Mitomycin C for Haze Prophylaxis
Pathophysiology of Corneal Haze
The healthy cornea is composed of transparent cells surrounded by highly organized extracellular matrix. Due to this organized composition, the cornea is ableto maintain its clarity to let light pass through. Corneal haze is a clouding of the normally clear stroma. Haze can occur as a complication of refractive laser surgery, especially following Photorefractive Keratectomy (PRK), but its incidence has declined since doctors have begun using 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 mechanisms. 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 have contractile properties that may 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 haze. It is known that there is a direct relationship between the amount of postsurgical stromal surface irregularity immediately postoperatively and postoperative 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 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 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. Most 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, non-resolving haze can significantly limit visual potential and may require further procedures.
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 theDNA and, prior to its use in refractive surgery, was used extensively in modulating wound healing in other areas of ophthalmic surgery (for example, in trabeculectomies performed to treat glaucoma or in pterygium surgery to reduce recurrence). After showing promise in treating haze that persisted after refractive surgery, several prospective studies showed that using the medication during the original surgery decreased the percentage of eyes that developed postoperative haze. In laboratory studies, the anterior stroma of the corneas that underwent mitomycin C treatment post-excimer ablation were found to have a decreased density of keratocytes when compared with eyes that underwent a similar laser procedure without mitomycin C.
In September 2021, a large meta-analysis was published to evaluate the visual outcomes and corneal haze formation after MMC is used intra-operatively following 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 both early and late onset corneal haze, with less loss of VA post operatively in treated group over control group. Postoperative endothelial cell density was not significantly different amongst the groups.
The standard technique for treating persistent corneal haze that develops as post-surgical complication has been to place a 0.02% mitomycin C-soaked sponge onto the corneal surface for two minutes. However, specific techniques for use of mitomycin C as primary prophylaxis continues to evolve. Both lower concentrations and shorter duration of exposure are being explored. 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. In a 2010 study, Virasch et al demonstrated that reducing the application time at surgery from two minutes to twelve seconds produced similar results in haze prevention and refractive outcomes. Most surgeons use mitomycin C 0.02% for 12 seconds for most moderate and high myopic ablations. After mitomycin C exposure, the eye is rinsed thoroughly with BSS to rinse off any residual mitomycin C.
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, Leccisotti et al. 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 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.
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