Late-Onset Stromal Scarring and Excessive Corneal Flattening After PRK–CXL in Keratoconus Suspects: A Report of Two Contralateral Case Variants

Late-Onset Stromal Scarring and Excessive Corneal Flattening After PRK–CXL in Keratoconus Suspects: A Report of Two Contralateral Case Variants | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Late-Onset Stromal Scarring and Excessive Corneal Flattening After PRK–CXL in Keratoconus Suspects: A Report of Two Contralateral Case Variants Adel Barbara This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9023698/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose: To report two cases of late-onset central stromal scarring and marked corneal flattening following combined photorefractive keratectomy (PRK) and corneal collagen cross-linking (CXL) performed for keratoconus (KC) suspect, despite nearly identical bilateral preoperative characteristics and treatment parameters. Methods: Two patients underwent same-day PRK–CXL in both eyes for refractive correction in KC suspect elsewhere . Preoperative tomography, pachymetry, ablation profiles, ultraviolet fluence, and post operative[P1] [ab2] regimens were comparable between fellow eyes. Patients were followed with serial clinical examinations and corneal imaging. Results: In each patient, one eye developed late-onset central stromal scarring with excessive corneal flattening and reduced visual acuity, whereas the contralateral eye demonstrated stable healing and favorable visual outcomes. Conclusions: These cases illustrate marked inter-eye variability in corneal wound healing after PRK–CXL in KC suspects, emphasizing the need for careful patient selection, conservative treatment planning, and long-term follow-up. Ethical Compliance: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards The authors declare that they have no financial, commercial, or proprietary interests in any product, device, or company mentioned in this manuscript, and no conflicts of interest relevant to the content of this article. Keratoconus Photorefractive keratectomy (PRK) Corneal collagen cross-linking (CXL) Combined PRK–CXL Stromal scarring Corneal flattening Wound healing Corneal biomechanics Late complications Visual rehabilitation. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Combined PRK and CXL has become an important therapeutic option for selected KC patients, offering both biomechanical stabilization and improvement in corneal regularity. CXL is well established as an effective method for halting KC progression, whereas adjunctive customized PRK can reduce irregular astigmatism and higher-order aberrations, thereby improving functional visual outcomes. When performed with conservative tissue ablation and standardized CXL parameters, simultaneous treatment has generally demonstrated favorable efficacy and an acceptable safety profile 1 In some cases the combined treatment is used to prevent KC progression after PRK in KC suspect cases 23 We report on two unusual cases of late-onset central stromal scarring and marked corneal flattening following combined PRK and CXL in two patients, KC suspect cases, Both eyes of each patient were highly similar before surgery and showed an initially favorable postoperative course with stable vision and clear corneas. However, only one eye in each patient developed delayed central stromal opacity accompanied by progressive, flattening. These changes resulted in deterioration in visual quality whereas the fellow eyes remained clear and stable throughout follow-up. Case 1 A 40-year-old woman presented to our clinic on January 25 with a two-year history of progressive visual deterioration in her left eye. Thirteen years earlier, she had undergone bilateral combined PRK and CXL at another center for astigmatic correction in both eyes (O.U ). The procedures were performed according to the Dresden protocol except for the riboflavin it was isotonic riboflavin 0.1%, with surgery carried out in July 2011 OD and September 2011 OS with no intra or immediate pos operative complications. Preoperative refraction in 2011 showed − 0.75 D sphere / −2.25 D cylinder at 41° in the right eye (OD)and − 0.50 D sphere / −2.75 D cylinder at 131° in the left eye(OS), with a best-corrected visual acuity (BCVA) of 1.0 in both eyes. Thinnest corneal thickness (TCT):OD 566 µm, OS 551 µm. Corneal imaging was interpreted as KC suspect in both eyes . Ablation depths were 44 µm in OD and 45 µm in OS. Two years after surgery, uncorrected visual acuity (UCVA) was 0.9 OD and 0.4 OS with the latter achieving a BCVA of 0.7 with + 1.25 D. At presentation to our clinic, UCVA OD 0.85 and 0.33 OS. Refraction OS was + 2.00 / −3.50 D at 105°, yielding a BCVA of 0.5. Slit-lamp examination revealed a central stromal scar measuring 5 mm in diameter and involving approximately one-third of stromal depth. The remainder of the anterior and posterior segment examination, including lens status, fundus, and intraocular pressure, was unremarkable in both eyes. (Figs. 1 , 2 , 3 ) Corneal tomography demonstrated inferonasal steepening with central and supertemporal flattening in OS. TCT measured 479µm OD 447 µm OS. Prior to referral, the patient had been treated with a one-month course of topical corticosteroids without improvement and was subsequently suspected to have post-refractive ectasia, prompting referral to our clinic. Case 2 A 36-year-old man presented with decreased vision in his left eye. He had undergone bilateral PRK and CXL at another institution in 2013. Preoperative UCVA O.U was 0.1, with BCVA of 1.0. Manifest refraction was + 4.00 / −4.75 D at 17° OD and + 0.25 / −4.50 D at 166° OS. TCT measured 518 µm OD and 519 µm OS. Corneal imaging was interpreted as KC suspect in both eyes. Ablation depths were 59 µm and 62 µm respectively. The CXL protocol consisted of epithelium-off crosslinking using isotonic riboflavin 0.1%, 9mW/cm² for ten minutes for a total energy of 5.4 J/cm². with no intra or immediate pos operative complications Seven months postoperatively, UCVA improved to 0.75 OD and 0.65 OS, with a BSCVA of 0.8 O.U .(Fig. 12, 13, 14) Refraction was + 0.50 / −1.00 D at 142° OD and + 2.75 / −1.25 D at 60° OS. Two and a half years after surgery, UCVA measured 0.9 OD 0.15 OS, though BSCVA remained relatively preserved 0.9OD and 0.8, respectively). Refraction at that time showed + 0.50 / −0.50 D at 40° OD and + 3.75 / −1.00 D at 60° OS .Almost 3.5 years post operatively OD : No change in VA and refraction OS UCVA 0.2, refraction + 5.25/-2.75 at 60° ,BCVA 0.8 At our clinic eleven years after surgery, UCVA measured 0.6 in the right eye and 0.1 in the left eye. BCVA was 0.7 and 0.6, respectively. Objective refraction of OS was + 6.75 / −2.75 D at 55°, while subjective tolerance reached + 4.25 / −2.75 D at the same axis. Slit-lamp examination revealed scattered central corneal opacities, both superficial and deeper OS. The remainder of the ocular examination—including lens, fundus, and intraocular pressure—was normal in both eyes. TCT 444 µm OD and 368 µm OS. Corneal tomography demonstrated central corneal flattening in the left eye .(Figs. 4 , 5 ). Discussion CXL has become the accepted standard of care to halt the progression of KC. Multiple randomized and observational studies have shown that CXL can prevent further ectatic progression in the majority of treated eyes, with a mean flattening of maximal keratometry (Kmax) typically in the range of 1–2 diopters and a modest improvement in corrected and uncorrected visual acuity in many patients 4 . Nevertheless persistent stromal haze, scarring, infections, and endothelial damage have been reported in a small proportion of patients 5 . 6 7 Combined CXL and PRK are used to both stabilize the ectatic process and partially regularize the anterior corneal surface. Topography-guided or wavefront-guided PRK with limited ablation depth, performed either sequentially after CXL or simultaneously with CXL, can reduce irregular astigmatism and higher-order aberrations and thereby improve functional visual acuity and quality of life in carefully selected keratoconus patients. Several protocols (e.g. “Athens,” “Cretan,” and other center-specific approaches) have reported encouraging short-term outcomes with improved UCVA and BCVA and moderate reductions in Kmax, often with low reported rates of sight-threatening complications. 89101112 In spite of the positive results reported after PRK combined with CXL haze formation and scarring are also reported 131415 Frucht-Pery et al report on 5 cases of haze following combined treatment. these observations strongly suggest that the frequency and visual impact of such late complications may be underestimated in the literature, partly due to short follow-up periods and publication bias in favor of favorable refractive outcomes 16 . Corneal scarring after epithelium-off CXL results from disruption of corneal collagen architecture, keratocyte apoptosis, and wound-healing abnormalities triggered by UV exposure and epithelial removal. Normal post-CXL haze peaks at 1 month and usually regresses by 6–12 months, but excessive or persistent haze occurs when healing is exaggerated, inflammation is increased, or procedural deviations occur 17 . Post-PRK haze arises from an inflammatory wound-healing cascade triggered by epithelial and basement-membrane disruption. Cytokines such as IL-1, IL-6, PDGF, and especially TGF-β activate keratocytes and drive their transformation into myofibroblasts, which produce disorganized extracellular matrix that scatters light and causes stromal opacification 18 The combination of both treatments increases the risk of haze formation because both mechanisms of haze formation are operated and more keratocytes apoptosis are induced. Each of these steps triggers its own wound-healing cascade; when performed together, they likely interact in complex ways. Mitomycin C (MMC) is used after PRK to modulate wound healing, for preventing corneal haze formation 19 Controversy and variable outcomes are reported after the use of MMC after combined PRK and CXL 20 Most of the literature on combined PRK + CXL consists of small, non-randomized series with relatively short follow-up, heterogeneous inclusion criteria, variable CXL protocols, and limited data on late adverse events. Consequently, the true incidence, spectrum, and time course of serious complications such as late stromal scarring and progressive flattening after combined PRK + CXL remain unknown and are likely under-reported. In this article, we present two additional cases of KC suspect eyes that developed late-onset, visually significant stromal scarring associated with marked corneal flattening after combined PRK and CXL. Both eyes initially had satisfactory postoperative visual recovery before manifesting progressive flattening and central scarring years after surgery. These cases expand the spectrum of delayed complications after PRK + CXL and underscore the need for cautious patient selection, realistic counseling, and long-term follow-up when considering photoablative procedures in crosslinked keratoconic corneas 16 . The two cases described in this report illustrate a clinically significant pattern of late-onset stromal scarring accompanied by excessive corneal flattening following combined PRK and CXL for KC suspect. Importantly, in both patients the two eyes were highly similar preoperatively in terms of refractive error and topographic profile. Combined PRK–CXL was performed bilaterally using almost identical ablation patterns, yet only one eye in each patient developed the late scarring and progressive flattening, while the fellow eye remained clear and stable.Despite these differences, the early postoperative course in all four eyes was acceptable, with stable or improved vision and initially clear corneas. The subsequent appearance of central stromal opacification—with progressive, non-physiological flattening—occurred late, well after the expected healing period. This led to significant visual degradation. These cases share some features with previously published isolated reports of late stromal scarring after combined surface ablation and CXL, but they also underscore distinct and unresolved clinical questions: why only one eye is affected despite nearly identical preoperative characteristics and procedural parameters, and what underlying wound-healing mechanisms may predispose to this asymmetric late stromal response. Our two cases share several features: Preoperative excellent corrected visual acuity, with no clinical KC, only asuspect of topographical KC interpreted by the surgeons. PRK was an elective procedure and CXL was added as a "preventive" treatment. In our two cases, the common denominator was a combined PRK + CXL procedure applied to KC suspect corneas primarily to improve visual function, with ablation depths and residual thicknesses considered “acceptable” by current standards. Our cases, in which good early visual results were followed by late complications, illustrate that excellent early postoperative acuity does not guarantee long-term stability. Once deep stromal scarring and pronounced flattening have developed, therapeutic options are limited. High-dose topical corticosteroids may be tried early when the first signs first appear. Conclusion These two cases illustrate that, although combined PRK–CXL is generally a safe and effective option for carefully selected keratoconus-suspect patients, individual variability in stromal wound healing may occasionally lead to unexpected late changes. Even when preoperative characteristics and treatment parameters are nearly identical between fellow eyes, postoperative healing can follow different trajectories. Recognizing this variability highlights the importance of long-term follow-up and continued refinement of patient-selection criteria. With broader clinical experience and future research aimed at understanding individual wound-healing profiles. Declarations Informed consent was obtained from the patients for publication of these two case reports and accompanying images. References Al-Mohaimeed MM. Combined corneal CXL and photorefractive keratectomy for treatment of keratoconus: a review. Int J Ophthalmol . 2019;12(12):1929. doi:10.18240/IJO.2019.12.16 Kymionis G, Kontadakis G, Grentzelos M, Petrelli M. Long-term follow-up of combined photorefractive keratectomy and corneal crosslinking in keratoconus suspects. Clin Ophthalmol . 2021;15:2403-2410. doi:10.2147/OPTH.S294775;JOURNAL:JOURNAL:DOPH20;WGROUP:STRING:PUBLICATION Koosha N, Fathian A, Peyman A, Nourbakhsh SA, Noorshargh P, Pourazizi M. Combined simultaneous photorefractive keratectomy and collagen cross-linking in keratoconus suspect patients. J Fr Ophtalmol . 2023;46(8):921-928. doi:10.1016/J.JFO.2022.11.029 Wollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. Am J Ophthalmol . 2003;135(5):620-627. doi:10.1016/s0002-9394(02)02220-1 Koller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. J Cataract Refract Surg . 2009;35(8):1358-1362. doi:10.1016/j.jcrs.2009.03.035 Agarwal R, Jain P, Arora R. Complications of corneal collagen cross-linking. Indian J Ophthalmol . 2022;70(5):1466. doi:10.4103/IJO.IJO_1595_21 Raiskup F, Hoyer A, Spoerl E. Permanent Corneal Haze After Riboflavin-UVA-Induced Cross-Linking in Keratoconus. J Refract Surg . 2009;25(9):S824-S828. doi:10.3928/1081597X-20090813-12 Kanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. J Refract Surg . 2009;25(9). doi:10.3928/1081597X-20090813-10 Kanellopoulos AJ. Comparison of Sequential vs Same-Day Simultaneous Collagen Cross-Linking and Topography-Guided PRK for Treatment of Keratoconus. J Refract Surg . 2009;25(9):S812-S818. doi:10.3928/1081597X-20090813-10 Al-Mohaimeed MM. Combined corneal CXL and photorefractive keratectomy for treatment of keratoconus: a review. Int J Ophthalmol . 2019;12(12):1929. doi:10.18240/IJO.2019.12.16 Awwad ST, Bteich Y, Assaf JF, et al. Prospective Objective Analysis of Corneal Haze Following Customized Transepithelial PRK Without Mitomycin C Combined With Accelerated Corneal Cross-Linking Versus Corneal Cross-Linking Alone. J Refract Surg . 2024;40(9):e583-e594. doi:10.3928/1081597X-20240715-03;WEBSITE:WEBSITE:SLACK-SITE;WGROUP:STRING:PUBLICATION Kankariya V, Kymionis G, Kontadakis G, Yoo S. Update on Simultaneous Topo-guided Photorefractive Keratectomy Immediately Followed by Corneal Collagen Cross-linking for Treatment of Progressive Keratoconus. Int J Keratoconus Ectatic Corneal Dis Ect Cor Dis . 11(33). doi:10.5005/jp-journals-10025-1035 Kymionis GD, Grentzelos MA, Voulgari N. Stromal scarring and visual acuity loss after combined PRk and CXL for keratoconus. J Refract Surg . 2019;35(6):399. doi:10.3928/1081597X-20190520-02 Moraes RLB, Ghanem RC, Ghanem VC, Santhiago MR. Haze and visual acuity loss after sequential photorefractive keratectomy and corneal cross-linking for keratoconus. J Refract Surg . 2019;35(2):109-114. doi:10.3928/1081597X-20190114-01;PAGE:STRING:ARTICLE/CHAPTER Güell JL, Verdaguer P, Elies D, Gris O, Manero F. Late onset of a persistent, deep stromal scarring after PRK and corneal cross-linking in a patient with forme fruste keratoconus. J Refract Surg . 2014;30(4):286-288. doi:10.3928/1081597X-20140320-09 Frucht-Pery, Joseph DW. Controversies in the Management of Keratoconus edited by Adel Barbara published by Sptinger. In: ; 2019. Natarajan R, Giridhar D. Corneal scarring after epithelium-off collagen cross-linking. Indian J Ophthalmol . 2025;73(1):28-34. doi:10.4103/IJO.IJO_95_24 Moshirfar M, Wang Q, Theis J, et al. Management of Corneal Haze After Photorefractive Keratectomy. Ophthalmol Ther 2023 126 . 2023;12(6):2841-2862. doi:10.1007/S40123-023-00782-1 Ouerdane Y, Zaazouee M, Mohamed M, et al. Mitomycin C application after photorefractive keratectomy in high, moderate, or low myopia: Systematic review and meta-analysis. Indian J Ophthalmol . 2021;69(12):3421. doi:10.4103/IJO.IJO_3768_20 Awwad ST, Bteich Y, Assaf JF, et al. Prospective Objective Analysis of Corneal Haze Following Customized Transepithelial PRK Without Mitomycin C Combined With Accelerated Corneal Cross-Linking Versus Corneal Cross-Linking Alone. J Refract Surg . 2024;40(9):e583-e594. doi:10.3928/1081597X-20240715-03;WEBSITE:WEBSITE:SLACK-SITE;WGROUP:STRING:PUBLICATION Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9023698","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":600212083,"identity":"b2beda89-5ea8-4a4f-93fd-966e853367a0","order_by":0,"name":"Adel Barbara","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIie3PsQrCMBCA4dRCupx0bRHqK1QKfZ4UwamokFEHQdDNWRHxFeobFA50Cc4FRaxCJwen4iTaQXCqcRPMB7npfsIRoig/iWlYzOfTjoTEUgl5Jbr7dUItqcQcN2Ps9g9tc45ZD/p7xyR6ekpKEktkDKdrzq1ty9/BOvPsAfW8sOybJHQRKAsGgjwTikEUA62VJfWkc0W4s2ApjJzDXSJxk5BgdcSCSICvV0cSSUNkLs4mjDcEcHsxQc8efrjF2TTTczdnbUcYq+slR8c0hum59Px3FSimLrte0G7fbCuKovyNBwDiVKIZRpCVAAAAAElFTkSuQmCC","orcid":"","institution":"IVISION","correspondingAuthor":true,"prefix":"","firstName":"Adel","middleName":"","lastName":"Barbara","suffix":""}],"badges":[],"createdAt":"2026-03-03 21:01:41","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":true,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-9023698/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9023698/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104403581,"identity":"a15aee29-a373-4de1-b74b-cdf0903651d6","added_by":"auto","created_at":"2026-03-11 12:18:37","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":96879,"visible":true,"origin":"","legend":"\u003cp\u003e1 Axial map O.U , Topcon 2000 , Japan .\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9023698/v1/eb263b1a6f3eecb757948d4e.jpg"},{"id":104180076,"identity":"0936fc2e-733e-4d93-b503-83fe0bc37da6","added_by":"auto","created_at":"2026-03-08 17:11:18","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":166514,"visible":true,"origin":"","legend":"\u003cp\u003eOCT OD, CASIA2 , Tomey , Japan .\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9023698/v1/2285669ee6dcbbeb203f5312.jpg"},{"id":104180075,"identity":"17a8d8a4-41ac-40a5-aa15-68a088876254","added_by":"auto","created_at":"2026-03-08 17:11:18","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":151641,"visible":true,"origin":"","legend":"\u003cp\u003eOCT OS, CASIA2 , Tomey , Japan.\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9023698/v1/16e27a23c2b7d93f42581599.jpg"},{"id":104180079,"identity":"aea303cc-9af7-4cbd-a36a-9079ca46f6aa","added_by":"auto","created_at":"2026-03-08 17:11:18","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":90846,"visible":true,"origin":"","legend":"\u003cp\u003eOCT . OD, CASIA2 , Tomey , Japan.\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9023698/v1/78589ed52e44caa807c5f3f9.jpg"},{"id":104180077,"identity":"77dbce10-da61-48ad-952d-14b308941fbc","added_by":"auto","created_at":"2026-03-08 17:11:18","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":156545,"visible":true,"origin":"","legend":"\u003cp\u003eOCT OS, CASIA2 , Tomey , Japan.\u003c/p\u003e","description":"","filename":"Picture5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-9023698/v1/35d8693ac688fd863608d93e.jpg"},{"id":104410680,"identity":"ce99e47a-f604-448b-8a22-6de220b925f7","added_by":"auto","created_at":"2026-03-11 12:53:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":954411,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9023698/v1/dfaec56c-5f2d-4b1e-af4f-be3ad7b284a8.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eLate-Onset Stromal Scarring and Excessive Corneal Flattening After PRK–CXL in Keratoconus Suspects: A Report of Two Contralateral Case Variants\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCombined PRK and CXL has become an important therapeutic option for selected KC patients, offering both biomechanical stabilization and improvement in corneal regularity. CXL is well established as an effective method for halting KC progression, whereas adjunctive customized PRK can reduce irregular astigmatism and higher-order aberrations, thereby improving functional visual outcomes. When performed with conservative tissue ablation and standardized CXL parameters, simultaneous treatment has generally demonstrated favorable efficacy and an acceptable safety profile \u003csup\u003e1\u003c/sup\u003e In some cases the combined treatment is used to prevent KC progression after PRK in KC suspect cases \u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWe report on two unusual cases of late-onset central stromal scarring and marked corneal flattening following combined PRK and CXL in two patients, KC suspect cases, Both eyes of each patient were highly similar before surgery and showed an initially favorable postoperative course with stable vision and clear corneas. However, only one eye in each patient developed delayed central stromal opacity accompanied by progressive, flattening. These changes resulted in deterioration in visual quality whereas the fellow eyes remained clear and stable throughout follow-up.\u003c/p\u003e"},{"header":"Case 1","content":"\u003cp\u003eA 40-year-old woman presented to our clinic on January 25 with a two-year history of progressive visual deterioration in her left eye. Thirteen years earlier, she had undergone bilateral combined PRK and CXL at another center for astigmatic correction in both eyes (O.U ). The procedures were performed according to the Dresden protocol except for the riboflavin it was isotonic riboflavin 0.1%, with surgery carried out in July 2011 OD and September 2011 OS with no intra or immediate pos operative complications.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePreoperative refraction in 2011 showed\u0026thinsp;\u0026minus;\u0026thinsp;0.75 D sphere / \u0026minus;2.25 D cylinder at 41\u0026deg; in the right eye (OD)and \u0026minus;\u0026thinsp;0.50 D sphere / \u0026minus;2.75 D cylinder at 131\u0026deg; in the left eye(OS), with a best-corrected visual acuity (BCVA) of 1.0 in both eyes. Thinnest corneal thickness (TCT):OD 566 \u0026micro;m, OS 551 \u0026micro;m. Corneal imaging was interpreted as KC suspect in both eyes .\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eAblation depths were 44 \u0026micro;m in OD and 45 \u0026micro;m in OS. Two years after surgery, uncorrected visual acuity (UCVA) was 0.9 OD and 0.4 OS with the latter achieving a BCVA of 0.7 with +\u0026thinsp;1.25 D.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAt presentation to our clinic, UCVA OD 0.85 and 0.33 OS. Refraction OS was +\u0026thinsp;2.00 / \u0026minus;3.50 D at 105\u0026deg;, yielding a BCVA of 0.5. Slit-lamp examination revealed a central stromal scar measuring 5 mm in diameter and involving approximately one-third of stromal depth. The remainder of the anterior and posterior segment examination, including lens status, fundus, and intraocular pressure, was unremarkable in both eyes. (Figs.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e1\u003c/span\u003e, \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e2\u003c/span\u003e,\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e3\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eCorneal tomography demonstrated inferonasal steepening with central and supertemporal flattening in OS. TCT measured 479\u0026micro;m OD 447 \u0026micro;m OS. Prior to referral, the patient had been treated with a one-month course of topical corticosteroids without improvement and was subsequently suspected to have post-refractive ectasia, prompting referral to our clinic.\u003c/p\u003e "},{"header":"Case 2","content":" \u003cp\u003eA 36-year-old man presented with decreased vision in his left eye. He had undergone bilateral PRK and CXL at another institution in 2013.\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003ePreoperative UCVA O.U was 0.1, with BCVA of 1.0. Manifest refraction was +\u0026thinsp;4.00 / \u0026minus;4.75 D at 17\u0026deg; OD and +\u0026thinsp;0.25 / \u0026minus;4.50 D at 166\u0026deg; OS. TCT measured 518 \u0026micro;m OD and 519 \u0026micro;m OS. Corneal imaging was interpreted as KC suspect in both eyes.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAblation depths were 59 \u0026micro;m and 62 \u0026micro;m respectively. The CXL protocol consisted of epithelium-off crosslinking using isotonic riboflavin 0.1%, 9mW/cm\u0026sup2; for ten minutes for a total energy of 5.4 J/cm\u0026sup2;. with no intra or immediate pos operative complications\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eSeven months postoperatively, UCVA improved to 0.75 OD and 0.65 OS, with a BSCVA of 0.8 O.U .(Fig.\u0026nbsp;12, 13, 14) Refraction was +\u0026thinsp;0.50 / \u0026minus;1.00 D at 142\u0026deg; OD and +\u0026thinsp;2.75 / \u0026minus;1.25 D at 60\u0026deg; OS. Two and a half years after surgery, UCVA measured 0.9 OD 0.15 OS, though BSCVA remained relatively preserved 0.9OD and 0.8, respectively). Refraction at that time showed\u0026thinsp;+\u0026thinsp;0.50 / \u0026minus;0.50 D at 40\u0026deg; OD and +\u0026thinsp;3.75 / \u0026minus;1.00 D at 60\u0026deg; OS .Almost 3.5 years post operatively OD : No change in VA and refraction OS UCVA 0.2, refraction\u0026thinsp;+\u0026thinsp;5.25/-2.75 at 60\u0026deg; ,BCVA 0.8\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cp\u003eAt our clinic eleven years after surgery, UCVA measured 0.6 in the right eye and 0.1 in the left eye. BCVA was 0.7 and 0.6, respectively. Objective refraction of OS was +\u0026thinsp;6.75 / \u0026minus;2.75 D at 55\u0026deg;, while subjective tolerance reached\u0026thinsp;+\u0026thinsp;4.25 / \u0026minus;2.75 D at the same axis.\u003c/p\u003e \u003cp\u003eSlit-lamp examination revealed scattered central corneal opacities, both superficial and deeper OS. The remainder of the ocular examination\u0026mdash;including lens, fundus, and intraocular pressure\u0026mdash;was normal in both eyes. TCT 444 \u0026micro;m OD and 368 \u0026micro;m OS. Corneal tomography demonstrated central corneal flattening in the left eye .(Figs.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, \u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e ).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eCXL has become the accepted standard of care to halt the progression of KC. Multiple randomized and observational studies have shown that CXL can prevent further ectatic progression in the majority of treated eyes, with a mean flattening of maximal keratometry (Kmax) typically in the range of 1\u0026ndash;2 diopters and a modest improvement in corrected and uncorrected visual acuity in many patients\u003csup\u003e4\u003c/sup\u003e. Nevertheless persistent stromal haze, scarring, infections, and endothelial damage have been reported in a small proportion of patients\u003csup\u003e5\u003c/sup\u003e.\u003csup\u003e6 7\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eCombined CXL and PRK are used to both stabilize the ectatic process and partially regularize the anterior corneal surface. Topography-guided or wavefront-guided PRK with limited ablation depth, performed either sequentially after CXL or simultaneously with CXL, can reduce irregular astigmatism and higher-order aberrations and thereby improve functional visual acuity and quality of life in carefully selected keratoconus patients. Several protocols (e.g. \u0026ldquo;Athens,\u0026rdquo; \u0026ldquo;Cretan,\u0026rdquo; and other center-specific approaches) have reported encouraging short-term outcomes with improved UCVA and BCVA and moderate reductions in Kmax, often with low reported rates of sight-threatening complications.\u003csup\u003e89101112\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn spite of the positive results reported after PRK combined with CXL haze formation and scarring are also reported \u003csup\u003e131415\u003c/sup\u003e Frucht-Pery et al report on 5 cases of haze following combined treatment. these observations strongly suggest that the frequency and visual impact of such late complications may be underestimated in the literature, partly due to short follow-up periods and publication bias in favor of favorable refractive outcomes\u003csup\u003e16\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCorneal scarring after epithelium-off CXL results from disruption of corneal collagen architecture, keratocyte apoptosis, and wound-healing abnormalities triggered by UV exposure and epithelial removal. Normal post-CXL haze peaks at 1 month and usually regresses by 6\u0026ndash;12 months, but excessive or persistent haze occurs when healing is exaggerated, inflammation is increased, or procedural deviations occur\u003csup\u003e17\u003c/sup\u003e. Post-PRK haze arises from an inflammatory wound-healing cascade triggered by epithelial and basement-membrane disruption. Cytokines such as IL-1, IL-6, PDGF, and especially TGF-β activate keratocytes and drive their transformation into myofibroblasts, which produce disorganized extracellular matrix that scatters light and causes stromal opacification\u003csup\u003e18\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eThe combination of both treatments increases the risk of haze formation because both mechanisms of haze formation are operated and more keratocytes apoptosis are induced. Each of these steps triggers its own wound-healing cascade; when performed together, they likely interact in complex ways.\u003c/p\u003e \u003cp\u003eMitomycin C (MMC) is used after PRK to modulate wound healing, for preventing corneal haze formation\u003csup\u003e19\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eControversy and variable outcomes are reported after the use of MMC after combined PRK and CXL\u003csup\u003e20\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eMost of the literature on combined PRK\u0026thinsp;+\u0026thinsp;CXL consists of small, non-randomized series with relatively short follow-up, heterogeneous inclusion criteria, variable CXL protocols, and limited data on late adverse events. Consequently, the true incidence, spectrum, and time course of serious complications such as late stromal scarring and progressive flattening after combined PRK\u0026thinsp;+\u0026thinsp;CXL remain unknown and are likely under-reported.\u003c/p\u003e \u003cp\u003eIn this article, we present two additional cases of KC suspect eyes that developed late-onset, visually significant stromal scarring associated with marked corneal flattening after combined PRK and CXL. Both eyes initially had satisfactory postoperative visual recovery before manifesting progressive flattening and central scarring years after surgery. These cases expand the spectrum of delayed complications after PRK\u0026thinsp;+\u0026thinsp;CXL and underscore the need for cautious patient selection, realistic counseling, and long-term follow-up when considering photoablative procedures in crosslinked keratoconic corneas\u003csup\u003e16\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe two cases described in this report illustrate a clinically significant pattern of late-onset stromal scarring accompanied by excessive corneal flattening following combined PRK and CXL for KC suspect. Importantly, in both patients the two eyes were highly similar preoperatively in terms of refractive error and topographic profile. Combined PRK\u0026ndash;CXL was performed bilaterally using almost identical ablation patterns, yet only one eye in each patient developed the late scarring and progressive flattening, while the fellow eye remained clear and stable.Despite these differences, the early postoperative course in all four eyes was acceptable, with stable or improved vision and initially clear corneas. The subsequent appearance of central stromal opacification\u0026mdash;with progressive, non-physiological flattening\u0026mdash;occurred late, well after the expected healing period. This led to significant visual degradation.\u003c/p\u003e \u003cp\u003eThese cases share some features with previously published isolated reports of late stromal scarring after combined surface ablation and CXL, but they also underscore distinct and unresolved clinical questions: why only one eye is affected despite nearly identical preoperative characteristics and procedural parameters, and what underlying wound-healing mechanisms may predispose to this asymmetric late stromal response.\u003c/p\u003e \u003cp\u003eOur two cases share several features: Preoperative excellent corrected visual acuity, with no clinical KC, only asuspect of topographical KC interpreted by the surgeons. PRK was an elective procedure and CXL was added as a \"preventive\" treatment.\u003c/p\u003e \u003cp\u003eIn our two cases, the common denominator was a combined PRK\u0026thinsp;+\u0026thinsp;CXL procedure applied to KC suspect corneas primarily to improve visual function, with ablation depths and residual thicknesses considered \u0026ldquo;acceptable\u0026rdquo; by current standards. Our cases, in which good early visual results were followed by late complications, illustrate that excellent early postoperative acuity does not guarantee long-term stability.\u003c/p\u003e \u003cp\u003eOnce deep stromal scarring and pronounced flattening have developed, therapeutic options are limited. High-dose topical corticosteroids may be tried early when the first signs first appear.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThese two cases illustrate that, although combined PRK\u0026ndash;CXL is generally a safe and effective option for carefully selected keratoconus-suspect patients, individual variability in stromal wound healing may occasionally lead to unexpected late changes. Even when preoperative characteristics and treatment parameters are nearly identical between fellow eyes, postoperative healing can follow different trajectories. Recognizing this variability highlights the importance of long-term follow-up and continued refinement of patient-selection criteria. With broader clinical experience and future research aimed at understanding individual wound-healing profiles.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eInformed consent was obtained from the patients for publication of these two case reports and accompanying images.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAl-Mohaimeed MM. Combined corneal CXL and photorefractive keratectomy for treatment of keratoconus: a review. \u003cem\u003eInt J Ophthalmol\u003c/em\u003e. 2019;12(12):1929. doi:10.18240/IJO.2019.12.16\u003c/li\u003e\n\u003cli\u003eKymionis G, Kontadakis G, Grentzelos M, Petrelli M. Long-term follow-up of combined photorefractive keratectomy and corneal crosslinking in keratoconus suspects. \u003cem\u003eClin Ophthalmol\u003c/em\u003e. 2021;15:2403-2410. doi:10.2147/OPTH.S294775;JOURNAL:JOURNAL:DOPH20;WGROUP:STRING:PUBLICATION\u003c/li\u003e\n\u003cli\u003eKoosha N, Fathian A, Peyman A, Nourbakhsh SA, Noorshargh P, Pourazizi M. Combined simultaneous photorefractive keratectomy and collagen cross-linking in keratoconus suspect patients. \u003cem\u003eJ Fr Ophtalmol\u003c/em\u003e. 2023;46(8):921-928. doi:10.1016/J.JFO.2022.11.029\u003c/li\u003e\n\u003cli\u003eWollensak G, Spoerl E, Seiler T. Riboflavin/ultraviolet-a-induced collagen crosslinking for the treatment of keratoconus. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e. 2003;135(5):620-627. doi:10.1016/s0002-9394(02)02220-1\u003c/li\u003e\n\u003cli\u003eKoller T, Mrochen M, Seiler T. Complication and failure rates after corneal crosslinking. \u003cem\u003eJ Cataract Refract Surg\u003c/em\u003e. 2009;35(8):1358-1362. doi:10.1016/j.jcrs.2009.03.035\u003c/li\u003e\n\u003cli\u003eAgarwal R, Jain P, Arora R. Complications of corneal collagen cross-linking. \u003cem\u003eIndian J Ophthalmol\u003c/em\u003e. 2022;70(5):1466. doi:10.4103/IJO.IJO_1595_21\u003c/li\u003e\n\u003cli\u003eRaiskup F, Hoyer A, Spoerl E. Permanent Corneal Haze After Riboflavin-UVA-Induced Cross-Linking in Keratoconus. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 2009;25(9):S824-S828. doi:10.3928/1081597X-20090813-12\u003c/li\u003e\n\u003cli\u003eKanellopoulos AJ. Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 2009;25(9). doi:10.3928/1081597X-20090813-10\u003c/li\u003e\n\u003cli\u003eKanellopoulos AJ. Comparison of Sequential vs Same-Day Simultaneous Collagen Cross-Linking and Topography-Guided PRK for Treatment of Keratoconus. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 2009;25(9):S812-S818. doi:10.3928/1081597X-20090813-10\u003c/li\u003e\n\u003cli\u003eAl-Mohaimeed MM. Combined corneal CXL and photorefractive keratectomy for treatment of keratoconus: a review. \u003cem\u003eInt J Ophthalmol\u003c/em\u003e. 2019;12(12):1929. doi:10.18240/IJO.2019.12.16\u003c/li\u003e\n\u003cli\u003eAwwad ST, Bteich Y, Assaf JF, et al. Prospective Objective Analysis of Corneal Haze Following Customized Transepithelial PRK Without Mitomycin C Combined With Accelerated Corneal Cross-Linking Versus Corneal Cross-Linking Alone. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 2024;40(9):e583-e594. doi:10.3928/1081597X-20240715-03;WEBSITE:WEBSITE:SLACK-SITE;WGROUP:STRING:PUBLICATION\u003c/li\u003e\n\u003cli\u003eKankariya V, Kymionis G, Kontadakis G, Yoo S. Update on Simultaneous Topo-guided Photorefractive Keratectomy Immediately Followed by Corneal Collagen Cross-linking for Treatment of Progressive Keratoconus. \u003cem\u003eInt J Keratoconus Ectatic Corneal Dis Ect Cor Dis\u003c/em\u003e. 11(33). doi:10.5005/jp-journals-10025-1035\u003c/li\u003e\n\u003cli\u003eKymionis GD, Grentzelos MA, Voulgari N. Stromal scarring and visual acuity loss after combined PRk and CXL for keratoconus. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 2019;35(6):399. doi:10.3928/1081597X-20190520-02\u003c/li\u003e\n\u003cli\u003eMoraes RLB, Ghanem RC, Ghanem VC, Santhiago MR. Haze and visual acuity loss after sequential photorefractive keratectomy and corneal cross-linking for keratoconus. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 2019;35(2):109-114. doi:10.3928/1081597X-20190114-01;PAGE:STRING:ARTICLE/CHAPTER\u003c/li\u003e\n\u003cli\u003eG\u0026uuml;ell JL, Verdaguer P, Elies D, Gris O, Manero F. Late onset of a persistent, deep stromal scarring after PRK and corneal cross-linking in a patient with forme fruste keratoconus. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 2014;30(4):286-288. doi:10.3928/1081597X-20140320-09\u003c/li\u003e\n\u003cli\u003eFrucht-Pery, Joseph DW. Controversies in the Management of Keratoconus edited by Adel Barbara published by Sptinger. In: ; 2019.\u003c/li\u003e\n\u003cli\u003eNatarajan R, Giridhar D. Corneal scarring after epithelium-off collagen cross-linking. \u003cem\u003eIndian J Ophthalmol\u003c/em\u003e. 2025;73(1):28-34. doi:10.4103/IJO.IJO_95_24\u003c/li\u003e\n\u003cli\u003eMoshirfar M, Wang Q, Theis J, et al. Management of Corneal Haze After Photorefractive Keratectomy. \u003cem\u003eOphthalmol Ther 2023 126\u003c/em\u003e. 2023;12(6):2841-2862. doi:10.1007/S40123-023-00782-1\u003c/li\u003e\n\u003cli\u003eOuerdane Y, Zaazouee M, Mohamed M, et al. Mitomycin C application after photorefractive keratectomy in high, moderate, or low myopia: Systematic review and meta-analysis. \u003cem\u003eIndian J Ophthalmol\u003c/em\u003e. 2021;69(12):3421. doi:10.4103/IJO.IJO_3768_20\u003c/li\u003e\n\u003cli\u003eAwwad ST, Bteich Y, Assaf JF, et al. Prospective Objective Analysis of Corneal Haze Following Customized Transepithelial PRK Without Mitomycin C Combined With Accelerated Corneal Cross-Linking Versus Corneal Cross-Linking Alone. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 2024;40(9):e583-e594. doi:10.3928/1081597X-20240715-03;WEBSITE:WEBSITE:SLACK-SITE;WGROUP:STRING:PUBLICATION\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Keratoconus, Photorefractive keratectomy (PRK), Corneal collagen cross-linking (CXL), Combined PRK–CXL, Stromal scarring, Corneal flattening, Wound healing, Corneal biomechanics, Late complications, Visual rehabilitation.","lastPublishedDoi":"10.21203/rs.3.rs-9023698/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9023698/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003ePurpose: To report two cases of late-onset central stromal scarring and marked corneal flattening following combined photorefractive keratectomy (PRK) and corneal collagen cross-linking (CXL) performed for keratoconus (KC) suspect, despite nearly identical bilateral preoperative characteristics and treatment parameters.\u003c/p\u003e\n\u003cp\u003eMethods: Two patients underwent same-day PRK–CXL in both eyes for refractive correction in KC suspect elsewhere . Preoperative tomography, pachymetry, ablation profiles, ultraviolet fluence, and post operative[P1] [ab2] \u0026nbsp;regimens were comparable between fellow eyes. Patients were followed with serial clinical examinations and corneal imaging.\u003c/p\u003e\n\u003cp\u003eResults: In each patient, one eye developed late-onset central stromal scarring with excessive corneal flattening and reduced visual acuity, whereas the contralateral eye demonstrated stable healing and favorable visual outcomes.\u003c/p\u003e\n\u003cp\u003eConclusions: These cases illustrate marked inter-eye variability in corneal wound healing after PRK–CXL in KC suspects, emphasizing the need for careful patient selection, conservative treatment planning, and long-term follow-up.\u003c/p\u003e\n\u003cp\u003eEthical Compliance: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no financial, commercial, or proprietary interests in any product, device, or company mentioned in this manuscript, and no conflicts of interest relevant to the content of this article.\u003c/p\u003e","manuscriptTitle":"Late-Onset Stromal Scarring and Excessive Corneal Flattening After PRK–CXL in Keratoconus Suspects: A Report of Two Contralateral Case Variants","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 17:11:13","doi":"10.21203/rs.3.rs-9023698/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"26f979c4-1ca0-4dfc-919c-491029367e03","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-03-08T17:11:13+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 17:11:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9023698","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9023698","identity":"rs-9023698","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}