Although advancements in laser technology have made corneal haze a rare occurrence after photorefractive keratectomy (PRK), corneal surgeons should nevertheless remain vigilant in decreasing the risk of and treating the sight-altering condition. (See “Corneal Haze and PRK: An Overview,” below.) This article discusses how to accomplish both.
Corneal Haze and PRK: An Overview
Because PRK disrupts the basement membrane and underlying stroma, corneas that undergo this procedure can take longer to heal than those that have common epithelial defects. This delay in re-epithelialization, prolonged myofibroblast proliferation, and excessive extracellular matrix deposition is what creates corneal haze and its deleterious effects, such as halos. What’s more, postoperative PRK corneal haze can range from faint and visually insignificant, to severely dense and visually limiting with corneal opacity and regression.
Decreasing Risk
There are both primary and secondary risk factors for developing corneal haze after PRK.1,2 Primary: spherical correction, high myopia (>-6.00 D), hyperopia, astigmatism correction (>3.00 D), and prior corneal surgery. Secondary: autoimmune conditions, atopy, dry eye disease, epithelial basement membrane dystrophy, neurotrophic keratopathy, and UV exposure.
In a multivariate regression analysis reviewing risk factors for haze, a significant effect of preoperative refraction and ablation depth on the severity of corneal haze was shown, with the overall risk being higher for hyperopia (10.8%) and high myopia (2.1%) compared to moderate myopia (1.1%).3
The following are available to reduce the likelihood of corneal haze:
• Intraoperative mitomycin C (MMC). MMC is an alkylating agent that inhibits DNA replication and cell proliferation. When applied to the stromal bed following PRK, it is shown to increase keratocyte apoptosis and inhibit mitosis of myofibroblast precursor cells during the weeks following PRK.4 While many surgeons utilize MMC for all PRK treatments, a statistically significant effect has been noted in patients who have myopic PRK treatments over 6.00 D.5
In terms of the dosage and duration of use, both vary from surgeon to surgeon and often differ depending on the ablation depth and ablation pattern.
For example, the U.S. Army Surface Ablation Study used 0.02% MMC for 30 seconds for all moderate to high myopic treatments, which ranged from -3.88 D to -9.38 D, while another study titrated 0.02% MMC times on the level of myopia, with 10 seconds per diopter of treatment.6,7 Another retrospective evaluation of PRK cited a time of 20 seconds to 60 seconds for 0.02% MMC, depending on surgeon preference, but concluded that longer MMC application times might have benefit in haze prevention in hyperopic and large myopic or astigmatic corrections.6
That said, several studies support concentrations of 0.02%.4,8 Special care should be taken to ensure proper dilution of the drug, because MMC can be toxic to the cornea at higher concentrations. Contact with the limbal stem cells, conjunctiva, or sclera should also be avoided, as this can result in sterile melting, limbal stem cell deficiency, or delayed healing.5
• Topical corticosteroids. These are prescribed to prevent corneal haze and myopic regression, as they are anti-inflammatory agents that preclude keratocyte-to-fibroblast transformation.
Dose and duration vary by surgeon and may differ depending on the magnitude of treatment and treatment type. That said, typical routines involve a four-times-a-day regimen, with a slow taper for anywhere from several weeks to months.
As topical corticosteroids can increase IOP, patients using them should be monitored regularly. Additionally, though uncommon in short-term treatments, the risk of cataract should be discussed with these patients. In patients who have undergone a PRK enhancement for prior LASIK, one should keep in mind that a steroid response can still cause pressure-induced stromal keratitis (PISK).
• Chilled balanced salt solution (BSS). Rinsing the cornea with chilled BSS after the ablation following MMC application has been shown to significantly reduce corneal haze and decrease postoperative pain.9 While still employed by some corneal surgeons, this intervention may have been more relevant when excimer laser-related, thermal energy-induced inflammation was more of a concern. Today’s lasers are lower energy.
Of note: Even with the above preventative interventions, corneal haze occurs in 1.3% to 3.6% of patients after PRK,1,3 making it a sometimes-frustrating disease to manage.6
Treatment
Currently, official treatment options are limited. However, there are some promising medications and interventions on the horizon, many of which are currently off-label. While evidence is limited on these treatments, early results are favorable. (See “Potential Treatments,” below) Corneal haze may also reoccur while tapering or after stopping treatment. Therefore, monitoring the patient with close follow-up is important, as is counseling patients to alert their physician when they feel symptoms return.
The following treatments are available, should PRK-caused corneal haze occur:
• Mechanical debridement. When the corneal haze is limited to the superficial stroma (typically up to one-third of thickness), it can be treated with mechanical debridement with or without PTK.15 Debridement can be performed using a diamond burr or crescent blade after removing the epithelium.
• Phototherapeutic keratectomy (PTK). PTK can be applied to smoothen the stromal bed. The success of this intervention relies heavily on the depth of the haze. Anterior-segment OCT can aid in accurately quantifying the depth of pathology. Superficial PTK is for superficial haze, while deep PTK is for deeper haze.
Following either mechanical debridement or PTK, MMC should be applied to the surface to prevent corneal haze recurrence, as risk of scarring can be high with repeat ablation.15
• Lamellar or penetrating keratoplasty. While most patients will respond well to PTK, a small percentage may have persistent corneal haze or haze at a depth not amenable to laser ablation. In these cases, the patient may require a lamellar or penetrating keratoplasty (PKP). Due to the higher risk profile of PKP and the potential complications, such as damage to the lens, that can follow, less-invasive options should be exhausted before proceeding with PKP.
Potential Treatments
The following have shown the makings of effective treatments for
PRK-caused corneal haze:
• Losartan. Topical losartan is an angiotensin-converting enzyme (ACE) II inhibitor. The anti-hypertensive medication has been shown to inhibit certain TGF ß-stimulated processes involving corneal myofibroblasts.10 The inhibited pathways of myofibroblasts are thought to be major contributors to the development and maintenance of stromal scar and fibrosis.11 It is believed that myofibroblasts are continuously remodeling and maintaining corneal fibrosis, so inhibiting this process may reduce haze well after the initial insult. In one case study, a patient with post-PRK corneal haze who was treated with losartan 0.8% 6 times a day over 4 months experienced improvement in visual acuity and glare up to the end of the 4 months.12 That said, the literature on this potential treatment in humans in sparse, so further studies are needed to elucidate its safety and efficacy, as well as the ideal dosage, frequency, and duration of treatment.
• Blood-derived solution. A blood-derived solution that is plasma-rich in growth factors (PRGF), including platelet-derived growth factor and nerve growth factor, has recently been shown to prevent and inhibit TGF-ß1-induced myofibroblast differentiation.13 Studies are limited, but early research is promising for the use of topical PRGF to potentially reduce corneal scarring.
• Vitamin C. Systemic ascorbic acid, or vitamin C, has been proposed as a potential adjunct to PRK to reduce postoperative corneal haze. This is because the anterior segment has a high concentration of vitamin C, which has been proposed to have a protective role as a UV filter for the eye. Since corneal scarring following PRK has been shown to be associated with UV exposure, the thought is that oral vitamin C supplementation around the time of PRK could prevent or reduce corneal haze.14
Keeping a Watchful Eye
While the incidence of corneal haze has decreased substantially from the 92% prevalence in the early 1990s, it remains a possible outcome of PRK. As a result, it is essential corneal physicians keep a watchful eye out for this outcome, so they can take the action steps outlined in this article to prevent and/or treat it, should it develop. CP
References:
1. Moshirfar M, Wang Q, Theis J, et al. Management of Corneal Haze After Photorefractive Keratectomy. Ophthalmol Ther. 2023;12(6):2841-2862. doi:10.1007/s40123-023-00782-1
2. Cua IY, Pepose JS. Late corneal scarring after photorefractive keratectomy concurrent with development of systemic lupus erythematosus. J Refract Surg. 2002;18:750-752
3. Hashemi H, Pakbin M, Pakravan M, et al. Effect of Short Versus Long-Term Steroid on Corneal Haze After Photorefractive Keratectomy: A Randomized, Double-Masked Clinical Trial. Am J Ophthalmol. 2022;235:211-220. doi:10.1016/j.ajo.2021.09.028
4. Carlos de Oliveira R, Wilson SE. Biological effects of mitomycin C on late corneal haze stromal fibrosis following PRK. Exp Eye Res. 2020 Nov;200:108218. doi: 10.1016/j.exer.2020.108218. Epub 2020 Sep 6. PMID: 32905844; PMCID: PMC7655619.
5. Majmudar PA, Schallhorn SC, Cason JB, et al. Mitomycin-C in corneal surface excimer laser ablation techniques: a report by the American Academy of Ophthalmology. Ophthalmology. 2015;122(6):1085-1095. doi:10.1016/j.ophtha.2015.01.019
6. Sia RK, Ryan DS, Edwards JD, Stutzman RD, Bower KS. The U.S. Army Surface Ablation Study: Comparison of PRK, MMC-PRK, LASEK in Moderate to High myopia. J Refract Surg. 2014: 30(4)256-64.
7. Hashemi H, Miraftab M, Ghaffari R, Asgari S.Femtosecond-Assisted LASIK Versus PRK: Comparison of 6-Month Visual Acuity and Quality Outcome for High Myopia. Eye Contact Lens. 2016;42: 354-357.
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9. Kaiserman I, Sadi N, Mimouni M, Sela T, Munzer G, Levartovsky S. Corneal Breakthrough Haze After Photorefractive Keratectomy With Mitomycin C: Incidence and Risk Factors. Cornea. 2017;36(8):961-966. doi:10.1097/ICO.0000000000001231
10. Niizuma T, Ito S, Hayashi M, Futemma M, Utsumi T, Ohashi K. Cooling the cornea to prevent side effects of photorefractive keratectomy. J Refract Corneal Surg. 1994;10(2 Suppl):S262-S266.
11. Sudanaboina P, Murthy SI, Rathi VM. Excimer laser phototherapeutic keratectomy with mitomycin C application to treat haze after myopic photorefractive keratectomy. Indian J Ophthalmol. 2020;68(12):3030-3031. doi:10.4103/ijo.IJO_1845_20
12. Wilson SE. Magic Bullets: The Coming Age of Meaningful Pharmacological Control of the Corneal Responses to Injury and Disease. J Ocul Pharmacol Ther. Published online September 26, 2022. doi:10.1089/jop.2022.0088
13. de Oliveira RC, Tye G, Sampaio LP, et al. TGFβ1 and TGFβ2 proteins in corneas with and without stromal fibrosis: Delayed regeneration of apical epithelial growth factor barrier and the epithelial basement membrane in corneas with stromal fibrosis. Exp Eye Res. 2021;202:108325. doi:10.1016/j.exer.2020.108325
14. Pereira-Souza AL, Ambrósio R Jr, Bandeira F, Salomão MQ, Souza Lima A, Wilson SE. Topical Losartan for Treating Corneal Fibrosis (Haze): First Clinical Experience. J Refract Surg. 2022;38(11):741-746. doi:10.3928/1081597X-20221018-02
15. Anitua E, Muruzabal F, Alcalde I, Merayo-Lloves J, Orive G. Plasma rich in growth factors (PRGF-Endoret) stimulates corneal wound healing and reduces haze formation after PRK surgery. Exp Eye Res. 2013 Oct;115:153-61. doi: 10.1016/j.exer.2013.07.007. Epub 2013 Jul 18. PMID: 23872360.
