Mitomycin C for Haze Prophylaxis
Pathophysiology of Corneal Haze
The healthy cornea is composed of transparent cells surrounded by highly organized material (known as the extracellular matrix). With this organized composition, light is able to pass easily through the tissue and the cornea is able to maintain its clarity. Corneal haze is a clouding of the normally clear front surface of the eye. Haze can occur as a complication of refractive laser surgery (surgery designed to eliminate the need for glasses). This is sometimes seen following the refractive procedure known as Photorefractive Keratectomy (PRK), but its incidence has declined since doctors have begun using the medicine mitomycin C directly following the laser procedure.
Corneal haze development is thought to be secondary to side effects of the cornea’s innate wound healing mechaisms. Animal studies show that, following PRK, there is an initial apoptosis of keratocytes (programmed cell death of normal cornea cells). In response, some keratocytes undergo transformation to myofibroblasts. A cell-signaling molecule known as TGF-Beta, which arises from the wounded epithelium, is thought to help mediate this transformation. Myofibroblasts can have contractile properties that are intended to help close wounds, but they are not as transparent as normal corneal cells. These keratocytes are not only more numerous, but also demonstrate greater reflectivity of their cell bodies and nuclei at post-operative month one. However, these changes in density and reflectivity have been noted to diminish over time. Additionally, the extra-cellular matrix produced by myofibroblasts is disorganized and denser than the usual matrix, and consequently scatters more light causing a haze. It is known that there is a direct relationship between the amount of postsurgical stromal surface irregularity immediately postoperatively and the haze and loss of 1 or more lines of visual acuity at 1 year.
The risk of corneal haze increases with the depth of the ablation (how much tissue the laser removes). The more nearsighted a patient is, the more tissue that will need to be removed. Consequently, patients with medium to high myopia (greater than six diopters) will have a higher risk of a haze than those who are less nearsighted. The race of the patient may also increase the risk of haze. Tabbara, et al found an elevated risk of corneal haze following PRK in Saudi patients with brown irides (the colored portion of the eye) when compared to Caucasian patients with blue irides. Increased ultraviolet light exposure may serve as an additional risk factor for later occurring haze. Consequently, many surgeons recommend using UV light protective sunglasses, especially in the first year following surgery.
Early post-ablation haze tends to first emerge a few weeks after a PRK procedure. Its natural history is to intensify until it reaches its peak at approximately one to two months after PRK. The haze then begins to slowly resolve as the patient reaches their sixth to twelfth post-operative month. Symptoms depend on the degree of haze, but his early transitory haze may even be asymptomatic. A second form of haze develops later (often two to five months after surgery) and is more likely to cause a significant decrease in a patient’s vision.
The haze appears in the subepithelial layer of the cornea and presents as a reticular pattern of opacity. The density of the haze is graded from one, which represents trace haze, to four, which represents marked haze.
As above, the major sign is the characteristic slit lamp exam appearance. The patient’s refraction is generally not fully stabilized while haze is present, so another sign may be changes in patients’ refractive needs as the haze develops and regresses.
The degree of haze correlates with the severity of symptoms. ome patients with mild haze do not note visual distortion, while those with greater haze may complain of decreased vision.
Medical Management of Corneal Haze
If haze does develop, it is usually observed initially since it often resolves without surgical intervention. Topical steroid drops are often employed in an attempt to medically reduce haze. Patients are encouraged to wear sunglasses since ultraviolet light can exacerbate haze and they are also encouraged to use frequent artificial tears. While the lubrication from the tears is not expected to directly treat the haze, it can address any dry eye component that may be adding to their visual symptoms. The medical follow up for corneal haze following refractive surgery is very patient specific and depends on such factors as the degree of corneal haze on physical exam as well as the magnitude of visual disturbance experienced by the patient.
Overall, the prognosis of corneal haze is good since it is often self resolving and even if a small amount remains by physical exam, it does not always interfere with vision. However, in severe cases, nonresolving haze can significantly limit visual potential.
Mitomycin C For Prevention of Corneal Haze
Mitomycin C is now widely used to prevent post-ablation haze. This medication was originally isolated from the organism Streptomyces caespitosus and developed as a chemotherapeutic agent. Mitomycin C acts to stop cells from proliferating by cross-linking DNA and, prior to its use in refractive surgery, had already proven efficacious in modulating wound healing in other areas of ophthalmic surgery (for example, in trabeculectomies performed to treat glaucoma). After showing promise in treating haze that persisted after refractive surgery, several prospective studies were conducted that showed that using the medication during the original surgery decreased the percentage of eyes that developed haze. In laboratory studies, the anterior stroma of the corneas that underwent mitomycin C treatment were found to have a decreased density of keratocytes when compared with eyes that underwent a similar laser procedure without mitomycin C.
Though mitomycin C is used most often to prevent haze following primary PRK, some physicians have advocated its use in other procedures such as use with PRK to later treat eyes that were unable to complete LASIK because of a flap complication during their planned LASIK procedure.
Recently, a large meta-analysis study has been published to evaluate the visual outcomes and corneal haze formation after intra-operative MMC used during PRK for myopia and myopic astigmatism. 11 randomized control trials were included and 2232 eyes in MMC and 1304 eyes in control group were analyzed. MMC was shown to decrease rate of corneal haze both early and late onset with less loss of VA post operatively over control group. Post operative endothelial cell density was not significantly different amongst the groups.
The standard technique for treating persistent corneal haze that developed as a complication after surgery had been to place a 0.02% mitomycin C soaked sponge onto the corneal surface for two minutes.However, specific techniques for using mitomycin C as part of the original surgical procedure to prevent haze are continuing to evolve. Surgeons are exploring the efficacy of lower doses and shorter exposure times. While reducing the dose to 0.002% mitomycin C seemed to produce similar results as the 0.02% for shallow ablations, it was not as efficacious in preventing haze in cases of high myopia that required greater ablation depths.However, Virasch et al recently demonstrated that reducing the application time at surgery from two minutes to twelve seconds still produced similar results in haze prevention and refractive results.
Since mitomycin C does cause damage to cellular DNA, research is underway to try to better understand any safety concerns that the medication may pose. While there could be a theoretical concern for delayed healing of the epithelium (top layer of the cornea that needs to reform over the treated area), Leccisotti demonstrated that the epithelium appears to heal over at the same rate with or without the mitomycin C. There has also been a special interest in the effect of mitomycin C on the corneal endothelium. The endothelium (the inside layer of the cornea) serves to pump out fluid from the stroma, keeping the tissue relatively dehydrated and consequently clear. This layer of the cornea serves a vital purpose, but it does not regenerate, making any damage to it particularly worrisome. To date, there has been conflicting evidence about whether mitomycin C use results in a decrease in the number of endothelial cells in treated eyes, with some studies demonstrating a decline and others noting no statistically significant difference in cell counts.  Larger studies with greater follow up are needed to help delineate this risk.
When PRK with mitomycin C is performed, a bandage contact lens is generally inserted post-operatively to help to decrease discomfort until the epithelium heals over the treated area (a process that usually takes about five days). During the post-operative period, the patient is usually treated with topical steroids and prophylactic topical antibiotics as well as artificial tears to help with lubrication. The patient’s vision following this procedure is typically sharp on the first post-operative day, but as the epithelium heals and begins to reach the central visual axis (around post-operative day three to five), there is an anticipated decline in visual acuity. This is followed by a gradual improvement as the epithelium continues to fully heal.
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