin C in their corneas than nocturnal animals
and that reindeer have the highest level of all. Dr. Ringvold had theorized that
reindeer were provided by nature with a protective mechanism. (Reindeer are indigenous
to Norway, where there are 24 hours of sunlight for up to 2 months during the summer,
and also intense ultraviolet [UV] rays from the snow [see Figure 1]).
Prior to that, Dr. Stojanovic identified a correlation between postoperative corneal haze and UV exposure. He found that while he was only getting 3% to 4% of corneal haze in his PRK patients, all of those cases were emerging during the summer months or when patients were exposed to significant amounts of UV rays. Figures 2 and 3 show the breakdown of patients that developed late-onset corneal haze and the relationship between the development of late-onset corneal haze and PRK, respectively.
Dr. Stojanovic combined his theories with Dr. Ringvold's, and they, along with fellow researchers, applied the information to a clinical model. "We found that ascorbic acid seems to have a prophylactic effect when it comes to development of both 'regular' haze and late-onset corneal haze after PRK, and we recommend 500 mg vitamin C b.i.d. from 2 weeks prior to surgery until 2 weeks after the surgery, and whenever exposed to excessive UVR, during the whole first year after surgery," says Dr. Stojanovic.
Mitomycin C for All?
A random sample of refractive surgeons who perform surface ablation reveals that some doctors use MMC in every case; a second group relegates the use of MMC to only those patients who are at an increased risk of developing haze; and some refuse to use it in any case.
Marguerite McDonald, M.D., Ophthalmic Consultants of Long Island, Rockville Centre, N.Y., falls into the moderate MMC use category. She uses it to minimize postop haze and regression in surface ablation cases for patients who are -6 D and greater or +3 D and higher, and with 3 D of astigmatism or more.
"Patients with higher prescriptions are at increased risk for haze," explains Dr. McDonald.
She also uses mitomycin C for surface ablation patients who had previous corneal surgeries and have had incisional issues because they are at greater risk of haze. Dr. McDonald points to older technology and the lack of smooth incisions as reasons for the increased risk.
"Smoothness has been absolutely correlated with haze. If the patient has a lumpy, bumpy incision like we used to create with our earliest, most primitive lasers, the chance of haze increases," says Dr. McDonald. "Marcelo V. Netto, M.D., and Steven E. Wilson, M.D., recently showed that the lumpier and more irregular the cornea, the more likely that the keratocytes would become myofibroblasts, which are cloudy cells that also produce extracellular matrices and collagen in an irregular fashion."
In those patients who do run the risk of haze and regression, Dr. McDonald and others believe avoiding it is worth the risk inherent in MMC. She uses MMC 0.02% on a circular Weck-cel sponge, squeezed until it is almost dry. She places it on the eye and holds it in place for 15 seconds and then irrigates profusely.
Dr. McDonald says many refractive surgeons are now following suit and employing the weaker concentration. "I'm the only one I know of who squeezes the sponge as dry as I can get it. It is commonly used wet. By using it 'dry,' I figure I'm further limiting the exposure to patients," she says.
A few years back, Dr. McDonald explains, surgeons would put mitomycin 0.03% in a 'well,' and it would inevitably leak and kill any cells it came in contact with.
Figure 1. This picture taken at midnight in the middle of the summer in Norway illustrates the UV-related postop haze issue for patients there.
|Figure 2. This chart shows the patient breakdown of those who developed late onset corneal haze and some of their individual information.
|Figure 3. The chart shows that only 11 subjects who belonged to the "high UV-exposure group" developed late-onset corneal haze after PRK, while none of the PRK treated subjects from the "low UV-exposure group" developed late-onset corneal haze.
"In those days, surgeons would hold the MMC in the well on top of the eye for a full 2 minutes," she adds.
There are still those who use a well, instead of a sponge, but exposure time is now limited to 12 to 15 seconds.
"The risk is extremely low in the weak concentrations that we're now using and with the short exposure times, but it is a very toxic chemical," acknowledges Dr. McDonald. "There are those who never use it, and they have a point. We don't have long-term follow-up on MMC cases."
Neal Sher, M.D., adjunct clinical professor of ophthalmology at the University of Minnesota Medical School, and a partner at Eye Care Associates, both in Minneapolis, is not convinced that postop PRK haze is totally related to the extent of correction. He believes some of the time it is idiosyncratic. Because of this, he uses MMC for all his surface ablation patients, and he also adds supplemental vitamin C to the regimen.
"I am using MMC 0.02% on all surface ablations," states Dr. Sher. "I use it for 15 seconds as a baseline and double the amount for prior corneal surgery, including prior penetrating keratoplasty, RK, PRK and LASIK," said Dr. Sher. He also adds 10 seconds of exposure, for a total of 20 to 25 seconds, for cases above 5 D and another 10 seconds for cases above 9 D.
William Trattler, M.D., uses MMC on
all of his higher risk surface ablation patients. "I started using it for higher
myopes when Randy Epstein, M.D., and Parag A. Majmujar, M.D., of Chicago Cornea
Consultants, demonstrated that 12 seconds of MMC 0.02% worked as well as
2 minutes of exposure," states Dr. Trattler. "I feel very comfortable using it for only 12 seconds in patients with 6 D to 7 D or more of myopia as well as in patients who have had previous surgery on their corneas."
It is extremely uncommon for him to see late haze following surface ablation due to the smoother ablation patterns present in the latest generation excimer lasers. For many years he used a 3 to 4 month course of topical steroids rather than MMC in his high myopia cases. "I now routinely use MMC in high risk cases to avoid that one potential patient who would develop haze and have a less than satisfactory outcome," he says.
Michigan ophthalmologist Thomas V. Claringbold, II, D.O., does not use MMC at all for surface ablation. "It has been associated in the past with damage to eye tissue," says Dr. Claringbold. "When it's been placed on the sclera there have been problems with it melting through the eye."
Dr. Claringbold stresses there have been no such reports with respect to MMC's use in surface ablation to date, but adds, "We really don't know what's in store years down the road." Furthermore, he remains cautious, particularly because the MMC is used in dilute strength for surface ablation, which, he points out leaves room for error. Another major reason Dr. Claringbold does not use MMC is that his incidence rate of postop haze (less than 1% in his LASEK patients) has never been high enough to warrant the use of the drug. Since moving to the prophylactic use of vitamin C, the rate has dropped to zero.
Dr. Stojanovic's study resulted in the growing use of vitamin C prophylaxis for surface ablation. He noted a correlation in his earlier work between postop haze and ultraviolet (UV) light exposure and a study of ascorbic acid (vitamin C) in the corneal tissue of nocturnal and diurnal animals. (To learn more, read "Rudolph's Secret Weapon," on page 44).
Among other things, the study's findings led to a recommendation to saturate the anterior eye with systemic ascorbic acid prior to excimer laser surgery to reduce postoperative haze, regression and glare.
Dr. Stojanovic tested this recommendation in a therapeutic setting. He compared a group of 212 patients who had PRK between 1996 and 1998 but did not take vitamin C, with a group of 152 patients who had PRK between 1998 and 2000 and took 500 mg of vitamin C twice a day 1 week prior to surgery and for 2 weeks after surgery.
Haze was evaluated at 1 day, 1 week, 3 months and6 months and was graded on a scale of 0 to 4. Late corneal haze was defined as an acute haze of grade 2 (moderate, with difficult refraction) or higher beginning at least 4 months after treatment. None of the people in the vitamin-C group developed late corneal haze, but 3.5% of those in the non-supplemented group did. What's more, higher myopia correlated with an increased risk of haze.
Since reporting those findings, Dr. Stojanovic has performed in excess of 1,000 surface ablations, and all patients took vitamin C. "Only one patient developed late grade 2 haze which needed treatment," explains Dr. Stojanovic. "That patient did not follow the postoperative protocol and the patient had also been exposed to excessive UV radiation."
Fewer than 10 cases developed grade 1 haze, which resolved in time without treatment. "I would like to emphasize that all of the cases were treated with high-frequency small-spot lasers that left very smooth ablation surface, which I also think was beneficial in avoiding haze," says Dr. Stojanovic.
Dr. McDonald also believes the advent of modern lasers has helped to mitigate or avoid haze. "Most ablations are so smooth that haze really isn't an issue in patients with lower levels of hyperopia, myopia and cylinder."
Part of Dr. Stojanovic's conclusion to the 2003 report recommended a randomized, double-blind study. "One tends to be on a conservative, or more skeptical side when
one deals with a new approach. That is why my conclusion concerning a routine use of vitamin C implied a necessary prospective study," says Dr. Stojanovic.
Making the Move to Vitamin C
Dr. Claringbold says there are no hard and fast
rules regarding dosage or duration, but he adds that he prescribes 1,000 mg a day,
starting when the prospective patient begins to even consider the surgery, and continuing
for 6 months
Dr. Trattler recommends 1,000 mg vitamin C per day, adding that it, along with other factors, has helped reduce the incidence of late onset corneal haze in his surface ablation patients. Dr. Sher also uses it and his recommended dosage is 500 mg b.i.d. starting several days before surgery and continuing for up to 6 months postop.
Vitamin C over Mitomycin C?
Will the use of vitamin C eventually preclude the need for mitomycin C? "There are those who say it might," says Dr. McDonald, "but here's the problem: All the best research is funded by National Institutes of Health grants or companies. None of the companies have any real interest in MMC."
Dr. Claringbold says some refractive surgeons still will not consider vitamin C with respect to haze prevention because there is no definitive study supporting it. "They might be more inclined to use a chemical like MMC, because they know why and how its working."