Corneal Cross-Linking in Keratoconus: A Scoping Review of Clinical Evidence and Public Health Implications

Corneal Cross-Linking in Keratoconus: A Scoping Review of Clinical Evidence and Public Health Implications | 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 Systematic Review Corneal Cross-Linking in Keratoconus: A Scoping Review of Clinical Evidence and Public Health Implications Rodrigo Ojeda-Salamanca, Bryan Villagra, Nicolás Figueroa Vargas, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7714413/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 Objective. To map and synthesize recent evidence on the efficacy, safety, adherence, and cost-effectiveness of corneal cross-linking (CXL) for keratoconus, with emphasis on its public health implications. Methods. A scoping review was conducted following Arksey and O’Malley’s framework, complemented by the recommendations of Levac, Colquhoun, and O’Brien, and in accordance with the PRISMA-ScR guideline. Studies published between 2021 and 2024 were retrieved from Scopus, PubMed, and Web of Science. Two independent reviewers performed study selection and data extraction. Quantitative data were analyzed through descriptive statistics, while qualitative findings were synthesized using specialized software. Results. From 596 initial records, 43 studies were included. Retrospective (46.51%) and prospective (37.21%) designs predominated, mainly focused on adult populations. CXL stabilized keratoconus progression in 90–95% of cases. The standard protocol remained the reference, while the accelerated protocol showed comparable efficacy with practical advantages, particularly in pediatric populations. Transepithelial and iontophoresis-assisted modalities exhibited acceptable safety but heterogeneous efficacy. Adapted protocols for ultrathin corneas expanded clinical indications without compromising endothelial safety. Conclusions. Available evidence supports CXL as an effective and cost-effective intervention to halt keratoconus progression, reduce the need for corneal transplantation, and preserve visual function. Its applicability across diverse clinical settings underscores its value as a public health priority. However, gaps remain regarding protocol standardization and context-specific economic evaluations. Ophthalmology Corneal cross-linking Keratoconus Ophthalmology Scoping review Public health Figures Figure 1 Figure 2 Figure 3 Introduction Keratoconus is a progressive corneal disease of high clinical and social relevance, where early detection and timely treatment are essential to preserve vision and avoid major surgical interventions (1). Traditionally, therapeutic management of keratoconus was limited to optical correction with rigid contact lenses or, in advanced stages, corneal transplantation. However, both approaches fail to address the underlying pathophysiology of the disease and do not halt the progressive corneal deformation (2,3). In this context, corneal cross-linking (CXL) has emerged as the main therapeutic strategy capable of modifying corneal biomechanics and slowing disease progression. The scientific literature has documented multiple modalities and adaptations of this technique, aiming to balance efficacy, safety, and clinical applicability, particularly in high-risk populations such as pediatric patients or those with ultrathin corneas (4–6). Keratoconus as a Visual and Public Health Problem Keratoconus is a progressive corneal ectasia of multifactorial etiology (genetic, environmental, and lifestyle factors, among others) (7–9), characterized by corneal thinning and deformation that lead to irregular astigmatism, reduced visual acuity, and, in advanced stages, the need for corneal transplantation. It is considered a relatively rare disease; however, recent studies estimate a global prevalence of 289 per 100,000 inhabitants, affecting more than 23.7 million people worldwide, with a higher prevalence in men than in women (10,11). Advances in high-precision ophthalmic imaging, such as corneal topography and tomography, have revealed an even higher prevalence, since their widespread use in countries previously lacking such technology has enabled the timely detection of subclinical cases, particularly among adolescents and young adults (12,13). Its early impact on productive and academic life underscores its relevance as a public health concern, as it compromises quality of life and generates a significant social and economic burden. Therapeutics and Technological Evolution CXL represents the first etiopathogenic treatment capable of modifying corneal biomechanics. It combines riboflavin with ultraviolet-A (UV-A) radiation to induce covalent cross-links in stromal collagen fibers, thereby increasing stromal stiffness and halting ectatic progression (14,15). The standard protocol (sCXL), introduced in the early 2000s, remains the reference technique due to its proven efficacy and favorable safety profile (15). From this foundation, multiple adaptations have emerged, such as accelerated CXL (aCXL), aimed at reducing surgical time; transepithelial CXL (tCXL), which provides greater patient comfort; and iontophoresis-assisted CXL, still under investigation, with promising yet inconclusive preliminary evidence (16–18). In addition, protocols adapted for ultrathin corneas (sub400, hypoosmolar riboflavin, or UV-permeable contact lenses) have broadened the eligible patient population, while innovations such as oxygen supplementation and stromal lenticule implantation are exploring new frontiers in efficacy and safety (19). Parallel advances in optics, including modern contact lenses and orthokeratology, have emerged as novel alternatives, though their evidence remains heterogeneous (20,21). Furthermore, the diversity of CXL modalities complicates direct comparisons in narrative reviews (22,23). These modifications underscore the ongoing pursuit of balancing effectiveness, safety, comfort, and clinical applicability. Clinical Evidence and Research Gaps Non-systematic explorations of the scientific literature consistently suggest that CXL effectively stabilizes keratoconus progression in most cases, with a low rate of complications that are generally mild and transient (24,25). However, the available evidence presents important limitations, both in study design and in the heterogeneity of protocols. These constraints hinder direct comparisons and limit the extrapolation of universal conclusions. Thus, while CXL has been the therapeutic standard in keratoconus management, research gaps remain that warrant further lines of investigation. Method The objective of this study is to explore the evidence on the efficacy, safety, adherence, and cost-effectiveness of different treatment modalities for keratoconus, to identify the most effective and applicable strategies in both clinical practice and public health. The research protocol is published in the Open Science Framework in accordance with open science guidelines ( 26 ), under DOI registration number 10.17605/OSF.IO/MHV7C , within the category “Methods and Measures,” and under a CC-By Attribution 4.0 International License, where the inclusion and exclusion criteria, variables, and analysis software are specified. This study is a scoping and exploratory review aimed at analyzing the existing literature on the comparative effectiveness of therapeutic alternatives in patients with keratoconus. For the development and conduct of the review, we followed the methodological framework proposed by Arksey and O'Malley ( 27 ), complemented with the recommendations of Levac, Colquhoun, and O'Brien ( 28 ). In addition, the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines were used to structure the presentation of results and ensure transparency. The keywords and query strategy, the RIS files managed with Zotero, and the data extraction table that underpin the analytical basis of this study are available in the open science repository Zenodo under a Creative Commons Attribution 4.0 International License, DOI 10.5281/zenodo.17137608 This study involved two independent reviewers, whose calibration yielded a Cohen’s Kappa coefficient of 0.70, indicating substantial agreement. Screening was conducted in two stages: title and abstract review, followed by full-text assessment. The reviewers determined the included and excluded studies, documenting the reasons for exclusion. The process was performed manually without artificial intelligence assistance and managed through Rayyan. Based on these steps, the PRISMA flow diagram was constructed in accordance with Hadaway et al. ( 29 ). Quantitative analyses were performed using Jamovi statistical software, and qualitative analyses were conducted with Atlas.ti. The outputs of these analyses are presented in this article and have also been uploaded to the Zenodo repository previously identified. Results The PRISMA flow diagram was developed according to the inclusion and exclusion criteria and a five-year time horizon. In the identification stage, 596 records were retrieved from electronic databases: PubMed (n = 21), Scopus (n = 333), and Web of Science (n = 242). No additional records from protocols were identified. Subsequently, 28 duplicates were removed, leaving 568 records for the screening phase. The included studies were published primarily between 2021 and 2024, showing a progressive increase in recent scientific output. The year with the highest number of publications was 2023 (10 studies, 23.3%), followed by 2021 (9 studies, 20.9%). During the screening phase, no records were excluded automatically or for other reasons. A total of 568 full reports were sought for retrieval, of which 1 could not be accessed. In the eligibility phase, 567 reports were assessed and 524 were excluded for not meeting the established criteria: 271 for intervention-related reasons, 248 for study design, and 5 for availability. Ultimately, a total of 43 studies were included, which constitute the basis for the analysis and synthesis of results in this investigation, as presented in Fig. 1 . Quantitative Characterization A total of 43 studies met the inclusion criteria and were analyzed in detail. Regarding methodological design, a predominance of retrospective studies was identified (n = 20; 46.51%) and prospective studies (n = 16; 37.21%), followed by randomized controlled trials (n = 5; 11.63%) and cost-effectiveness simulations or models (n = 2; 4.65%). With respect to the study population, most investigations focused on adults (n = 31; 72.09%), with a notable difference compared to studies addressing pediatric populations (n = 11; 25.58%); meanwhile, one study (2.33%) included mixed cohorts or lacked explicit age classification. The detailed age range of participants extended from 13 to 36 years, as summarized in Table 1 , with distribution represented in Fig. 2 . Table 1 Average age distribution and eyes as units of analysis Design N Age Eyes AVG Med SD Min Max AVG Med SD Min Max Retrospective 20 23.1 23.4 6.57 13.0 36.0 144.7 48.5 239.7 7 976 Clinical Trial 5 22.8 24.6 4.39 15.2 26.1 37.4 54.0 24.6 10 58 Simulation 2 24.5 24.5 9.19 18.0 31.0 3 500.0 3 500.0 2 121.3 2 000 5 000 Prospective 16 21.2 21.6 4.60 13.0 28.6 106.3 74.5 154.2 19 670 Statistical summary of the mean age and number of eyes of participants grouped by study design. Uniform means and medians are observed across ages, but variable in the number of eyes. The standard deviation is significant for both ages and eyes in the samples studied. Sample sizes varied widely, ranging from small studies with 7 eyes to large series exceeding 1,000 eyes, as shown in Table 1 . Patient follow-up across studies ranged from 6 months to 10 years, with a predominance of short-term studies (< 2 years), a substantial number of intermediate follow-up studies (2–5 years), and at least five investigations reporting more than 5 years of observation, including two with 10-year results. Microsimulation models extended the analytical horizon up to 52 years, providing insights into cost-effectiveness, as detailed in Table 2 . Table 2 Participant follow-up by study type in months Design N AVG Med SD Min Max Follow-up time (months) Retrospective 20 29.8 12.0 29.9 6 120 Clinical Trial 5 27.6 24.0 13.1 12 48 Simulation 2 372.0 372.0 356.4 120 624 Prospective 16 33.4 27.0 22.3 1 84 Summary of the follow-up period in the studies. It is notable that 60% of the studies have short-term follow-up, 25.6% have long-term follow-up, and the majority (55.8%) evaluate efficacy and safety over a period of 1 to 3 years. The combined analysis of the 43 included studies, encompassing a total of 312 records on outcomes, effects, conclusions, limitations, and observations, offers a comprehensive characterization of the current state of evidence regarding CXL in the management of keratoconus. Qualitative Description In the inductive coding analysis, the following codes showed the highest frequency: “Efficacy (Gr = 29),” “Little Replicability (Gr = 21),” “No Adverse Effects (Gr = 20),” “Limited Technology (Gr = 17),” “Corneal Opacity (Gr = 16),” and “Security (Gr = 15).” These represent the central themes most frequently co-occurring with others. This distribution of codes allowed the identification of potential axes for qualitative analysis by categories, as illustrated in the force diagram in Fig. 3 : Safety: The co-occurrence between Security, Corneal Opacity , and CXL suggests that most discussions focus on ensuring safety when applying protocol variations. Limitations: The connection between Small Sample, Short Follow-up , and Retrospective Design highlights recurring concerns about study design and follow-up limitations. Innovations: Codes such as Sub-400, Application of Oxygen , and Thin Corneas co-occur with Security and Efficacy , indicating that novel techniques are primarily evaluated in terms of safety. Isolated or less frequent codes: Pregnant Women, Sponsorship Bias , and Comfort emerged as marginal findings, of interest but with limited weight in the overall discussion. The analysis shows that the core of the literature on keratoconus treatment is organized around three main poles: Clinical efficacy and safety (aCXL, sCXL, corneal opacities, safety). Methodological limitations (sample size, follow-up, study design). Expansion of indications (sub-400, supplemental oxygen, thin corneas) Analysis of Results The integrated analysis of the 43 included studies shows that CXL, in its various modalities, currently represents the therapeutic cornerstone in the management of keratoconus, both for its clinical efficacy and its safety profile. In terms of outcomes and effects, more than 90% of studies reported stabilization of disease progression, with differences in efficacy among modalities. Overall, approximately 42% found equivalence between sCXL and aCXL; a smaller proportion (~ 30%) highlighted specific benefits of aCXL, while an important number of studies (~ 42%) emphasized the applicability of sub400 protocols in ultrathin corneas. The most common limitations reported across articles were small sample size (44%), retrospective or non-randomized design (~ 49%), methodological heterogeneity (~ 51%), and short-term follow-up (42%). Findings show that CXL halts disease progression in about 90%–95% of cases, with a low rate of clinical failure and serious complications. The standard protocol (sCXL) remains the reference, although accelerated protocols (aCXL) have demonstrated comparable efficacy, with practical advantages such as reduced surgical time and better adherence, particularly relevant in pediatric populations, where the disease course is more aggressive. Modalities such as transepithelial CXL (tCXL) or iontophoresis-assisted CXL maintain an acceptable safety profile, though their efficacy is more heterogeneous, with reported progression rates up to 22%, which supports their use only in highly selected clinical contexts. Meanwhile, protocols adapted for ultrathin corneas (sub400 or hypoosmolar riboflavin) represent an advance, as they expand treatment indications without compromising endothelial safety. From the qualitative perspective, several transversal methodological limitations condition the validity of findings, including the predominance of retrospective designs, small sample sizes, heterogeneous protocols, and lack of standardized progression criteria. Nevertheless, multicenter and randomized trials provide greater methodological consistency, and external validity is strengthened by real-world clinical studies. Regarding safety, complications were mostly mild and transient, with stromal haze being the most frequent reported initially at 15%, declining to < 3% annually at mid-term follow-up. Severe cases, such as infections, were exceptional. An interesting observation was the association between moderate haze and a greater biomechanical effect reflected in Kmax flattening, which opens new hypotheses on treatment response physiology. In terms of clinical applicability, results reinforce the need for individualized management. The choice between sCXL and aCXL may be guided by age, adherence, and clinical setting, while in special circumstances (pregnancy, chronic eye rubbing, or allergies) close monitoring is required due to the risk of late progression. In pediatric patients, the importance of early interventions with biomechanically robust protocols is strongly supported. Finally, cost-effectiveness studies consistently indicate that CXL is highly cost-effective, particularly when performed early, as it reduces the need for corneal transplantation and preserves visual function. However, the generalizability of these analyses is limited by dependence on local pricing and the omission of indirect costs in available models. Overall, quantitative and qualitative results reaffirm CXL as a safe, effective, and high-impact public health intervention, with durable clinical benefits and a range of modalities that expand its indications. The evidence further suggests that treatment is evolving toward protocol personalization and the integration of technological innovations, consolidating CXL as the first-line strategy in modern keratoconus management. Discussion The findings of this review confirm that CXL constitutes the most robust intervention to halt the progression of keratoconus. The standard protocol (sCXL) maintains its role as the reference, with proven efficacy and a favorable safety profile. In parallel, accelerated protocols (aCXL) have demonstrated comparable clinical outcomes in keratometric and visual parameters, with practical advantages such as shorter surgical times and greater tolerance, particularly in pediatric and young populations where therapeutic adherence is critical for success. In contrast, transepithelial modalities (tCXL) show more variable efficacy, limiting their generalization, although their less invasive nature may be useful in specific contexts. Therapeutic innovation has expanded the scope of CXL to previously restricted scenarios. Adapted protocols for ultrathin corneas (sub400, hypoosmolar riboflavin, UV-permeable contact lenses) have demonstrated feasibility and safety, avoiding the exclusion of vulnerable patients and reducing the need for transplantation. At the methodological level, common limitations include protocol heterogeneity, small sample sizes, and the absence of standardized definitions of progression. Nevertheless, external validity is strengthened in multicenter studies and real-world clinical registries, which provide a more realistic perspective on the applicability of CXL across different health systems. It is noteworthy that there is limited systematized evidence regarding the use of contact lenses in keratoconus therapy. Currently, the development of specialized lenses is emerging as a complementary pillar of visual rehabilitation, with miniscleral and hybrid lenses shown to reduce higher-order aberrations and improve visual quality without significant differences between designs, while next-generation and customized hybrid lenses provide significant improvements in visual acuity and comfort in advanced keratoconus patients ( 20 ). These findings reinforce a combined approach, where optical therapy and biomechanical intervention are integrated into a comprehensive management model. With respect to orthokeratology (Ortho-K) combined with CXL, the evidence remains exploratory. Available studies, both in animal models and pilot clinical trials, suggest that it may slow corneal regression, but current protocols fail to maintain a sustained long-term effect ( 30 ). Nonetheless, this line of research opens a promising field for combined and personalized therapies. According to the evidence analyzed, and from a public health perspective, CXL emerges as a highly cost-effective intervention, particularly when implemented at early stages, by preventing visual disability, reducing the need for corneal transplantation, and decreasing the economic burden on healthcare systems. Moreover, the incorporation of advanced contact lenses can broaden the possibilities of functional rehabilitation and help preserve patient autonomy and quality of life—fundamental aspects in young populations, where the disease has a greater socioeconomic impact. In this regard, integrating CXL within national vision health programs could represent an effective and sustainable secondary prevention strategy, aligned with goals of equity and universal access. Finally, knowledge gaps remain that justify the need for multicenter clinical trials with standardized protocols, response biomarkers, and long-term follow-up. Likewise, cost-effectiveness studies tailored to each health system are required to optimize resource allocation and consolidate CXL as the therapeutic cornerstone in modern keratoconus management. Conclusion Corneal cross-linking is consolidated as the most effective and safest treatment to halt the progression of keratoconus, ensuring sustained visual and keratometric stability in the long term. Accelerated protocols show clinical outcomes equivalent to the standard approach, with advantages in surgical time and adherence, particularly in pediatric and young populations, while transepithelial and iontophoretic modalities present more heterogeneous efficacy and require individualized selection. Adapted protocols for ultrathin corneas broaden treatment indications and help reduce the need for transplantation. From a public health perspective, CXL stands out as a cost-effective intervention that should be prioritized at early stages, although challenges remain regarding protocol standardization, biomarker validation, and the development of context-specific economic studies. Abbreviations CXL: Corneal Cross-linking UV-A: Ultraviolet-A sCXL: Standard Corneal Cross-linking aCXL: Accelerated Corneal Cross-linking tCXL: Transepithelial Corneal Cross-linking Ortho-K: Orthokeratology PRISMA-ScR: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews Declarations Ethics approval and consent to participate Not applicable Consent for publication Not applicable Available of data and materials The scoping review protocol is published in the Open Science Framework and is available at https://doi.org/10.17605/OSF.IO/MHV7C The datasets generated and/or analysed during the current study are available in the Zenodo repository, DOI 10.5281/zenodo.16951705 Competing interests The authors declare that they have no competing interests Funding The authors declare that no funding has been received for the development of this research. Author’s contributions HB participated in the development of the research idea and the co-construction of the reference framework. He designed the methodological framework and co-constructed the scoping review protocol. He led the calibration of screeners and participated in data extraction. He developed the analysis of results, discussion, and conclusions. He wrote the manuscript. RO participated in the development of the research idea and the co-construction of the reference framework and co-construction of the scoping review protocol. He designed the instructions for screeners and participated in data extraction. BV and NF conducted the article screening, defining the analytical basis that supports this research. Acknowledgements Not applicable Author’s information HB is a professor in the Department of Public Health at the Universidad San Sebastián and a professor in the ophthalmology specialty of the Medical Technology program. He is also a practicing medical technologist specializing in ophthalmology and optometry. RO is a medical technologist specializing in ophthalmology and optometry and a member of the International Academy of Keratoconus for Eye Care Professionals. BV is a medical technologist specializing in ophthalmology and optometry, currently a master's student in epidemiology. NF is a medical technologist specializing in ophthalmology and optometry, a primary care professional, and a student pursuing a master's degree in public health. References Deshmukh R, Ong ZZ, Rampat R, Alió del Barrio JL, Barua A, Ang M, et al. Management of keratoconus: an updated review. Front Med [Internet]. 2023;10. Disponible en: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85164502517&doi=10.3389%2ffmed.2023.1212314&partnerID=40&md5=15fdce2476f3c8327e9d7c890ff39bb0 Feizi S, Javadi MA, Alemzadeh-Ansari M, Arabi A, Shahraki T, Kheirkhah A. Management of corneal complications in vernal keratoconjunctivitis: A review. Ocul Surf. 2021;19:282-9. Itoi M, Itoi M. Management of Keratoconus With Corneal Rigid Gas-Permeable Contact Lenses. Eye Contact Lens Sci Clin Pract. marzo de 2022;48(3):110-4. Ang RET, Guloy AJA, Cruz EM, Lo JJGC. Evaluation of refractive, tomographic and biomechanical changes after customized accelerated corneal collagen cross-linking in keratoconus patients: a retrospective observational study. BMC Ophthalmol. 1 de julio de 2025;25(1):378. Elalfy M, Chatzimichail E, Mahgoub K, Hajjar-Sese A, Naveed H, Panos GD, et al. Clinical Outcomes of Repeated Corneal Crosslinking for Progressive Keratoconus After Failure of Primary Procedure; Safety and Efficacy at 12-Month Follow-Up. Ophthalmol Ther [Internet]. 27 de agosto de 2025 [citado 29 de agosto de 2025]; Disponible en: https://link.springer.com/10.1007/s40123-025-01227-7 Hamid A, Jahadi-Hosseini H, Khalili MR, Jahanbani-Ardakani H. Corneal Biomechanical Changes after Corneal Cross-Linking in Patients with Keratoconus. J Curr Ophthalmol. octubre de 2022;34(4):409-13. Cheung IMY, Angelo L, Gokul A, Ziaei M. Non-genetic risk factors for keratoconus and its progression. Clin Exp Optom [Internet]. 2025; Disponible en: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85214262193&doi=10.1080%2f08164622.2024.2443454&partnerID=40&md5=dd033bd4deeb8661420f400b9c5438d5 Sharif R, Bak-Nielsen S, Hjortdal J, Karamichos D. Pathogenesis of Keratoconus: The intriguing therapeutic potential of Prolactin-inducible protein. Prog Retin Eye Res. 2018;67:150-67. Vought R, Greenstein SA, Gelles J, Hersh PS. The Pathophysiology of Keratoconus. Cornea. febrero de 2025;44(2):137-43. Fernández Berdasco K, Alfaya Muñoz LB, Corzo Fernández CR, Señaris González A, Baamonde Arbaiza B. Clinical-epidemiological characteristics of keratoconus in Asturias. Arch Soc Esp Oftalmol Engl Ed. febrero de 2023;98(2):65-71. Sriranganathan A, Chan CC, Dhillon J, Felfeli T. Global Incidence and Prevalence of Keratoconus: A Systematic Review and Meta-Analysis. Cornea [Internet]. 20 de agosto de 2025 [citado 28 de agosto de 2025]; Disponible en: https://journals.lww.com/10.1097/ICO.0000000000003973 Heidari Z, Mohammadpour M, Hajizadeh F, Fotouhi A, Hashemi H. Corneal layer thickness in keratoconus using optical coherence tomography. Clin Exp Optom. 2 de enero de 2024;107(1):32-9. Masiwa LE, Moodley V. A review of corneal imaging methods for the early diagnosis of pre-clinical Keratoconus. J Optom. octubre de 2020;13(4):269-75. Aldairi W, AlQahtani R, Alzaid S, Mousa A, Khandekar R, Al-Swailem SA. Accelerated versus conventional corneal collagen crosslinking: Short-term clinical outcomes in stabilizing keratoconus. Saudi J Ophthalmol. enero de 2022;36(1):47-52. Felter E, Khoramnia R, Friedrich M, Son HS, Auffarth GU, Augustin VA. Biomechanical changes following corneal crosslinking in keratoconus patients. Graefes Arch Clin Exp Ophthalmol. noviembre de 2024;262(11):3635-42. Kandel H, Abbondanza M, Gupta A, Mills R, Watson A, Petsoglou C, et al. Comparison of standard versus accelerated corneal collagen cross-linking for keratoconus: 5-year outcomes from the Save Sight Keratoconus Registry. EYE. enero de 2024;38(1):95-102. Kaya Ergen S, Subaşı S, Yılmaz Tuğan B, Yüksel N, Altıntaş Ö. The effect of transepithelial corneal collagen cross-linking treatment on optical quality of the cornea in keratoconus: 12-month clinical results. Int Ophthalmol. 18 de marzo de 2024;44(1):146. Roszkowska AM, Oliverio GW, Hydzik-Sajak K, De Crescenzo M, Aragona P. Five-year results of iontophoresis-assisted transepithelial corneal cross-linking for keratoconus. Int Ophthalmol. 3 de julio de 2023;43(10):3601-7. Ozek D, Karaca EE, Kemer OE. Accelerated corneal cross-linking with hypo-osmolar riboflavin in thin keratoconic corneas: 2-year follow-up. Arq Bras Oftalmol. agosto de 2020;83(4):277-82. Lim L, Lim EWL. Current perspectives in the management of keratoconus with contact lenses. Eye. diciembre de 2020;34(12):2175-96. Wang Z, Wang Z, Meng Y, Wang P, Yibulayin S, Jiang B, et al. Posterior corneal elevation changes during 12 month of overnight orthokeratology. Heliyon. abril de 2023;9(4):e14887. Aldayel AA, Alwael HM, Alshathri RM, Alnasser HA, Alfawzan LA. A Comparison Between Cross-Linking Protocols in Patients With Progressive Keratoconus: A Review. Cureus [Internet]. 2 de noviembre de 2022 [citado 29 de agosto de 2025]; Disponible en: https://www.cureus.com/articles/82753-a-comparison-between-cross-linking-protocols-in-patients-with-progressive-keratoconus-a-review Sarma P, Kaur H, Hafezi F, Bhattacharyya J, Kirubakaran R, Prajapat M, et al. Short- and long-term safety and efficacy of corneal collagen cross-linking in progressive keratoconus: A systematic review and meta-analysis of randomized controlled trials. Taiwan J Ophthalmol. abril de 2023;13(2):191-202. Angelo L, Gokul Boptom A, McGhee C, Ziaei M. Corneal Crosslinking: Present and Future. Asia-Pac J Ophthalmol. 2022;11(5):441-52. Ferdi AC, Kandel H, Nguyen V, Tan J, Arnalich-Montiel F, Abbondanza M, et al. Five-year corneal cross-linking outcomes: A Save Sight Keratoconus Registry Study. Clin Experiment Ophthalmol. 2023;51(1):9-18. Van den Akker O, Peters GJ, Bakker C, Carlsson R, Coles NA, Corker KS, et al. Generalized Systematic Review Registration Form [Internet]. MetaArXiv; 2020. Disponible en: https://doi.org/g5fj Arksey H, O’Malley L. Scoping studies: towards a methodological framework. Int J Soc Res Methodol. febrero de 2005;8(1):19-32. Levac D, Colquhoun H, O’Brien KK. Scoping studies: advancing the methodology. Implement Sci. diciembre de 2010;5(1):69. Haddaway NR, Page MJ, Pritchard CC, McGuinness LA. PRISMA2020 : An R package and Shiny app for producing PRISMA 2020‐compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis. Campbell Syst Rev. junio de 2022;18(2):e1230. Liao C, Lin X, Keel S, Ha J, Yang X, He M. Effects of corneal crosslinking on corneal shape stabilization after orthokeratology. Sci Rep. 11 de febrero de 2020;10(1):2357. 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7714413","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":520665837,"identity":"53e78ba2-5a94-4fef-aa6e-db00eb02ab50","order_by":0,"name":"Rodrigo Ojeda-Salamanca","email":"","orcid":"https://orcid.org/0000-0002-4368-724X","institution":"Universidad San Sebastián","correspondingAuthor":false,"prefix":"","firstName":"Rodrigo","middleName":"","lastName":"Ojeda-Salamanca","suffix":""},{"id":520665838,"identity":"4dfa7ad4-4787-4df8-ac24-a2cecbb1dde1","order_by":1,"name":"Bryan Villagra","email":"","orcid":"https://orcid.org/0009-0004-7002-3184","institution":"Pontificia Universidad Católica de Chile","correspondingAuthor":false,"prefix":"","firstName":"Bryan","middleName":"","lastName":"Villagra","suffix":""},{"id":520665839,"identity":"49c23002-6dba-4844-a327-c84e95a9a127","order_by":2,"name":"Nicolás Figueroa Vargas","email":"","orcid":"https://orcid.org/0009-0006-2147-1081","institution":"Universidad de Chile","correspondingAuthor":false,"prefix":"","firstName":"Nicolás","middleName":"Figueroa","lastName":"Vargas","suffix":""},{"id":520665840,"identity":"da55a5b2-24e8-4e71-b9f9-09e07436075d","order_by":3,"name":"Hugo Berríos-Arvey","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABAUlEQVRIiWNgGAWjYBACAwkwCcTMzAckUKT4CGphZ0sAs3lgUmx4tYAAP48BcVrMpZuPfa4osLHnb+b5eONDjU2ePXsDm+SPPwzyuLRYzjmWPPOMQVrijMO8my1nHEsr5uE5wCbN28Zg2IbLYTdyjBkbDA4nMBzm3SbN23A4sUcigU2asYEhAadfbuR/Bmmxlz/M8wyo5X9ij/wDsMPwaMlhBmlh3HCYB+iehgNAWxjYJHjY8Gi5cwzksLTEjYfZjIF+SU7sOZPYbM3bJoHbL7ebHzM2/LGxlzt/+CEwxOwS29sPH7z544+NPD8OLdgA0O8MDBKEVI2CUTAKRsEowAMAbQVRrPm4nzkAAAAASUVORK5CYII=","orcid":"https://orcid.org/0009-0007-2541-3660","institution":"Universidad San Sebastián","correspondingAuthor":true,"prefix":"","firstName":"Hugo","middleName":"","lastName":"Berríos-Arvey","suffix":""}],"badges":[],"createdAt":"2025-09-25 15:20:15","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7714413/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7714413/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":92259227,"identity":"0a3f12c2-c19f-49a2-b3ff-88ec9d2b7dc3","added_by":"auto","created_at":"2025-09-26 12:11:35","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":390995,"visible":true,"origin":"","legend":"","description":"","filename":"ArticleBMC.docx","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/cb6fe84c4e53b34d2a8a5a12.docx"},{"id":92259433,"identity":"9c5297fe-f44e-4252-aea2-500081f7ae5c","added_by":"auto","created_at":"2025-09-26 12:19:35","extension":"json","order_by":1,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":342,"visible":true,"origin":"","legend":"","description":"","filename":"rs7714413.json","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/0967ed8ed1b01061b9b0868d.json"},{"id":92259231,"identity":"6c354f16-b8ef-4e6d-8a9c-3b1e0bb7fc0e","added_by":"auto","created_at":"2025-09-26 12:11:35","extension":"xml","order_by":2,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":91647,"visible":true,"origin":"","legend":"","description":"","filename":"rs77144130enriched.xml","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/d373a8371db1dfaaeb12bd8c.xml"},{"id":92259235,"identity":"294a0d00-16ad-4989-8f56-33c7a692fd07","added_by":"auto","created_at":"2025-09-26 12:11:36","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":171626,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/7bedf9d5afb0e0a805561e84.png"},{"id":92259232,"identity":"95783e2a-3d9a-40e2-b2ac-b75ab42614f6","added_by":"auto","created_at":"2025-09-26 12:11:35","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":64758,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/88c897b1347c5d01b7d657b1.png"},{"id":92259233,"identity":"7b22139c-48fe-4551-b901-d2ccb5e02c9a","added_by":"auto","created_at":"2025-09-26 12:11:36","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":52076,"visible":true,"origin":"","legend":"","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/9f1255076ed2557dc7185277.png"},{"id":92259234,"identity":"f2af7981-b9c8-41ec-b1a7-c0509d80c790","added_by":"auto","created_at":"2025-09-26 12:11:36","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":40659,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/0f70a5a4fbd4d68e7889f47c.png"},{"id":92259237,"identity":"0c369bc9-c60a-40c6-96bf-156220e92c1b","added_by":"auto","created_at":"2025-09-26 12:11:36","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":15773,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/78589fb060139a547727e1a2.png"},{"id":92259239,"identity":"16c09c51-68f6-453a-8ead-57fd046a1e5e","added_by":"auto","created_at":"2025-09-26 12:11:36","extension":"png","order_by":8,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":16602,"visible":true,"origin":"","legend":"","description":"","filename":"Onlinefloatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/2ae5bc2992ad558892ff2f1f.png"},{"id":92259236,"identity":"50ca8dc3-d6d9-435a-9e5a-2c5ebf99b5e2","added_by":"auto","created_at":"2025-09-26 12:11:36","extension":"xml","order_by":9,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":89313,"visible":true,"origin":"","legend":"","description":"","filename":"rs77144130structuring.xml","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/fe96ec7ffa0a0657d272923e.xml"},{"id":92259238,"identity":"5143de69-7cd2-49a0-82e4-a5a3ca1c458f","added_by":"auto","created_at":"2025-09-26 12:11:36","extension":"html","order_by":10,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":99454,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/cbccfefd95caef5294dda62b.html"},{"id":92259228,"identity":"f09738dc-e180-4a0c-93a6-40a18519380b","added_by":"auto","created_at":"2025-09-26 12:11:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":190380,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA Diagram\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe PRISMA diagram illustrates the process of identifying, screening, and determining eligibility for studies. Of the 596 records identified in three databases, duplicates were removed and articles excluded after screening. Ultimately, 43 studies that met the selection criteria were included for analysis.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/db267404b925f9214e4aef67.png"},{"id":92259226,"identity":"d800851b-8b1e-47c0-a206-12433364c042","added_by":"auto","created_at":"2025-09-26 12:11:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":44757,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAge distribution of participants by study design\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mean ages by study design have relatively similar medians, but heterogeneous ranges and densities. Retrospective designs dominate the population volume with high bias, while clinical trials present low bias but few data.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/0e263bda036850b080ba8987.png"},{"id":92259229,"identity":"f48572b2-e030-475c-ac6f-b4b84a0c386c","added_by":"auto","created_at":"2025-09-26 12:11:35","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":87838,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eCo-occurrence strength diagram\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eForce diagram depicting the distribution of codes and categories in qualitative analysis. It particularly highlights the relationship between codes with limited technology, heterogeneous samples, and examination techniques, which are associated with the quality of the available evidence.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/132408b33a49df6ab838c07f.png"},{"id":92259434,"identity":"7e1cd547-1541-4088-8987-6b8f71a74c34","added_by":"auto","created_at":"2025-09-26 12:19:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":851750,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7714413/v1/03f3c2d7-41a3-4dad-9635-04949b5c0a47.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eCorneal Cross-Linking in Keratoconus: A Scoping Review of Clinical Evidence and Public Health Implications\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eKeratoconus is a progressive corneal disease of high clinical and social relevance, where early detection and timely treatment are essential to preserve vision and avoid major surgical interventions (1). Traditionally, therapeutic management of keratoconus was limited to optical correction with rigid contact lenses or, in advanced stages, corneal transplantation. However, both approaches fail to address the underlying pathophysiology of the disease and do not halt the progressive corneal deformation (2,3). In this context, corneal cross-linking (CXL) has emerged as the main therapeutic strategy capable of modifying corneal biomechanics and slowing disease progression. The scientific literature has documented multiple modalities and adaptations of this technique, aiming to balance efficacy, safety, and clinical applicability, particularly in high-risk populations such as pediatric patients or those with ultrathin corneas (4–6).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eKeratoconus as a Visual and Public Health Problem\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eKeratoconus is a progressive corneal ectasia of multifactorial etiology (genetic, environmental, and lifestyle factors, among others) (7–9), characterized by corneal thinning and deformation that lead to irregular astigmatism, reduced visual acuity, and, in advanced stages, the need for corneal transplantation. It is considered a relatively rare disease; however, recent studies estimate a global prevalence of 289 per 100,000 inhabitants, affecting more than 23.7 million people worldwide, with a higher prevalence in men than in women (10,11). Advances in high-precision ophthalmic imaging, such as corneal topography and tomography, have revealed an even higher prevalence, since their widespread use in countries previously lacking such technology has enabled the timely detection of subclinical cases, particularly among adolescents and young adults (12,13). Its early impact on productive and academic life underscores its relevance as a public health concern, as it compromises quality of life and generates a significant social and economic burden.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTherapeutics and Technological Evolution\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCXL represents the first etiopathogenic treatment capable of modifying corneal biomechanics. It combines riboflavin with ultraviolet-A (UV-A) radiation to induce covalent cross-links in stromal collagen fibers, thereby increasing stromal stiffness and halting ectatic progression (14,15). The standard protocol (sCXL), introduced in the early 2000s, remains the reference technique due to its proven efficacy and favorable safety profile (15). From this foundation, multiple adaptations have emerged, such as accelerated CXL (aCXL), aimed at reducing surgical time; transepithelial CXL (tCXL), which provides greater patient comfort; and iontophoresis-assisted CXL, still under investigation, with promising yet inconclusive preliminary evidence (16–18).\u003c/p\u003e\n\u003cp\u003eIn addition, protocols adapted for ultrathin corneas (sub400, hypoosmolar riboflavin, or UV-permeable contact lenses) have broadened the eligible patient population, while innovations such as oxygen supplementation and stromal lenticule implantation are exploring new frontiers in efficacy and safety (19).\u003c/p\u003e\n\u003cp\u003eParallel advances in optics, including modern contact lenses and orthokeratology, have emerged as novel alternatives, though their evidence remains heterogeneous (20,21). Furthermore, the diversity of CXL modalities complicates direct comparisons in narrative reviews (22,23). These modifications underscore the ongoing pursuit of balancing effectiveness, safety, comfort, and clinical applicability.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eClinical Evidence and Research Gaps\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNon-systematic explorations of the scientific literature consistently suggest that CXL effectively stabilizes keratoconus progression in most cases, with a low rate of complications that are generally mild and transient (24,25). However, the available evidence presents important limitations, both in study design and in the heterogeneity of protocols. These constraints hinder direct comparisons and limit the extrapolation of universal conclusions.\u003c/p\u003e\n\u003cp\u003eThus, while CXL has been the therapeutic standard in keratoconus management, research gaps remain that warrant further lines of investigation.\u003c/p\u003e"},{"header":"Method","content":"\u003cp\u003eThe objective of this study is to explore the evidence on the efficacy, safety, adherence, and cost-effectiveness of different treatment modalities for keratoconus, to identify the most effective and applicable strategies in both clinical practice and public health.\u003c/p\u003e\u003cp\u003eThe research protocol is published in the Open Science Framework in accordance with open science guidelines (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e), under DOI registration number \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.17605/OSF.IO/MHV7C\u003c/span\u003e\u003cspan address=\"10.17605/OSF.IO/MHV7C\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e, within the category \u0026ldquo;Methods and Measures,\u0026rdquo; and under a CC-By Attribution 4.0 International License, where the inclusion and exclusion criteria, variables, and analysis software are specified.\u003c/p\u003e\u003cp\u003e This study is a scoping and exploratory review aimed at analyzing the existing literature on the comparative effectiveness of therapeutic alternatives in patients with keratoconus.\u003c/p\u003e\u003cp\u003eFor the development and conduct of the review, we followed the methodological framework proposed by Arksey and O'Malley (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e), complemented with the recommendations of Levac, Colquhoun, and O'Brien (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). In addition, the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews) guidelines were used to structure the presentation of results and ensure transparency.\u003c/p\u003e\u003cp\u003eThe keywords and query strategy, the RIS files managed with Zotero, and the data extraction table that underpin the analytical basis of this study are available in the open science repository Zenodo under a Creative Commons Attribution 4.0 International License, DOI \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.5281/zenodo.17137608\u003c/span\u003e\u003cspan address=\"10.5281/zenodo.17137608\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\u003cp\u003e This study involved two independent reviewers, whose calibration yielded a Cohen\u0026rsquo;s Kappa coefficient of 0.70, indicating substantial agreement. Screening was conducted in two stages: title and abstract review, followed by full-text assessment. The reviewers determined the included and excluded studies, documenting the reasons for exclusion. The process was performed manually without artificial intelligence assistance and managed through Rayyan. Based on these steps, the PRISMA flow diagram was constructed in accordance with Hadaway et al. (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eQuantitative analyses were performed using Jamovi statistical software, and qualitative analyses were conducted with Atlas.ti. The outputs of these analyses are presented in this article and have also been uploaded to the Zenodo repository previously identified.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThe PRISMA flow diagram was developed according to the inclusion and exclusion criteria and a five-year time horizon. In the identification stage, 596 records were retrieved from electronic databases: PubMed (n\u0026thinsp;=\u0026thinsp;21), Scopus (n\u0026thinsp;=\u0026thinsp;333), and Web of Science (n\u0026thinsp;=\u0026thinsp;242). No additional records from protocols were identified. Subsequently, 28 duplicates were removed, leaving 568 records for the screening phase.\u003c/p\u003e\u003cp\u003eThe included studies were published primarily between 2021 and 2024, showing a progressive increase in recent scientific output. The year with the highest number of publications was 2023 (10 studies, 23.3%), followed by 2021 (9 studies, 20.9%).\u003c/p\u003e\u003cp\u003eDuring the screening phase, no records were excluded automatically or for other reasons. A total of 568 full reports were sought for retrieval, of which 1 could not be accessed.\u003c/p\u003e\u003cp\u003eIn the eligibility phase, 567 reports were assessed and 524 were excluded for not meeting the established criteria: 271 for intervention-related reasons, 248 for study design, and 5 for availability.\u003c/p\u003e\u003cp\u003eUltimately, a total of 43 studies were included, which constitute the basis for the analysis and synthesis of results in this investigation, as presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eQuantitative Characterization\u003c/h2\u003e\u003cp\u003eA total of 43 studies met the inclusion criteria and were analyzed in detail. Regarding methodological design, a predominance of retrospective studies was identified (n\u0026thinsp;=\u0026thinsp;20; 46.51%) and prospective studies (n\u0026thinsp;=\u0026thinsp;16; 37.21%), followed by randomized controlled trials (n\u0026thinsp;=\u0026thinsp;5; 11.63%) and cost-effectiveness simulations or models (n\u0026thinsp;=\u0026thinsp;2; 4.65%).\u003c/p\u003e\u003cp\u003eWith respect to the study population, most investigations focused on adults (n\u0026thinsp;=\u0026thinsp;31; 72.09%), with a notable difference compared to studies addressing pediatric populations (n\u0026thinsp;=\u0026thinsp;11; 25.58%); meanwhile, one study (2.33%) included mixed cohorts or lacked explicit age classification. The detailed age range of participants extended from 13 to 36 years, as summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, with distribution represented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eAverage age distribution and eyes as units of analysis\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"12\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eDesign\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c7\" namest=\"c3\"\u003e\u003cp\u003eAge\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c12\" namest=\"c8\"\u003e\u003cp\u003eEyes\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAVG\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMed\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eMin\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMax\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eAVG\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMed\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eMin\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c12\"\u003e\u003cp\u003eMax\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eRetrospective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e23.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e23.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e6.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e13.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e36.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e144.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e48.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e239.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e976\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical Trial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e22.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e24.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e15.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e26.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e37.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e54.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e24.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e58\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSimulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e24.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e24.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e9.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e18.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e31.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e3 500.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e3 500.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e2 121.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e2 000\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e5 000\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProspective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e21.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e21.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e4.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e13.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e28.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e106.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e74.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e154.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c12\"\u003e\u003cp\u003e670\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"12\"\u003eStatistical summary of the mean age and number of eyes of participants grouped by study design. Uniform means and medians are observed across ages, but variable in the number of eyes. The standard deviation is significant for both ages and eyes in the samples studied.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eSample sizes varied widely, ranging from small studies with 7 eyes to large series exceeding 1,000 eyes, as shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003ePatient follow-up across studies ranged from 6 months to 10 years, with a predominance of short-term studies (\u0026lt;\u0026thinsp;2 years), a substantial number of intermediate follow-up studies (2\u0026ndash;5 years), and at least five investigations reporting more than 5 years of observation, including two with 10-year results. Microsimulation models extended the analytical horizon up to 52 years, providing insights into cost-effectiveness, as detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eParticipant follow-up by study type in months\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"8\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eDesign\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eN\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAVG\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eMed\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eSD\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eMin\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eMax\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"3\" rowspan=\"4\"\u003e\u003cp\u003eFollow-up time (months)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eRetrospective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e29.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e12.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e29.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClinical Trial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e27.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e24.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e13.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e48\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSimulation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e372.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e372.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e356.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e120\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e624\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003eProspective\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e33.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e27.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e\u003cp\u003e22.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"8\"\u003eSummary of the follow-up period in the studies. It is notable that 60% of the studies have short-term follow-up, 25.6% have long-term follow-up, and the majority (55.8%) evaluate efficacy and safety over a period of 1 to 3 years.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe combined analysis of the 43 included studies, encompassing a total of 312 records on outcomes, effects, conclusions, limitations, and observations, offers a comprehensive characterization of the current state of evidence regarding CXL in the management of keratoconus.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eQualitative Description\u003c/h3\u003e\n\u003cp\u003eIn the inductive coding analysis, the following codes showed the highest frequency: \u003cem\u003e\u0026ldquo;Efficacy (Gr\u0026thinsp;=\u0026thinsp;29),\u0026rdquo; \u0026ldquo;Little Replicability (Gr\u0026thinsp;=\u0026thinsp;21),\u0026rdquo; \u0026ldquo;No Adverse Effects (Gr\u0026thinsp;=\u0026thinsp;20),\u0026rdquo; \u0026ldquo;Limited Technology (Gr\u0026thinsp;=\u0026thinsp;17),\u0026rdquo; \u0026ldquo;Corneal Opacity (Gr\u0026thinsp;=\u0026thinsp;16),\u0026rdquo;\u003c/em\u003e and \u003cem\u003e\u0026ldquo;Security (Gr\u0026thinsp;=\u0026thinsp;15).\u0026rdquo;\u003c/em\u003e These represent the central themes most frequently co-occurring with others.\u003c/p\u003e\u003cp\u003eThis distribution of codes allowed the identification of potential axes for qualitative analysis by categories, as illustrated in the force diagram in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e:\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eSafety: The co-occurrence between \u003cem\u003eSecurity, Corneal Opacity\u003c/em\u003e, and \u003cem\u003eCXL\u003c/em\u003e suggests that most discussions focus on ensuring safety when applying protocol variations.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eLimitations: The connection between \u003cem\u003eSmall Sample, Short Follow-up\u003c/em\u003e, and \u003cem\u003eRetrospective Design\u003c/em\u003e highlights recurring concerns about study design and follow-up limitations.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eInnovations: Codes such as \u003cem\u003eSub-400, Application of Oxygen\u003c/em\u003e, and \u003cem\u003eThin Corneas\u003c/em\u003e co-occur with \u003cem\u003eSecurity\u003c/em\u003e and \u003cem\u003eEfficacy\u003c/em\u003e, indicating that novel techniques are primarily evaluated in terms of safety.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eIsolated or less frequent codes: \u003cem\u003ePregnant Women, Sponsorship Bias\u003c/em\u003e, and \u003cem\u003eComfort\u003c/em\u003e emerged as marginal findings, of interest but with limited weight in the overall discussion.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eThe analysis shows that the core of the literature on keratoconus treatment is organized around three main poles:\u003c/p\u003e\u003cp\u003e\u003col\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eClinical efficacy and safety (aCXL, sCXL, corneal opacities, safety).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eMethodological limitations (sample size, follow-up, study design).\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003cspan\u003e\u003cli\u003e\u003cp\u003eExpansion of indications (sub-400, supplemental oxygen, thin corneas)\u003c/p\u003e\u003c/li\u003e\u003c/span\u003e\u003c/ol\u003e\u003c/p\u003e\n\u003ch3\u003eAnalysis of Results\u003c/h3\u003e\n\u003cp\u003eThe integrated analysis of the 43 included studies shows that CXL, in its various modalities, currently represents the therapeutic cornerstone in the management of keratoconus, both for its clinical efficacy and its safety profile.\u003c/p\u003e\u003cp\u003eIn terms of outcomes and effects, more than 90% of studies reported stabilization of disease progression, with differences in efficacy among modalities. Overall, approximately 42% found equivalence between sCXL and aCXL; a smaller proportion (~\u0026thinsp;30%) highlighted specific benefits of aCXL, while an important number of studies (~\u0026thinsp;42%) emphasized the applicability of sub400 protocols in ultrathin corneas.\u003c/p\u003e\u003cp\u003eThe most common limitations reported across articles were small sample size (44%), retrospective or non-randomized design (~\u0026thinsp;49%), methodological heterogeneity (~\u0026thinsp;51%), and short-term follow-up (42%).\u003c/p\u003e\u003cp\u003eFindings show that CXL halts disease progression in about 90%\u0026ndash;95% of cases, with a low rate of clinical failure and serious complications. The standard protocol (sCXL) remains the reference, although accelerated protocols (aCXL) have demonstrated comparable efficacy, with practical advantages such as reduced surgical time and better adherence, particularly relevant in pediatric populations, where the disease course is more aggressive. Modalities such as transepithelial CXL (tCXL) or iontophoresis-assisted CXL maintain an acceptable safety profile, though their efficacy is more heterogeneous, with reported progression rates up to 22%, which supports their use only in highly selected clinical contexts. Meanwhile, protocols adapted for ultrathin corneas (sub400 or hypoosmolar riboflavin) represent an advance, as they expand treatment indications without compromising endothelial safety.\u003c/p\u003e\u003cp\u003eFrom the qualitative perspective, several transversal methodological limitations condition the validity of findings, including the predominance of retrospective designs, small sample sizes, heterogeneous protocols, and lack of standardized progression criteria. Nevertheless, multicenter and randomized trials provide greater methodological consistency, and external validity is strengthened by real-world clinical studies. Regarding safety, complications were mostly mild and transient, with stromal haze being the most frequent reported initially at 15%, declining to \u0026lt;\u0026thinsp;3% annually at mid-term follow-up. Severe cases, such as infections, were exceptional. An interesting observation was the association between moderate haze and a greater biomechanical effect reflected in Kmax flattening, which opens new hypotheses on treatment response physiology.\u003c/p\u003e\u003cp\u003eIn terms of clinical applicability, results reinforce the need for individualized management. The choice between sCXL and aCXL may be guided by age, adherence, and clinical setting, while in special circumstances (pregnancy, chronic eye rubbing, or allergies) close monitoring is required due to the risk of late progression. In pediatric patients, the importance of early interventions with biomechanically robust protocols is strongly supported.\u003c/p\u003e\u003cp\u003eFinally, cost-effectiveness studies consistently indicate that CXL is highly cost-effective, particularly when performed early, as it reduces the need for corneal transplantation and preserves visual function. However, the generalizability of these analyses is limited by dependence on local pricing and the omission of indirect costs in available models.\u003c/p\u003e\u003cp\u003eOverall, quantitative and qualitative results reaffirm CXL as a safe, effective, and high-impact public health intervention, with durable clinical benefits and a range of modalities that expand its indications. The evidence further suggests that treatment is evolving toward protocol personalization and the integration of technological innovations, consolidating CXL as the first-line strategy in modern keratoconus management.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003e The findings of this review confirm that CXL constitutes the most robust intervention to halt the progression of keratoconus. The standard protocol (sCXL) maintains its role as the reference, with proven efficacy and a favorable safety profile. In parallel, accelerated protocols (aCXL) have demonstrated comparable clinical outcomes in keratometric and visual parameters, with practical advantages such as shorter surgical times and greater tolerance, particularly in pediatric and young populations where therapeutic adherence is critical for success. In contrast, transepithelial modalities (tCXL) show more variable efficacy, limiting their generalization, although their less invasive nature may be useful in specific contexts.\u003c/p\u003e\u003cp\u003eTherapeutic innovation has expanded the scope of CXL to previously restricted scenarios. Adapted protocols for ultrathin corneas (sub400, hypoosmolar riboflavin, UV-permeable contact lenses) have demonstrated feasibility and safety, avoiding the exclusion of vulnerable patients and reducing the need for transplantation.\u003c/p\u003e\u003cp\u003eAt the methodological level, common limitations include protocol heterogeneity, small sample sizes, and the absence of standardized definitions of progression. Nevertheless, external validity is strengthened in multicenter studies and real-world clinical registries, which provide a more realistic perspective on the applicability of CXL across different health systems.\u003c/p\u003e\u003cp\u003eIt is noteworthy that there is limited systematized evidence regarding the use of contact lenses in keratoconus therapy. Currently, the development of specialized lenses is emerging as a complementary pillar of visual rehabilitation, with miniscleral and hybrid lenses shown to reduce higher-order aberrations and improve visual quality without significant differences between designs, while next-generation and customized hybrid lenses provide significant improvements in visual acuity and comfort in advanced keratoconus patients (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). These findings reinforce a combined approach, where optical therapy and biomechanical intervention are integrated into a comprehensive management model.\u003c/p\u003e\u003cp\u003eWith respect to orthokeratology (Ortho-K) combined with CXL, the evidence remains exploratory. Available studies, both in animal models and pilot clinical trials, suggest that it may slow corneal regression, but current protocols fail to maintain a sustained long-term effect (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). Nonetheless, this line of research opens a promising field for combined and personalized therapies.\u003c/p\u003e\u003cp\u003eAccording to the evidence analyzed, and from a public health perspective, CXL emerges as a highly cost-effective intervention, particularly when implemented at early stages, by preventing visual disability, reducing the need for corneal transplantation, and decreasing the economic burden on healthcare systems. Moreover, the incorporation of advanced contact lenses can broaden the possibilities of functional rehabilitation and help preserve patient autonomy and quality of life\u0026mdash;fundamental aspects in young populations, where the disease has a greater socioeconomic impact. In this regard, integrating CXL within national vision health programs could represent an effective and sustainable secondary prevention strategy, aligned with goals of equity and universal access.\u003c/p\u003e\u003cp\u003eFinally, knowledge gaps remain that justify the need for multicenter clinical trials with standardized protocols, response biomarkers, and long-term follow-up. Likewise, cost-effectiveness studies tailored to each health system are required to optimize resource allocation and consolidate CXL as the therapeutic cornerstone in modern keratoconus management.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCorneal cross-linking is consolidated as the most effective and safest treatment to halt the progression of keratoconus, ensuring sustained visual and keratometric stability in the long term. Accelerated protocols show clinical outcomes equivalent to the standard approach, with advantages in surgical time and adherence, particularly in pediatric and young populations, while transepithelial and iontophoretic modalities present more heterogeneous efficacy and require individualized selection. Adapted protocols for ultrathin corneas broaden treatment indications and help reduce the need for transplantation. From a public health perspective, CXL stands out as a cost-effective intervention that should be prioritized at early stages, although challenges remain regarding protocol standardization, biomarker validation, and the development of context-specific economic studies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cul\u003e\n \u003cli\u003eCXL: Corneal Cross-linking\u003c/li\u003e\n \u003cli\u003eUV-A: Ultraviolet-A\u003c/li\u003e\n \u003cli\u003esCXL: Standard Corneal Cross-linking\u003c/li\u003e\n \u003cli\u003eaCXL: Accelerated Corneal Cross-linking\u003c/li\u003e\n \u003cli\u003etCXL: Transepithelial Corneal Cross-linking\u003c/li\u003e\n \u003cli\u003eOrtho-K: Orthokeratology\u003c/li\u003e\n \u003cli\u003ePRISMA-ScR: Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews\u003c/li\u003e\n\u003c/ul\u003e\n"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eConsent for publication\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eAvailable of data and materials\u003c/p\u003e\n\u003cp\u003eThe scoping review protocol is published in the Open Science Framework and is available at https://doi.org/10.17605/OSF.IO/MHV7C\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are available in the Zenodo repository, DOI 10.5281/zenodo.16951705\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funding has been received for the development of this research.\u003c/p\u003e\n\u003cp\u003eAuthor\u0026rsquo;s contributions\u003c/p\u003e\n\u003cp\u003eHB participated in the development of the research idea and the co-construction of the reference framework. He designed the methodological framework and co-constructed the scoping review protocol. He led the calibration of screeners and participated in data extraction. He developed the analysis of results, discussion, and conclusions. He wrote the manuscript.\u003c/p\u003e\n\u003cp\u003eRO participated in the development of the research idea and the co-construction of the reference framework and co-construction of the scoping review protocol. He designed the instructions for screeners and participated in data extraction.\u003c/p\u003e\n\u003cp\u003eBV and NF conducted the article screening, defining the analytical basis that supports this research.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003eAuthor\u0026rsquo;s information\u003c/p\u003e\n\u003cp\u003eHB is a professor in the Department of Public Health at the Universidad San Sebasti\u0026aacute;n and a professor in the ophthalmology specialty of the Medical Technology program. He is also a practicing medical technologist specializing in ophthalmology and optometry.\u003c/p\u003e\n\u003cp\u003eRO is a medical technologist specializing in ophthalmology and optometry and a member of the International Academy of Keratoconus for Eye Care Professionals.\u003c/p\u003e\n\u003cp\u003eBV is a medical technologist specializing in ophthalmology and optometry, currently a master\u0026apos;s student in epidemiology.\u003c/p\u003e\n\u003cp\u003eNF is a medical technologist specializing in ophthalmology and optometry, a primary care professional, and a student pursuing a master\u0026apos;s degree in public health.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDeshmukh R, Ong ZZ, Rampat R, Ali\u0026oacute; del Barrio JL, Barua A, Ang M, et al. Management of keratoconus: an updated review. Front Med [Internet]. 2023;10. Disponible en: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85164502517\u0026amp;doi=10.3389%2ffmed.2023.1212314\u0026amp;partnerID=40\u0026amp;md5=15fdce2476f3c8327e9d7c890ff39bb0\u003c/li\u003e\n\u003cli\u003eFeizi S, Javadi MA, Alemzadeh-Ansari M, Arabi A, Shahraki T, Kheirkhah A. Management of corneal complications in vernal keratoconjunctivitis: A review. Ocul Surf. 2021;19:282-9. \u003c/li\u003e\n\u003cli\u003eItoi M, Itoi M. Management of Keratoconus With Corneal Rigid Gas-Permeable Contact Lenses. Eye Contact Lens Sci Clin Pract. marzo de 2022;48(3):110-4. \u003c/li\u003e\n\u003cli\u003eAng RET, Guloy AJA, Cruz EM, Lo JJGC. Evaluation of refractive, tomographic and biomechanical changes after customized accelerated corneal collagen cross-linking in keratoconus patients: a retrospective observational study. BMC Ophthalmol. 1 de julio de 2025;25(1):378. \u003c/li\u003e\n\u003cli\u003eElalfy M, Chatzimichail E, Mahgoub K, Hajjar-Sese A, Naveed H, Panos GD, et al. Clinical Outcomes of Repeated Corneal Crosslinking for Progressive Keratoconus After Failure of Primary Procedure; Safety and Efficacy at 12-Month Follow-Up. Ophthalmol Ther [Internet]. 27 de agosto de 2025 [citado 29 de agosto de 2025]; Disponible en: https://link.springer.com/10.1007/s40123-025-01227-7\u003c/li\u003e\n\u003cli\u003eHamid A, Jahadi-Hosseini H, Khalili MR, Jahanbani-Ardakani H. Corneal Biomechanical Changes after Corneal Cross-Linking in Patients with Keratoconus. J Curr Ophthalmol. octubre de 2022;34(4):409-13. \u003c/li\u003e\n\u003cli\u003eCheung IMY, Angelo L, Gokul A, Ziaei M. Non-genetic risk factors for keratoconus and its progression. Clin Exp Optom [Internet]. 2025; Disponible en: https://www.scopus.com/inward/record.uri?eid=2-s2.0-85214262193\u0026amp;doi=10.1080%2f08164622.2024.2443454\u0026amp;partnerID=40\u0026amp;md5=dd033bd4deeb8661420f400b9c5438d5\u003c/li\u003e\n\u003cli\u003eSharif R, Bak-Nielsen S, Hjortdal J, Karamichos D. Pathogenesis of Keratoconus: The intriguing therapeutic potential of Prolactin-inducible protein. Prog Retin Eye Res. 2018;67:150-67. \u003c/li\u003e\n\u003cli\u003eVought R, Greenstein SA, Gelles J, Hersh PS. The Pathophysiology of Keratoconus. Cornea. febrero de 2025;44(2):137-43. \u003c/li\u003e\n\u003cli\u003eFern\u0026aacute;ndez Berdasco K, Alfaya Mu\u0026ntilde;oz LB, Corzo Fern\u0026aacute;ndez CR, Se\u0026ntilde;aris Gonz\u0026aacute;lez A, Baamonde Arbaiza B. Clinical-epidemiological characteristics of keratoconus in Asturias. Arch Soc Esp Oftalmol Engl Ed. febrero de 2023;98(2):65-71. \u003c/li\u003e\n\u003cli\u003eSriranganathan A, Chan CC, Dhillon J, Felfeli T. Global Incidence and Prevalence of Keratoconus: A Systematic Review and Meta-Analysis. Cornea [Internet]. 20 de agosto de 2025 [citado 28 de agosto de 2025]; Disponible en: https://journals.lww.com/10.1097/ICO.0000000000003973\u003c/li\u003e\n\u003cli\u003eHeidari Z, Mohammadpour M, Hajizadeh F, Fotouhi A, Hashemi H. Corneal layer thickness in keratoconus using optical coherence tomography. Clin Exp Optom. 2 de enero de 2024;107(1):32-9. \u003c/li\u003e\n\u003cli\u003eMasiwa LE, Moodley V. A review of corneal imaging methods for the early diagnosis of pre-clinical Keratoconus. J Optom. octubre de 2020;13(4):269-75. \u003c/li\u003e\n\u003cli\u003eAldairi W, AlQahtani R, Alzaid S, Mousa A, Khandekar R, Al-Swailem SA. Accelerated versus conventional corneal collagen crosslinking: Short-term clinical outcomes in stabilizing keratoconus. Saudi J Ophthalmol. enero de 2022;36(1):47-52. \u003c/li\u003e\n\u003cli\u003eFelter E, Khoramnia R, Friedrich M, Son HS, Auffarth GU, Augustin VA. Biomechanical changes following corneal crosslinking in keratoconus patients. Graefes Arch Clin Exp Ophthalmol. noviembre de 2024;262(11):3635-42. \u003c/li\u003e\n\u003cli\u003eKandel H, Abbondanza M, Gupta A, Mills R, Watson A, Petsoglou C, et al. Comparison of standard versus accelerated corneal collagen cross-linking for keratoconus: 5-year outcomes from the Save Sight Keratoconus Registry. EYE. enero de 2024;38(1):95-102. \u003c/li\u003e\n\u003cli\u003eKaya Ergen S, Subaşı S, Yılmaz Tuğan B, Y\u0026uuml;ksel N, Altıntaş \u0026Ouml;. The effect of transepithelial corneal collagen cross-linking treatment on optical quality of the cornea in keratoconus: 12-month clinical results. Int Ophthalmol. 18 de marzo de 2024;44(1):146. \u003c/li\u003e\n\u003cli\u003eRoszkowska AM, Oliverio GW, Hydzik-Sajak K, De Crescenzo M, Aragona P. Five-year results of iontophoresis-assisted transepithelial corneal cross-linking for keratoconus. Int Ophthalmol. 3 de julio de 2023;43(10):3601-7. \u003c/li\u003e\n\u003cli\u003eOzek D, Karaca EE, Kemer OE. Accelerated corneal cross-linking with hypo-osmolar riboflavin in thin keratoconic corneas: 2-year follow-up. Arq Bras Oftalmol. agosto de 2020;83(4):277-82. \u003c/li\u003e\n\u003cli\u003eLim L, Lim EWL. Current perspectives in the management of keratoconus with contact lenses. Eye. diciembre de 2020;34(12):2175-96. \u003c/li\u003e\n\u003cli\u003eWang Z, Wang Z, Meng Y, Wang P, Yibulayin S, Jiang B, et al. Posterior corneal elevation changes during 12 month of overnight orthokeratology. Heliyon. abril de 2023;9(4):e14887. \u003c/li\u003e\n\u003cli\u003eAldayel AA, Alwael HM, Alshathri RM, Alnasser HA, Alfawzan LA. A Comparison Between Cross-Linking Protocols in Patients With Progressive Keratoconus: A Review. Cureus [Internet]. 2 de noviembre de 2022 [citado 29 de agosto de 2025]; Disponible en: https://www.cureus.com/articles/82753-a-comparison-between-cross-linking-protocols-in-patients-with-progressive-keratoconus-a-review\u003c/li\u003e\n\u003cli\u003eSarma P, Kaur H, Hafezi F, Bhattacharyya J, Kirubakaran R, Prajapat M, et al. Short- and long-term safety and efficacy of corneal collagen cross-linking in progressive keratoconus: A systematic review and meta-analysis of randomized controlled trials. Taiwan J Ophthalmol. abril de 2023;13(2):191-202. \u003c/li\u003e\n\u003cli\u003eAngelo L, Gokul Boptom A, McGhee C, Ziaei M. Corneal Crosslinking: Present and Future. Asia-Pac J Ophthalmol. 2022;11(5):441-52. \u003c/li\u003e\n\u003cli\u003eFerdi AC, Kandel H, Nguyen V, Tan J, Arnalich-Montiel F, Abbondanza M, et al. Five-year corneal cross-linking outcomes: A Save Sight Keratoconus Registry Study. Clin Experiment Ophthalmol. 2023;51(1):9-18. \u003c/li\u003e\n\u003cli\u003eVan den Akker O, Peters GJ, Bakker C, Carlsson R, Coles NA, Corker KS, et al. Generalized Systematic Review Registration Form [Internet]. MetaArXiv; 2020. Disponible en: https://doi.org/g5fj\u003c/li\u003e\n\u003cli\u003eArksey H, O\u0026rsquo;Malley L. Scoping studies: towards a methodological framework. Int J Soc Res Methodol. febrero de 2005;8(1):19-32. \u003c/li\u003e\n\u003cli\u003eLevac D, Colquhoun H, O\u0026rsquo;Brien KK. Scoping studies: advancing the methodology. Implement Sci. diciembre de 2010;5(1):69. \u003c/li\u003e\n\u003cli\u003eHaddaway NR, Page MJ, Pritchard CC, McGuinness LA. \u003cem\u003ePRISMA2020\u003c/em\u003e : An R package and Shiny app for producing PRISMA 2020‐compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis. Campbell Syst Rev. junio de 2022;18(2):e1230. \u003c/li\u003e\n\u003cli\u003eLiao C, Lin X, Keel S, Ha J, Yang X, He M. Effects of corneal crosslinking on corneal shape stabilization after orthokeratology. Sci Rep. 11 de febrero de 2020;10(1):2357. \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":"Corneal cross-linking, Keratoconus, Ophthalmology, Scoping review, Public health","lastPublishedDoi":"10.21203/rs.3.rs-7714413/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7714413/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective. \u003c/strong\u003eTo map and synthesize recent evidence on the efficacy, safety, adherence, and cost-effectiveness of corneal cross-linking (CXL) for keratoconus, with emphasis on its public health implications.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods.\u003c/strong\u003e A scoping review was conducted following Arksey and O’Malley’s framework, complemented by the recommendations of Levac, Colquhoun, and O’Brien, and in accordance with the PRISMA-ScR guideline. Studies published between 2021 and 2024 were retrieved from Scopus, PubMed, and Web of Science. Two independent reviewers performed study selection and data extraction. Quantitative data were analyzed through descriptive statistics, while qualitative findings were synthesized using specialized software.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults.\u003c/strong\u003e From 596 initial records, 43 studies were included. Retrospective (46.51%) and prospective (37.21%) designs predominated, mainly focused on adult populations. CXL stabilized keratoconus progression in 90–95% of cases. The standard protocol remained the reference, while the accelerated protocol showed comparable efficacy with practical advantages, particularly in pediatric populations. Transepithelial and iontophoresis-assisted modalities exhibited acceptable safety but heterogeneous efficacy. Adapted protocols for ultrathin corneas expanded clinical indications without compromising endothelial safety.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions.\u003c/strong\u003e Available evidence supports CXL as an effective and cost-effective intervention to halt keratoconus progression, reduce the need for corneal transplantation, and preserve visual function. Its applicability across diverse clinical settings underscores its value as a public health priority. However, gaps remain regarding protocol standardization and context-specific economic evaluations.\u003c/p\u003e","manuscriptTitle":"Corneal Cross-Linking in Keratoconus: A Scoping Review of Clinical Evidence and Public Health Implications","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-26 12:11:31","doi":"10.21203/rs.3.rs-7714413/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":"34b9cd67-8a02-4328-94b7-78c894d2bf6b","owner":[],"postedDate":"September 26th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":55347669,"name":"Ophthalmology"}],"tags":[],"updatedAt":"2025-09-26T12:11:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-26 12:11:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7714413","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7714413","identity":"rs-7714413","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}