Efficacy and Safety of KeraVio using Violet Light-Emitting Glasses and Cyanocobalamin Drops for Progressive Keratoconus: A Pilot Study

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Methods This prospective, single-arm exploratory study included three patients (mean age, 36.67 ± 11.24 years; 2 males, 1 female) with progressive keratoconus. Treatment consisted of 0.02% cyanocobalamin eye drops administered six times daily and VL irradiation via TLG-003 eyeglasses worn 4.5 hours per day for three months. Patients were followed for six months. The primary endpoint was the change in maximum keratometry (Kmax). Secondary endpoints included thinnest corneal thickness (TCT), demarcation line (DL), best-corrected visual acuity (BCVA), uncorrected visual acuity (UCVA), manifest refraction, intraocular pressure, corneal endothelial cell density, corneal haze, slit-lamp/fundus examination findings, and periocular skin changes. Results The mean Kmax change at 6 months was − 0.37 ± 6.82 D. The mean change in the TCT was − 7.33 ± 19.66 µm. BCVA and UCVA remained stable (mean BCVA change: −0.03 ± 0.15 logMAR; mean UCVA change: 0.04 ± 0.07 logMAR). No clinically observed changes in refraction, intraocular pressure, endothelial cell density, corneal clarity, or retinal findings were detected. No adverse events occurred. Conclusions KeraVio treatment with cyanocobalamin drops appeared to be safe for use in this small cohort. However, owing to the limited sample size and variable Kmax responses, further large-scale, controlled studies are needed to determine the efficacy of this treatment in the context of halting keratoconus progression. Trial registration number: jRCTs032230104 Registration Date: June 1st, 2023. keratoconus corneal cross-linking violet light cyanocobalamin eye Introduction Keratoconus is a progressive corneal ectasia in which the cornea gradually thins and protrudes forward, resulting in irregular astigmatism, increased myopia, and visual deterioration [ 1 ]. The standard treatment, corneal collagen cross-linking (CXL) with riboflavin activated by ultraviolet-A (UVA) light, can slow the advancement of the disease. However, because this procedure generally necessitates epithelial debridement, it is often accompanied by postoperative discomfort and may predispose patients to complications, including infectious keratitis [ 2 ]. To address these limitations, a noninvasive approach using violet light (VL; wavelength 360–400 nm) has been developed. VL irradiation using eyeglass-type devices influences corneal biomechanics, and the KeraVio protocol combines VL with a photosensitizer to achieve corneal cross-linking without epithelial removal [ 3 – 5 ]. In previous KeraVio treatments, we used flavin adenine dinucleotide (FAD), a compound similar to riboflavin [ 3 ]. However, the supply of the active ingredient will be discontinued after 2022, thus causing FAD eye drops to become unavailable in Japan. As alternatives to riboflavin or FAD, we focus on the role of cyanocobalamin (vitamin B12), the UV‒visible absorption spectrum of which peaks at the VL wavelength. The absorption spectrum of cyanocobalamin has characteristic peaks in both the visible light and ultraviolet regions at 361 nm [ 6 ]. This phenomenon is due to electronic transitions between the cobalt center and ligands within the molecule and is used for quantitative analysis in analytical chemistry and biochemistry. Cyanocobalamin eye drops improve fine movement accommodation in accommodative eye strain and are used clinically to treat eye strain in Japan [ 7 ]. These eye drops have been on the market for more than 40 years and are therefore considered sufficiently safe. Our hypothesis is that it is possible to confirm the effects of KeraVio treatment with the administration of cyanocobalamin drops and VL irradiation. In this study, riboflavin was replaced with cyanocobalamin (vitamin B12), which shares a similar absorption spectrum and has shown ex vivo efficacy in increasing corneal tensile strength. We conducted an exploratory clinical study to evaluate the safety and potential efficacy of cyanocobalamin-assisted KeraVio in progressive keratoconus. Methods Ex Vivo Study We examined the effect of VL exposure in combination with cyanocobalamin on corneal biomechanics using porcine eyes with intact epithelium. Fifteen corneas were randomly allocated into three groups. Two experimental arms consisted of VL irradiation with either cyanocobalamin or flavin adenine dinucleotide (FAD) eye drops (five corneas each), while untreated corneas exposed only to sham conditions served as controls. Irradiation was delivered with a 375-nm VL diode at an irradiance of 0.31 mW/cm² for 4.8 hours, providing a total energy dose of 5.4 J/cm². This level was selected to remain below the endothelial cytotoxic threshold, thereby ensuring tissue safety during exposure [ 8 – 10 ]. A collection of samples comprising the KeraVio with cyanocobalamin and FAD groups was also prepared (each, n = 5). For this group, during the initial 30 minutes of VL irradiation, 0.025% cyanocobalamin and 0.05% FAD drops were applied simultaneously to the corneal epithelium every 2 minutes. After VL or sham treatment, the corneas from the three groups were kept in a humid chamber for 30 minutes. Each cornea was then excised en bloc together with the sclera, leaving a 2–3 mm scleral rim, and mounted on a custom-made scale. A vertical strip, 5 mm in width, was subsequently dissected from the cornea. The strips were clamped with a jaw-to-jaw distance of 5 mm. The cross-sectional area of each specimen was calculated from its central corneal thickness. For mechanical testing, the samples were mounted on a computer-controlled universal testing machine (TA XTplusC Texture Analyser™, Stable Micro Systems, London, UK). The corneoscleral limbus was secured in a dedicated fixture, and a uniaxial tensile test was performed. Each strip was stretched at a constant rate of 1.8 mm/min until a maximum load of 5 N was reached. The elastic modulus was defined as the ratio of tensile stress (force per cross-sectional area) to tensile strain (relative elongation). For statistical analysis, the elastic modulus was consistently evaluated at 10% strain. Clinical Pilot Study We conducted a single-arm, prospective, exploratory trial (jRCTs032230104) at the Minami Aoyama Eye Clinic in Tokyo to investigate the safety and potential efficacy of KeraVio combined with cyanocobalamin. The protocol received approval from an independent review board, and all procedures conformed to the Declaration of Helsinki. Human Ethics and Consent to Participate declarations were not applicable. Written informed consent was obtained from every participant prior to enrollment as a consent to participate declaration. The consent to publish declarations were not applicable. In this study, the ethics board certificated that we have received written informed consent from the individuals for the publication of these details. The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon request. Inclusion and Exclusion Criteria Inclusion criteria were: male or female sex, any race or ethnicity, age ≥ 15 years, and a confirmed diagnosis of keratoconus by corneal topography or tomography. Eligible participants were also required to demonstrate disease progression within the 6 months prior to baseline in order to undergo KeraVio treatment, defined by at least one of the following: (1) an increase of ≥ 0.50 diopters (D) in maximum keratometry (Kmax); (2) an increase of ≥ 0.50 D in cylinder power on subjective manifest refraction; (3) an increase of ≥ 0.50 D in myopia on subjective manifest refraction; or (4) a reduction of ≥ 5 µm in the thinnest corneal thickness. To minimize lens-induced corneal shape alterations, contact lenses were discontinued before each visit (3 weeks for rigid gas-permeable lenses and 1 week for soft lenses). Exclusion criteria included photosensitivity, a history of epilepsy, hypersensitivity to fluorescein, or the presence of ocular or systemic conditions considered unsuitable for study participation. KeraVio Treatment In the KeraVio treatment group, subjects wore VL-emitting glasses that delivered violet light (VL, 375 nm) to the cornea for 4.5 hours daily over a 3-month period. During each 3-hour VL irradiation session, 0.02% cyanocobalamin eye drops were instilled onto the corneal epithelium every 30 minutes to facilitate corneal penetration. Prior to each session, the intended irradiance of 0.31 mW/cm² was confirmed with a UVA meter (LaserMate-Q; LASER 2000, Wessling, Germany) at a distance of 1.2 cm from the corneal surface, and adjusted with a potentiometer when necessary. The treatment protocol, consisting of VL exposure combined with cyanocobalamin instillation, was continued daily for 3 months, delivering a cumulative energy dose of 301.3 J/cm². Bilateral treatment was permitted if deemed clinically beneficial by the investigator; however, only the more severely affected eye of each subject was included in the efficacy and safety analyses. Outcome Measures Tomographic data were acquired using anterior segment optical coherence tomography (AS-OCT) (CASIA, Tomey Corporation, Nagoya, Japan) at baseline and at 1, 3, and 6 months following KeraVio treatment. Parameters assessed included keratometric values, thinnest corneal thickness, and the stromal demarcation line (DL) as identified by the AS-OCT system. The maximum keratometry value (Kmax) was selected as the primary efficacy endpoint because it reflects the steepening characteristic of corneal ectasia and provides an objective, quantitative measure that can be consistently assessed across study sites using standardized hardware and software. Additional keratometric values along the flat (K1) and steep (K2) meridians were also analyzed. Treatment success was defined as significant corneal flattening, specifically a reduction in Kmax greater than 1.00 D at 6 months compared with baseline. When a DL was detectable on AS-OCT scans, its depth was independently measured by two observers at 3 months post-treatment, following procedures described in our previous studies [ 11 , 12 ]. The DL was also qualitatively assessed. Uncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), and manifest refraction spherical equivalent (MRSE) were evaluated at baseline and at 3 and 6 months after KeraVio. Visual acuity was recorded in logarithm of the minimum angle of resolution (logMAR) units using a Landolt C chart. Safety Outcomes The safety analysis included all treated eyes. Safety assessments comprised endothelial cell density and intraocular pressure, measured at each visit using a specular microscope (NonconRobo, Konan, Nishinomiya, Japan) and a tonometer (TONOREF, Nidek Co.), respectively. In addition, slit-lamp examinations were performed to identify potential adverse events, including secondary cataracts, conjunctivitis, and eyelid complications. Statistical Analysis Statistical analysis was performed with the assistance of Statistical Analysis Software (version 9.4; SAS Institute, Cary, NC). The differences in the elastic modulus among the three treatment groups were tested using the Friedman nonparametric test coupled with Scheffe’s multiple comparison test. A P value of less than 0.05 was considered to indicate statistical significance. With respect to clinical data, statistical analysis was not performed because of the small number of cases included in the current study. Results Ex Vivo Study The elastic modulus and percentage strain of the treated corneas at 10% strain were determined for each of the three groups (Table 1 ). The average elastic moduli at 10% strain in the KeraVio without cyanocobalamin, KeraVio with FAD, and control groups were 285.20 ± 83.71 kPa, 181.80 ± 99.98 kPa, and 47.50 ± 19.66 kPa, respectively. The elastic modulus at 10% exhibited significant differences among the groups according to the nonparametric Friedman test performed with respect to the four groups (P = 0.135). Table 1 Elastic modulus at 10% strain in each group. KeraVio with cyanocobalamin KeraVio with flavin adenine dinucleotide Control Mean ± SD (kPa) 285.20 ± 83.71 181.80 ± 99.98 47.50 ± 19.66 Range 226.03 to 344.31 111.10 to 252.50 33.60 to 61.40 Clinical study Three eyes belonging to 3 patients were treated with KeraVio and cyanocobalamin. All included patients had progressive keratoconus and met the eligibility criteria. The participant demographics are presented in Table 2 . All patients remained in the study through the 6-month follow-up. Table 2 Demographic characteristics of patients included in the KeraVio treatment with a decrease in cyanocobalamin concentration (n = 3). Case Age (years) Sex (female/male) Kmax (diopters) # 1 34 Male 50.70 # 2 49 Male 82.47 # 3 27 Female 76.46 Mean ± SD 36.67 ± 11.24 n/a 69.88 ± 16.88 SD = standard deviation n/a = not applicable Table 3 shows the changes in corneal parameters from baseline to the 6-month observation period after treatment. The mean change in Kmax during the 6-month observation period was − 0.37 ± 6.82 D. However, in three cases, Kmax increased and decreased, resulting in variability. Similarly, the K1, K2, and thinnest corneal thickness results also varied, and no consistent trend was observed. The success rate (flattening of the Kmax > 1.00 D) was 33% (one-eye). No DL was observed after KeraVio with cyanocobalamin at 3 months. Table 3 Changes in corneal parameters after KeraVio with a decrease in cyanocobalamin concentration. Baseline 3 months 6 months Change from baseline to 6 months Kmax (D) # 1 50.70 50.83 51.04 0.34 # 2 82.47 73.63 74.96 -7.51 # 3 76.46 86.97 82.53 6.07 Mean ± SD 69.88 ± 16.88 70.48 ± 18.28 69.51 ± 16.44 -0.37 ± 6.82 K1 (D) # 1 42.25 42.60 42.47 0.22 # 2 53.18 51.82 52.47 -0.71 # 3 64.07 66.04 68.33 4.26 Mean ± SD 53.17 ± 10.91 53.49 ± 11.81 54.42 ± 13.04 1.26 ± 2.64 K2 (D) # 1 45.70 45.58 45.54 -0.16 # 2 60.71 59.35 58.12 -2.59 # 3 71.62 75.01 73.20 1.58 Mean ± SD 59.34 ± 13.01 59.98 ± 14.73 58.95 ± 13.85 -0.39 ± 2.09 Thinnest corneal thickness (µm) # 1 442 446 445 3.00 # 2 427 405 397 -30.00 # 3 225 226 230 5.00 Mean ± SD 364.67 ± 121.19 359.00 ± 116.99 357.33 ± 112.86 -7.33 ± 19.66 D = diopters Table 4 shows the changes in the UCVA, BCVA, MESE, and cylindrical refraction from baseline to the 6-month observation period after treatment. In all three patients, visual acuity and subjective refraction were clinically unchanged. Table 4 Changes in visual acuity and refraction after KeraVio with a decrease in cyanocobalamin concentration. Baseline 3 months 6 months Change from baseline to 6 months Uncorrected visual acuity (logMAR) # 1 1.10 1.22 1.10 0.00 # 2 0.70 0.70 0.82 0.12 # 3 2.00 2.00 2.00 0.00 Mean ± SD 1.27 ± 0.67 1.31 ± 0.65 1.31 ± 0.62 0.04 ± 0.07 Best-corrected visual acuity (logMAR) # 1 0.15 0.05 0.05 -0.11 # 2 0.15 0.22 0.30 0.15 # 3 1.22 1.30 1.10 -0.12 Mean ± SD 0.51 ± 0.62 0.52 ± 0.68 0.48 ± 0.55 -0.03 ± 0.15 Manifest refraction spherical equivalent (D) # 1 -4.50 -4.50 -4.50 0.00 # 2 -4.00 -4.00 -4.25 -0.25 #3 -21.00 -18.50 -20.00 1.00 Mean ± SD -9.83 ± 9.67 -9.00 ± 8.23 -9.58 ± 9.02 0.25 ± 0.66 Cylindrical refraction (D) # 1 -2.00 -2.00 -2.00 0.00 # 2 -6.00 -6.00 -5.50 0.50 # 3 -6.00 -5.00 -6.00 0.00 Mean ± SD -4.67 ± 2.31 -4.33 ± 2.08 -4.50 ± 2.18 0.17 ± 0.29 logMAR = logarithm of the minimal resolution angle D = diopters Table 5 presents the safety profile of KeraVio with cyanocobalamin treatment. Two patients demonstrated errors in corneal endothelial cell density and intraocular pressure, but all eyes remained clinically unchanged. With regard to adverse events, no vision-threatening complications were observed during the study, supporting the safety of the treatment. At the 6-month follow-up, neither pterygium, skin melanoma, lenticular opacity, nor transient corneal haze was detected in any treated eye. Table 5 Safety profile after KeraVio with a decrease in cyanocobalamin concentration. Baseline 3 months 6 months Endothelial cell density (cells/mm 2 ) # 1 3130 3021 3153 # 2 3034 3088 2924 # 3 unmeasurable unmeasurable unmeasurable Intraocular pressure (mmHg) # 1 13 15.0 10.0 # 2 unmeasurable 7.0 10.0 # 3 9 9.0 8.0 Discussion In this exploratory study, KeraVio treatment with cyanocobalamin and VL irradiation exhibited a favorable safety profile, with no adverse events or detrimental changes in ocular health parameters over six months. However, Kmax outcomes were highly variable among patients, and the small sample size precluded statistical analysis. Although the concept of replacing riboflavin with cyanocobalamin is supported by preclinical data, its clinical efficacy in keratoconus progression remains unproven. Notably, in our study, we investigated the therapeutic effects of cyanocobalamin and VL irradiation on progressive keratoconus; no similar studies have been reported to date. In a tensile strength test that used porcine eyes treated with cyanocobalamin eye drops and VL irradiation, no statistically significant differences in the elastic modulus were observed among the three groups. However, the cyanocobalamin and FAD groups presented higher values compared with the control group. This finding is consistent with our previous basic and clinical study using FAD eye drops and VL irradiation [ 3 ]. Cyanocobalamin is a drug that has an absorption peak at 361 nm and is therefore logically expected to have a corneal cross-linking effect [ 6 ]. However, in this study, corneal epithelial peeling was not performed in all porcine eyes. Thus, penetration of the drug into the corneal stroma was limited, and the extent to which cyanocobalamin penetrated the corneal stroma was unclear. Future studies should evaluate cyanocobalamin concentrations in the corneal stroma in the presence or absence of epithelial peeling. Unlu et al. reported that the combination of citicoline and vitamin B12 for keratoconus effectively promoted corneal nerve healing after CXL [ 13 ]. Furthermore, a report produced by Romano et al. revealed that vitamin B12 treatment promotes not only corneal re-epithelialization but also reinnervation after mechanical injury [ 14 ]. These findings suggest that cyanocobalamin is effective for corneal epithelial regeneration and is also an effective drug for treating keratoconus. Limitations of this study include its single-arm design, the lack of a control group, and the minimal sample size. Further randomized controlled trials with larger cohorts are necessary to validate the efficacy and determine the long-term safety of this approach. In conclusion, cyanocobalamin-assisted KeraVio appears to be a safe, noninvasive option for patients with progressive keratoconus. However, evidence of the effectiveness of this treatment is currently limited. Given the variability in Kmax responses and limited sample size, its efficacy requires confirmation on the basis of well-powered, controlled studies. Declarations Contributors: Conception and design: Kobashi, Tsubota Analysis and interpretation: Kobashi, Toda Data collection: Kobashi, Tsubota, Toda Obtained funding: Kobashi, Tsubota Overall responsibility: Kobashi, Tsubota Funding: This work was supported by Tsubota Laboratory, Inc. Disclaimer: The sponsor had no role in the study design; data collection, analysis or interpretation; writing of the report; or the decision to submit the article for publication. Competing interests: The author(s) disclose the following: H.K.: Consultant and equity owner, Tsubota Laboratory Inc. (Tokyo, Japan); Patent, Tsubota Laboratory Inc. K.T.: Employee and equity owner, Tsubota Laboratory, Inc.; Patent, Tsubota Laboratory, Inc. No other disclosures were reported. Patient consent for publication: Not needed. Ethics approval: The study adhered to the tenets of the Declaration of Helsinki. The study subjects completed a written informed consent form. This trial was approved by the Certified Review Board, Hattori Clinic and registered in the Japan Registry of Clinical Trials (jRCT): jRCTs032230104. https://jrct.mhlw.go.jp/en-latest-detail/jRCTs032230104 The ethics board certificated that authors have received written informed consent from the individuals for the publication of these details. Provenance and peer review: Not commissioned; externally peer reviewed. Data availability statement: The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon request. ORCID : Hidenaga Kobashi https://orcid.org/0000-0002-0767-4214 References Rabinowitz YS, Keratoconus. Surv Ophthalmol. 1998;42(4):297–319. Sorkin N, Varssano D. Corneal collagen crosslinking: a systematic review. Ophthalmologica. 2014;232(1):10–27. Kobashi H, Torii H, Toda I, Kondo S, Itoi M, Tsubota K. Clinical outcomes of KeraVio using violet light: emitting glasses and riboflavin drops for corneal ectasia: a pilot study. Br J Ophthalmol. 2021;105(10):1376–82. 10.1136/bjophthalmol-2020-316974 . Kobashi H, Yunoki S, Kato N, Shimazaki J, Ide T, Tsubota K. Evaluation of the Physiological Corneal Intrastromal Riboflavin Concentration and the Corneal Elastic Modulus After Violet Light Irradiation. Transl Vis Sci Technol. 2021;10(5):12. Kobashi H, Kumanomido T, Ide T, Kato N, Shimazaki J, Itoi M, Tsubota K. Ineffectiveness of KeraVio Treatment with Violet Light-Emitting Glasses Without Riboflavin Drops for Progressive Keratoconus. J Clin Med. 2025;14(3):773. Zobi F, Blacque O, Jacobs RA, Schaub MC, Bogdanova AY. 17 e- rhenium dicarbonyl CO-releasing molecules on a cobalamin scaffold for biological application. Dalton Trans. 2012;41(2):370–8. Nakashima K, Yamasaki H, Shimoda R, Kuroda N, Akiyama S, Baeyens WR. Flow-injection analysis of cobalt(II) utilizing enhanced lophine chemiluminescence with hydroxylammonium chloride. Biomed Chromatogr. 1997 Mar-Apr;11(2):63–4. Wollensak G, Spoerl E, Reber F, Seiler T. Keratocyte cytotoxicity of riboflavin/UVA-treatment in vitro. Eye. 2004;18:718–22. Wollensak G, Spoerl E, Wilsch M, Seiler T. Keratocyte apoptosis after corneal collagen cross-linking using ribofl avin/UVA treatment. Cornea. 2004;23:43–9. Wollensak G, Spoerl E, Wilsch M, Seiler T. Endothelial cell damage after riboflavin–ultraviolet-A treatment in the rabbit. J Cataract Refract Surg. 2003;29:1786–90. Kymionis GD, Grentzelos MA, Plaka AD, Tsoulnaras KI, Diakonis VF, Liakopoulos DA, Kankariya VP, Pallikaris AI. Correlation of the corneal collagen cross-linking demarcation line using confocal microscopy and anterior segment optical coherence tomography in keratoconic patients. Am J Ophthalmol. 2014;157(1):110–e1151. Kymionis GD, Tsoulnaras KI, Grentzelos MA, Plaka AD, Mikropoulos DG, Liakopoulos DA, Tsakalis NG, Pallikaris IG. Corneal stroma demarcation line after standard and high-intensity collagen crosslinking determined with anterior segment optical coherence tomography. J Cataract Refract Surg. 2014;40(5):736–40. Unlu M, Ozer F, Sahin Aslan E, Sener H, Erkilic K. Can the combination of citicoline and vitamin B12 be beneficial in the healing of corneal nerves after corneal cross-linking? Int Ophthalmol. 2025;45(1):54. Romano MR, Biagioni F, Carrizzo A, Lorusso M, Spadaro A, Micelli Ferrari T, Vecchione C, Zurria M, Marrazzo G, Mascio G, Sacchetti B, Madonna M, Fornai F, Nicoletti F, Lograno MD. Effects of vitamin B12 on the corneal nerve regeneration in rats. Exp Eye Res. 2014;120:109–17. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 18 Jan, 2026 Reviews received at journal 15 Jan, 2026 Reviewers agreed at journal 14 Jan, 2026 Reviewers invited by journal 06 Jan, 2026 Editor assigned by journal 19 Dec, 2025 Editor invited by journal 12 Dec, 2025 Submission checks completed at journal 05 Dec, 2025 First submitted to journal 05 Dec, 2025 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. 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07:17:02","extension":"html","order_by":4,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":84984,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-8182812/v1/db9eb89244dd50a8e5dc8318.html"},{"id":100376951,"identity":"2ff13d84-f033-46a5-b0f2-a8621c8f6676","added_by":"auto","created_at":"2026-01-16 08:46:30","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":851258,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8182812/v1/698a217b-bdfd-4980-bbce-b5a5f44fcc83.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eEfficacy and Safety of KeraVio using Violet Light-Emitting Glasses and Cyanocobalamin Drops\u003c/strong\u003e \u003cstrong\u003efor Progressive Keratoconus: A Pilot Study\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eKeratoconus is a progressive corneal ectasia in which the cornea gradually thins and protrudes forward, resulting in irregular astigmatism, increased myopia, and visual deterioration [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The standard treatment, corneal collagen cross-linking (CXL) with riboflavin activated by ultraviolet-A (UVA) light, can slow the advancement of the disease. However, because this procedure generally necessitates epithelial debridement, it is often accompanied by postoperative discomfort and may predispose patients to complications, including infectious keratitis [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo address these limitations, a noninvasive approach using violet light (VL; wavelength 360\u0026ndash;400 nm) has been developed. VL irradiation using eyeglass-type devices influences corneal biomechanics, and the KeraVio protocol combines VL with a photosensitizer to achieve corneal cross-linking without epithelial removal [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn previous KeraVio treatments, we used flavin adenine dinucleotide (FAD), a compound similar to riboflavin [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. However, the supply of the active ingredient will be discontinued after 2022, thus causing FAD eye drops to become unavailable in Japan. As alternatives to riboflavin or FAD, we focus on the role of cyanocobalamin (vitamin B12), the UV‒visible absorption spectrum of which peaks at the VL wavelength. The absorption spectrum of cyanocobalamin has characteristic peaks in both the visible light and ultraviolet regions at 361 nm [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This phenomenon is due to electronic transitions between the cobalt center and ligands within the molecule and is used for quantitative analysis in analytical chemistry and biochemistry. Cyanocobalamin eye drops improve fine movement accommodation in accommodative eye strain and are used clinically to treat eye strain in Japan [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. These eye drops have been on the market for more than 40 years and are therefore considered sufficiently safe. Our hypothesis is that it is possible to confirm the effects of KeraVio treatment with the administration of cyanocobalamin drops and VL irradiation. In this study, riboflavin was replaced with cyanocobalamin (vitamin B12), which shares a similar absorption spectrum and has shown ex vivo efficacy in increasing corneal tensile strength. We conducted an exploratory clinical study to evaluate the safety and potential efficacy of cyanocobalamin-assisted KeraVio in progressive keratoconus.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eEx Vivo Study\u003c/h2\u003e \u003cp\u003eWe examined the effect of VL exposure in combination with cyanocobalamin on corneal biomechanics using porcine eyes with intact epithelium. Fifteen corneas were randomly allocated into three groups. Two experimental arms consisted of VL irradiation with either cyanocobalamin or flavin adenine dinucleotide (FAD) eye drops (five corneas each), while untreated corneas exposed only to sham conditions served as controls.\u003c/p\u003e \u003cp\u003eIrradiation was delivered with a 375-nm VL diode at an irradiance of 0.31 mW/cm\u0026sup2; for 4.8 hours, providing a total energy dose of 5.4 J/cm\u0026sup2;. This level was selected to remain below the endothelial cytotoxic threshold, thereby ensuring tissue safety during exposure [\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A collection of samples comprising the KeraVio with cyanocobalamin and FAD groups was also prepared (each, n\u0026thinsp;=\u0026thinsp;5). For this group, during the initial 30 minutes of VL irradiation, 0.025% cyanocobalamin and 0.05% FAD drops were applied simultaneously to the corneal epithelium every 2 minutes.\u003c/p\u003e \u003cp\u003eAfter VL or sham treatment, the corneas from the three groups were kept in a humid chamber for 30 minutes. Each cornea was then excised en bloc together with the sclera, leaving a 2\u0026ndash;3 mm scleral rim, and mounted on a custom-made scale. A vertical strip, 5 mm in width, was subsequently dissected from the cornea. The strips were clamped with a jaw-to-jaw distance of 5 mm. The cross-sectional area of each specimen was calculated from its central corneal thickness. For mechanical testing, the samples were mounted on a computer-controlled universal testing machine (TA XTplusC Texture Analyser\u0026trade;, Stable Micro Systems, London, UK). The corneoscleral limbus was secured in a dedicated fixture, and a uniaxial tensile test was performed. Each strip was stretched at a constant rate of 1.8 mm/min until a maximum load of 5 N was reached. The elastic modulus was defined as the ratio of tensile stress (force per cross-sectional area) to tensile strain (relative elongation). For statistical analysis, the elastic modulus was consistently evaluated at 10% strain.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eClinical Pilot Study\u003c/h3\u003e\n\u003cp\u003eWe conducted a single-arm, prospective, exploratory trial (jRCTs032230104) at the Minami Aoyama Eye Clinic in Tokyo to investigate the safety and potential efficacy of KeraVio combined with cyanocobalamin. The protocol received approval from an independent review board, and all procedures conformed to the Declaration of Helsinki. Human Ethics and Consent to Participate declarations were not applicable. Written informed consent was obtained from every participant prior to enrollment as a consent to participate declaration. The consent to publish declarations were not applicable. In this study, the ethics board certificated that we have received written informed consent from the individuals for the publication of these details. The data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon request.\u003c/p\u003e\n\u003ch3\u003eInclusion and Exclusion Criteria\u003c/h3\u003e\n\u003cp\u003eInclusion criteria were: male or female sex, any race or ethnicity, age\u0026thinsp;\u0026ge;\u0026thinsp;15 years, and a confirmed diagnosis of keratoconus by corneal topography or tomography. Eligible participants were also required to demonstrate disease progression within the 6 months prior to baseline in order to undergo KeraVio treatment, defined by at least one of the following: (1) an increase of \u0026ge;\u0026thinsp;0.50 diopters (D) in maximum keratometry (Kmax); (2) an increase of \u0026ge;\u0026thinsp;0.50 D in cylinder power on subjective manifest refraction; (3) an increase of \u0026ge;\u0026thinsp;0.50 D in myopia on subjective manifest refraction; or (4) a reduction of \u0026ge;\u0026thinsp;5 \u0026micro;m in the thinnest corneal thickness. To minimize lens-induced corneal shape alterations, contact lenses were discontinued before each visit (3 weeks for rigid gas-permeable lenses and 1 week for soft lenses). Exclusion criteria included photosensitivity, a history of epilepsy, hypersensitivity to fluorescein, or the presence of ocular or systemic conditions considered unsuitable for study participation.\u003c/p\u003e\n\u003ch3\u003eKeraVio Treatment\u003c/h3\u003e\n\u003cp\u003eIn the KeraVio treatment group, subjects wore VL-emitting glasses that delivered violet light (VL, 375 nm) to the cornea for 4.5 hours daily over a 3-month period. During each 3-hour VL irradiation session, 0.02% cyanocobalamin eye drops were instilled onto the corneal epithelium every 30 minutes to facilitate corneal penetration. Prior to each session, the intended irradiance of 0.31 mW/cm\u0026sup2; was confirmed with a UVA meter (LaserMate-Q; LASER 2000, Wessling, Germany) at a distance of 1.2 cm from the corneal surface, and adjusted with a potentiometer when necessary. The treatment protocol, consisting of VL exposure combined with cyanocobalamin instillation, was continued daily for 3 months, delivering a cumulative energy dose of 301.3 J/cm\u0026sup2;. Bilateral treatment was permitted if deemed clinically beneficial by the investigator; however, only the more severely affected eye of each subject was included in the efficacy and safety analyses.\u003c/p\u003e\n\u003ch3\u003eOutcome Measures\u003c/h3\u003e\n\u003cp\u003eTomographic data were acquired using anterior segment optical coherence tomography (AS-OCT) (CASIA, Tomey Corporation, Nagoya, Japan) at baseline and at 1, 3, and 6 months following KeraVio treatment. Parameters assessed included keratometric values, thinnest corneal thickness, and the stromal demarcation line (DL) as identified by the AS-OCT system. The maximum keratometry value (Kmax) was selected as the primary efficacy endpoint because it reflects the steepening characteristic of corneal ectasia and provides an objective, quantitative measure that can be consistently assessed across study sites using standardized hardware and software. Additional keratometric values along the flat (K1) and steep (K2) meridians were also analyzed. Treatment success was defined as significant corneal flattening, specifically a reduction in Kmax greater than 1.00 D at 6 months compared with baseline. When a DL was detectable on AS-OCT scans, its depth was independently measured by two observers at 3 months post-treatment, following procedures described in our previous studies [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The DL was also qualitatively assessed.\u003c/p\u003e \u003cp\u003eUncorrected visual acuity (UCVA), best-corrected visual acuity (BCVA), and manifest refraction spherical equivalent (MRSE) were evaluated at baseline and at 3 and 6 months after KeraVio. Visual acuity was recorded in logarithm of the minimum angle of resolution (logMAR) units using a Landolt C chart.\u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSafety Outcomes\u003c/h2\u003e \u003cp\u003eThe safety analysis included all treated eyes. Safety assessments comprised endothelial cell density and intraocular pressure, measured at each visit using a specular microscope (NonconRobo, Konan, Nishinomiya, Japan) and a tonometer (TONOREF, Nidek Co.), respectively. In addition, slit-lamp examinations were performed to identify potential adverse events, including secondary cataracts, conjunctivitis, and eyelid complications.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analysis was performed with the assistance of Statistical Analysis Software (version 9.4; SAS Institute, Cary, NC). The differences in the elastic modulus among the three treatment groups were tested using the Friedman nonparametric test coupled with Scheffe\u0026rsquo;s multiple comparison test. A P value of less than 0.05 was considered to indicate statistical significance. With respect to clinical data, statistical analysis was not performed because of the small number of cases included in the current study.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eEx Vivo Study\u003c/h2\u003e \u003cp\u003eThe elastic modulus and percentage strain of the treated corneas at 10% strain were determined for each of the three groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The average elastic moduli at 10% strain in the KeraVio without cyanocobalamin, KeraVio with FAD, and control groups were 285.20\u0026thinsp;\u0026plusmn;\u0026thinsp;83.71 kPa, 181.80\u0026thinsp;\u0026plusmn;\u0026thinsp;99.98 kPa, and 47.50\u0026thinsp;\u0026plusmn;\u0026thinsp;19.66 kPa, respectively. The elastic modulus at 10% exhibited significant differences among the groups according to the nonparametric Friedman test performed with respect to the four groups (P\u0026thinsp;=\u0026thinsp;0.135).\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\u003eElastic modulus at 10% strain in each group.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\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\u003eKeraVio with cyanocobalamin\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eKeraVio with flavin adenine dinucleotide\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (kPa)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e285.20\u0026thinsp;\u0026plusmn;\u0026thinsp;83.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e181.80\u0026thinsp;\u0026plusmn;\u0026thinsp;99.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e47.50\u0026thinsp;\u0026plusmn;\u0026thinsp;19.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRange\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e226.03 to 344.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e111.10 to 252.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e33.60 to 61.40\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eClinical study\u003c/h2\u003e \u003cp\u003eThree eyes belonging to 3 patients were treated with KeraVio and cyanocobalamin. All included patients had progressive keratoconus and met the eligibility criteria. The participant demographics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. All patients remained in the study through the 6-month follow-up.\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\u003eDemographic characteristics of patients included in the KeraVio treatment with a decrease in cyanocobalamin concentration (n\u0026thinsp;=\u0026thinsp;3).\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge (years)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSex (female/male)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eKmax (diopters)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e50.70\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e82.47\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e76.46\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.67\u0026thinsp;\u0026plusmn;\u0026thinsp;11.24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003en/a\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e69.88\u0026thinsp;\u0026plusmn;\u0026thinsp;16.88\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eSD\u0026thinsp;=\u0026thinsp;standard deviation\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003en/a\u0026thinsp;=\u0026thinsp;not applicable\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e shows the changes in corneal parameters from baseline to the 6-month observation period after treatment. The mean change in Kmax during the 6-month observation period was \u0026minus;\u0026thinsp;0.37\u0026thinsp;\u0026plusmn;\u0026thinsp;6.82 D. However, in three cases, Kmax increased and decreased, resulting in variability. Similarly, the K1, K2, and thinnest corneal thickness results also varied, and no consistent trend was observed. The success rate (flattening of the Kmax\u0026thinsp;\u0026gt;\u0026thinsp;1.00 D) was 33% (one-eye). No DL was observed after KeraVio with cyanocobalamin at 3 months.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChanges in corneal parameters after KeraVio with a decrease in cyanocobalamin concentration.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\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\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eChange from baseline to 6 months\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eKmax (D)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e50.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.34\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e73.63\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e74.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-7.51\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e86.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e6.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e69.88\u0026thinsp;\u0026plusmn;\u0026thinsp;16.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70.48\u0026thinsp;\u0026plusmn;\u0026thinsp;18.28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69.51\u0026thinsp;\u0026plusmn;\u0026thinsp;16.44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.37\u0026thinsp;\u0026plusmn;\u0026thinsp;6.82\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eK1 (D)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e42.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e42.60\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e42.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e52.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.71\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e64.07\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e68.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4.26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e53.17\u0026thinsp;\u0026plusmn;\u0026thinsp;10.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.49\u0026thinsp;\u0026plusmn;\u0026thinsp;11.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e54.42\u0026thinsp;\u0026plusmn;\u0026thinsp;13.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.26\u0026thinsp;\u0026plusmn;\u0026thinsp;2.64\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eK2 (D)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e45.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e45.54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.16\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e60.71\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58.12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-2.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e73.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.58\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e59.34\u0026thinsp;\u0026plusmn;\u0026thinsp;13.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e59.98\u0026thinsp;\u0026plusmn;\u0026thinsp;14.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e58.95\u0026thinsp;\u0026plusmn;\u0026thinsp;13.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.39\u0026thinsp;\u0026plusmn;\u0026thinsp;2.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eThinnest corneal thickness (\u0026micro;m)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e442\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e446\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e445\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e427\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e405\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e397\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-30.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e225\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e226\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e230\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e5.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e364.67\u0026thinsp;\u0026plusmn;\u0026thinsp;121.19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e359.00\u0026thinsp;\u0026plusmn;\u0026thinsp;116.99\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e357.33\u0026thinsp;\u0026plusmn;\u0026thinsp;112.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-7.33\u0026thinsp;\u0026plusmn;\u0026thinsp;19.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eD\u0026thinsp;=\u0026thinsp;diopters\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e shows the changes in the UCVA, BCVA, MESE, and cylindrical refraction from baseline to the 6-month observation period after treatment. In all three patients, visual acuity and subjective refraction were clinically unchanged.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eChanges in visual acuity and refraction after KeraVio with a decrease in cyanocobalamin concentration.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eChange from baseline to 6 months\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eUncorrected visual acuity (logMAR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.27\u0026thinsp;\u0026plusmn;\u0026thinsp;0.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.04\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBest-corrected visual acuity (logMAR)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.11\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.12\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.48\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eManifest refraction spherical equivalent (D)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-4.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-4.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-4.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-4.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-4.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-4.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e#3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-21.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-18.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-20.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-9.83\u0026thinsp;\u0026plusmn;\u0026thinsp;9.67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-9.00\u0026thinsp;\u0026plusmn;\u0026thinsp;8.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-9.58\u0026thinsp;\u0026plusmn;\u0026thinsp;9.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.66\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eCylindrical refraction (D)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-2.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-6.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-6.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-5.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-6.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-5.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-6.00\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e-4.67\u0026thinsp;\u0026plusmn;\u0026thinsp;2.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e-4.33\u0026thinsp;\u0026plusmn;\u0026thinsp;2.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e-4.50\u0026thinsp;\u0026plusmn;\u0026thinsp;2.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.17\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003elogMAR\u0026thinsp;=\u0026thinsp;logarithm of the minimal resolution angle\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eD\u0026thinsp;=\u0026thinsp;diopters\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e presents the safety profile of KeraVio with cyanocobalamin treatment. Two patients demonstrated errors in corneal endothelial cell density and intraocular pressure, but all eyes remained clinically unchanged. With regard to adverse events, no vision-threatening complications were observed during the study, supporting the safety of the treatment. At the 6-month follow-up, neither pterygium, skin melanoma, lenticular opacity, nor transient corneal haze was detected in any treated eye.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSafety profile after KeraVio with a decrease in cyanocobalamin concentration.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\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\u003eBaseline\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 months\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6 months\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eEndothelial cell density (cells/mm\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3153\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3088\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2924\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eunmeasurable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eunmeasurable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eunmeasurable\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eIntraocular pressure (mmHg)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eunmeasurable\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e# 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this exploratory study, KeraVio treatment with cyanocobalamin and VL irradiation exhibited a favorable safety profile, with no adverse events or detrimental changes in ocular health parameters over six months. However, Kmax outcomes were highly variable among patients, and the small sample size precluded statistical analysis. Although the concept of replacing riboflavin with cyanocobalamin is supported by preclinical data, its clinical efficacy in keratoconus progression remains unproven. Notably, in our study, we investigated the therapeutic effects of cyanocobalamin and VL irradiation on progressive keratoconus; no similar studies have been reported to date.\u003c/p\u003e \u003cp\u003eIn a tensile strength test that used porcine eyes treated with cyanocobalamin eye drops and VL irradiation, no statistically significant differences in the elastic modulus were observed among the three groups. However, the cyanocobalamin and FAD groups presented higher values compared with the control group. This finding is consistent with our previous basic and clinical study using FAD eye drops and VL irradiation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCyanocobalamin is a drug that has an absorption peak at 361 nm and is therefore logically expected to have a corneal cross-linking effect [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. However, in this study, corneal epithelial peeling was not performed in all porcine eyes. Thus, penetration of the drug into the corneal stroma was limited, and the extent to which cyanocobalamin penetrated the corneal stroma was unclear. Future studies should evaluate cyanocobalamin concentrations in the corneal stroma in the presence or absence of epithelial peeling. Unlu et al. reported that the combination of citicoline and vitamin B12 for keratoconus effectively promoted corneal nerve healing after CXL [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Furthermore, a report produced by Romano et al. revealed that vitamin B12 treatment promotes not only corneal re-epithelialization but also reinnervation after mechanical injury [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These findings suggest that cyanocobalamin is effective for corneal epithelial regeneration and is also an effective drug for treating keratoconus.\u003c/p\u003e \u003cp\u003eLimitations of this study include its single-arm design, the lack of a control group, and the minimal sample size. Further randomized controlled trials with larger cohorts are necessary to validate the efficacy and determine the long-term safety of this approach.\u003c/p\u003e \u003cp\u003eIn conclusion, cyanocobalamin-assisted KeraVio appears to be a safe, noninvasive option for patients with progressive keratoconus. However, evidence of the effectiveness of this treatment is currently limited. Given the variability in Kmax responses and limited sample size, its efficacy requires confirmation on the basis of well-powered, controlled studies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eContributors:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConception and design: Kobashi, Tsubota\u003c/p\u003e\n\u003cp\u003eAnalysis and interpretation: Kobashi, Toda\u003c/p\u003e\n\u003cp\u003eData collection: Kobashi, Tsubota, Toda\u003c/p\u003e\n\u003cp\u003eObtained funding: Kobashi, Tsubota\u003c/p\u003e\n\u003cp\u003eOverall responsibility: Kobashi, Tsubota\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eThis work was supported by Tsubota Laboratory, Inc.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclaimer:\u0026nbsp;\u003c/strong\u003eThe sponsor had no role in the study design; data collection, analysis or interpretation; writing of the report; or the decision to submit the article for publication.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u003c/strong\u003e The author(s) disclose the following:\u003c/p\u003e\n\u003cp\u003eH.K.: Consultant and equity owner, Tsubota Laboratory Inc. (Tokyo, Japan); Patent, Tsubota Laboratory Inc.\u003c/p\u003e\n\u003cp\u003eK.T.: Employee and equity owner, Tsubota Laboratory, Inc.; Patent, Tsubota Laboratory, Inc.\u003c/p\u003e\n\u003cp\u003eNo other disclosures were reported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient consent for publication:\u0026nbsp;\u003c/strong\u003eNot needed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eThe study adhered to the tenets of the Declaration of Helsinki. The study subjects completed a written informed consent form. This trial was approved by the Certified Review Board, Hattori Clinic and registered in the Japan Registry of Clinical Trials (jRCT): jRCTs032230104.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ehttps://jrct.mhlw.go.jp/en-latest-detail/jRCTs032230104\u003c/p\u003e\n\u003cp\u003eThe ethics board certificated that authors have received written informed consent from the individuals for the publication of these details.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProvenance and peer review:\u003c/strong\u003e Not commissioned; externally peer reviewed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eThe data that support the findings of this study are not publicly available due to privacy reasons but are available from the corresponding author upon request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eORCID\u003c/strong\u003e\u003cstrong\u003e: Hidenaga\u0026nbsp;Kobashi\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ehttps://orcid.org/0000-0002-0767-4214\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRabinowitz YS, Keratoconus. Surv Ophthalmol. 1998;42(4):297\u0026ndash;319.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSorkin N, Varssano D. Corneal collagen crosslinking: a systematic review. Ophthalmologica. 2014;232(1):10\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKobashi H, Torii H, Toda I, Kondo S, Itoi M, Tsubota K. Clinical outcomes of KeraVio using violet light: emitting glasses and riboflavin drops for corneal ectasia: a pilot study. Br J Ophthalmol. 2021;105(10):1376\u0026ndash;82. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1136/bjophthalmol-2020-316974\u003c/span\u003e\u003cspan address=\"10.1136/bjophthalmol-2020-316974\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKobashi H, Yunoki S, Kato N, Shimazaki J, Ide T, Tsubota K. Evaluation of the Physiological Corneal Intrastromal Riboflavin Concentration and the Corneal Elastic Modulus After Violet Light Irradiation. Transl Vis Sci Technol. 2021;10(5):12.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKobashi H, Kumanomido T, Ide T, Kato N, Shimazaki J, Itoi M, Tsubota K. Ineffectiveness of KeraVio Treatment with Violet Light-Emitting Glasses Without Riboflavin Drops for Progressive Keratoconus. J Clin Med. 2025;14(3):773.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZobi F, Blacque O, Jacobs RA, Schaub MC, Bogdanova AY. 17 e- rhenium dicarbonyl CO-releasing molecules on a cobalamin scaffold for biological application. Dalton Trans. 2012;41(2):370\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakashima K, Yamasaki H, Shimoda R, Kuroda N, Akiyama S, Baeyens WR. Flow-injection analysis of cobalt(II) utilizing enhanced lophine chemiluminescence with hydroxylammonium chloride. Biomed Chromatogr. 1997 Mar-Apr;11(2):63\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWollensak G, Spoerl E, Reber F, Seiler T. Keratocyte cytotoxicity of riboflavin/UVA-treatment in vitro. Eye. 2004;18:718\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWollensak G, Spoerl E, Wilsch M, Seiler T. Keratocyte apoptosis after corneal collagen cross-linking using ribofl avin/UVA treatment. Cornea. 2004;23:43\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWollensak G, Spoerl E, Wilsch M, Seiler T. Endothelial cell damage after riboflavin\u0026ndash;ultraviolet-A treatment in the rabbit. J Cataract Refract Surg. 2003;29:1786\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKymionis GD, Grentzelos MA, Plaka AD, Tsoulnaras KI, Diakonis VF, Liakopoulos DA, Kankariya VP, Pallikaris AI. Correlation of the corneal collagen cross-linking demarcation line using confocal microscopy and anterior segment optical coherence tomography in keratoconic patients. Am J Ophthalmol. 2014;157(1):110\u0026ndash;e1151.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKymionis GD, Tsoulnaras KI, Grentzelos MA, Plaka AD, Mikropoulos DG, Liakopoulos DA, Tsakalis NG, Pallikaris IG. Corneal stroma demarcation line after standard and high-intensity collagen crosslinking determined with anterior segment optical coherence tomography. J Cataract Refract Surg. 2014;40(5):736\u0026ndash;40.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eUnlu M, Ozer F, Sahin Aslan E, Sener H, Erkilic K. Can the combination of citicoline and vitamin B12 be beneficial in the healing of corneal nerves after corneal cross-linking? Int Ophthalmol. 2025;45(1):54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRomano MR, Biagioni F, Carrizzo A, Lorusso M, Spadaro A, Micelli Ferrari T, Vecchione C, Zurria M, Marrazzo G, Mascio G, Sacchetti B, Madonna M, Fornai F, Nicoletti F, Lograno MD. Effects of vitamin B12 on the corneal nerve regeneration in rats. Exp Eye Res. 2014;120:109\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"keratoconus, corneal cross-linking, violet light, cyanocobalamin eye","lastPublishedDoi":"10.21203/rs.3.rs-8182812/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8182812/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo evaluate the efficacy and safety of KeraVio treatment, a minimally invasive corneal cross-linking technique that combines cyanocobalamin eye drops with violet light (VL) irradiation, in patients with progressive keratoconus.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis prospective, single-arm exploratory study included three patients (mean age, 36.67 ± 11.24 years; 2 males, 1 female) with progressive keratoconus. Treatment consisted of 0.02% cyanocobalamin eye drops administered six times daily and VL irradiation via TLG-003 eyeglasses worn 4.5 hours per day for three months. Patients were followed for six months. The primary endpoint was the change in maximum keratometry (Kmax). Secondary endpoints included thinnest corneal thickness (TCT), demarcation line (DL), best-corrected visual acuity (BCVA), uncorrected visual acuity (UCVA), manifest refraction, intraocular pressure, corneal endothelial cell density, corneal haze, slit-lamp/fundus examination findings, and periocular skin changes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe mean Kmax change at 6 months was − 0.37 ± 6.82 D. The mean change in the TCT was − 7.33 ± 19.66 µm. BCVA and UCVA remained stable (mean BCVA change: −0.03 ± 0.15 logMAR; mean UCVA change: 0.04 ± 0.07 logMAR). No clinically observed changes in refraction, intraocular pressure, endothelial cell density, corneal clarity, or retinal findings were detected. No adverse events occurred.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKeraVio treatment with cyanocobalamin drops appeared to be safe for use in this small cohort. However, owing to the limited sample size and variable Kmax responses, further large-scale, controlled studies are needed to determine the efficacy of this treatment in the context of halting keratoconus progression.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration number:\u003c/strong\u003e jRCTs032230104\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eRegistration Date:\u003c/strong\u003e June 1st, 2023.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of KeraVio using Violet Light-Emitting Glasses and Cyanocobalamin Drops for Progressive Keratoconus: A Pilot Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-01-08 15:42:14","doi":"10.21203/rs.3.rs-8182812/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"105126537829008457948860589639573021241","date":"2026-01-18T11:44:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-15T13:34:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"244493923110085391819732376048753316069","date":"2026-01-15T01:51:08+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-01-07T04:57:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-12-19T10:53:12+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-12-12T06:49:29+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-12-05T10:44:28+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-12-05T10:32:53+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"73434747-3e5d-435b-a13f-032e69a8b60a","owner":[],"postedDate":"January 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-01-08T15:42:14+00:00","versionOfRecord":[],"versionCreatedAt":"2026-01-08 15:42:14","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8182812","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8182812","identity":"rs-8182812","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}