Simultaneous topical application of cyclosporine and trehalose appears to keep keratoconus eyes stable: a prospective, longitudinal case series evaluated with artificial intelligence methods

Simultaneous topical application of cyclosporine and trehalose appears to keep keratoconus eyes stable: a prospective, longitudinal case series evaluated with artificial intelligence methods | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Simultaneous topical application of cyclosporine and trehalose appears to keep keratoconus eyes stable: a prospective, longitudinal case series evaluated with artificial intelligence methods Rohit Shetty, Pooja Khamar, Gairik Kundu, Panaah Shetty, Deepthi Honniganur, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7607476/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract A prospective, longitudinal case series on keratoconus (KC) eyes was studied where the eyes were treated with topical cyclosporine and trehalose. The study included 362 eyes of 181 patients. The eyes were followed up for a minimum period of 6 months. Corneal tomography was evaluated with Pentacam (OCULUS Optikgerate Gmbh, Germany) at 1st visit and at the last follow-up. Progression was initially evaluated based on change in maximum keratometry (Kmax). Then, this initial classification was assessed with an artificial intelligence model of 31 tomography variables of Pentacam to confirm the inference of progression based on Kmax alone. Based on a change in Kmax of 0.75, 1.0 and 1.25D criteria, more than 90% of the eyes were stable for each criteria at the last follow-up (initial classification). Further analysis with the AI revealed that less than 5% of the eyes had progressed at the last follow-up (final classification). Hence, topical cyclosporine and trehalose appeared to effectively stabilize KC and provide a suitable non-surgical option to manage the inflammation driving the disease. Health sciences/Diseases Health sciences/Health care Health sciences/Medical research Introduction Keratoconus (KC) is a progressive corneal ectasia characterized by stromal thinning and conical protrusion that can lead to visual impairment if left untreated [ 1 ]. Inflammation, oxidative stress, and impaired autophagy play a significant role in the disease pathogenesis [ 2 – 4 ]. In progressive KC, corneal crosslinking (CXL) is the first-line intervention to halt biomechanical weakening of the cornea [ 5 ]. Both CXL and corneal transplantation can be performed in advanced KC patients. However, there remains a therapeutic void in early or mild disease, particularly in patients without definitive progression. Adjunct medical therapy with anti-inflammatory eye drops may overcome this limitation. Elevated levels of pro-inflammatory cytokines, e.g., interleukin-6 (IL-6), tumor necrosis alpha-α (TNF- α), and matrix metalloproteinase-9 (MMP-9), have been identified in the tears of patients with KC, reflecting chronic inflammation [ 2 , 6 ]. Mechanical factors, such as eye rubbing, further promote inflammatory responses and protease release, contributing to corneal degradation [ 3 ]. Simultaneously, oxidative stress markers, such as lipid peroxidation products and nitrites, are elevated in KC corneas, while antioxidants like glutathione and total antioxidant capacity are diminished [ 7 ]. KC corneas also demonstrate abnormal enzyme profiles, including increased catalase and cathepsin V/L2 and reduced tissue inhibitors of metalloproteinases (TIMP-1), reflecting an imbalance in matrix remodeling [ 8 ]. Fibroblasts derived from KC corneas produce more reactive oxygen species (ROS) and undergo higher rates of apoptosis under oxidative challenge compared to healthy corneas [ 9 ]. Additionally, the dysregulation of autophagy may also drive progression of KC. The KC corneas exhibit elevated levels of autophagy-related markers, such as LC3, particularly in the epithelium overlying the cone apex [ 10 ]. This suggests stress-induced autophagy activation, but studies also point to a dysfunctional response due to an incomplete autophagic flux [ 10 , 11 ]. Impaired autophagy can lead to accumulation of toxic protein aggregates and uncontrolled inflammation, creating a feedback loop that exacerbates corneal thinning and degradation [ 12 ]. Trehalose, a naturally occurring disaccharide composed of two glucose molecules linked via an α,α-1,1-glycosidic bond, acts as a cytoprotective, antioxidant, anti-inflammatory, and autophagy-enhancing agent [ 13 – 15 ]. Trehalose stabilizes cellular proteins and membranes under extreme stress, such as dehydration and heat [ 13 ]. Recently, trehalose has demonstrated efficacy in protecting corneal epithelial cells from desiccation-induced death and in managing dry eye disease [ 14 ]. It promotes autophagic flux through activation of the Keap1-Nrf2 antioxidant pathway, suppresses inflammatory cytokine production, and mitigates apoptosis in corneal cells exposed to oxidative stress [ 4 , 15 ]. Thus, trehalose may serve as a novel adjunctive option for modifying disease progression in early keratoconus. In this study, we evaluated the effect of a topical trehalose 3% eye drop (administered four times daily) in combination with cyclosporine 0.05% (twice daily) in patients with early to moderate keratoconus and low-moderate risk of progression. Cyclosporine, an anti-inflammatory immunomodulator, was used to address ocular surface inflammation potentially stemming from allergic eye disease or mechanical irritation. An artificial intelligence (AI)-based random forest model previously validated on longitudinal Pentacam tomography data was used to objectively assess progression status over time [ 16 ]. We aimed to determine whether this pharmacologic regimen could promote disease stability and reduce tomographic signs of progression over a follow-up period of at least six months. Methods This was a prospective, longitudinal case series of KC patients visiting the out-patient department of Narayana Nethralaya eye hospital, Bangalore, India. The study was approved by the ethics committee of the hospital. The study adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from the patient. All the eyes were confirmed cases of KC. All eyes were put on topical medications: cyclosporine 0.05% eye drops twice daily and 3% trehalose mixed with sodium hyaluronate four times per day for at least 6 months. The change in maximum curvature of the anterior surface (Kmax) between 2 visits (at least 6 months apart) was observed. Exclusion criteria were eyes that underwent cross-linking, other ectatic conditions such as keratoglobus, pellucid marginal degeneration, post-refractive surgery ectasia, autoimmune disorders, any ocular or corneal surgery prior to the 1st visit of the patient or during the course of disease follow-up, patients on topical drops other than the above specified drops, patients with corneal scarring, and patients using contact lenses. All eyes underwent Pentacam imaging (OCULUS Optikgerate Gmbh, Germany). Only those images unaffected by blinking or eyelashes were used. These images were automatically classified as “OK” by the Pentacam software. Further, the detected anterior and posterior edges of the corneal scans were manually confirmed so that no missing portions of the detected edges confounded the tomography of the cornea. 17 We used our recently published AI model, which used the tomography parameters of the cornea from the 1 st and latest follow-up visits of the patient. 16 Generally, the maximum anterior curvature (Kmax) is used for evaluating progression, such as an increase by 1D. However, the anterior surface of the cornea is very fluid and undergoes dynamic topology changes due to epithelium remodeling, eye rubbing, and inflammation in KC. Hence, we devised an AI model that evaluated multiple tomography parameters from Pentacam so that a distinction between local and global progression could be ascertained. 16 Here, local progression could be simply a change in Kmax (a point or local measure) with no concomitant change in other tomography parameters, whereas global would indicate simultaneous change in both Kmax and other parameters. Here, the former can be interpreted as stable, and the latter can be considered a true instance of progression. 16 The Pentacam parameters were exported from each measurement as a comma-separated value (csv) file. The average of parameters from repeat scans was used if multiple image sessions were available at the same time point. The following Pentacam parameters were used to calculate the difference data 16 : Flat and steep axis curvature, mean curvature, axis and magnitude of astigmatism, and asphericity (Q-factor) of the anterior and posterior corneal surface (a total of 12 parameters). Central and minimum corneal thickness, Belin-Ambrosio overall deviation (BAD-D) index (a total of 3 parameters). The BAD-D index is an aggregate parameter of all the D indices calculated by Pentacam. Index of surface variance (ISV), Index of Height Asymmetry (IHA), Index of Vertical Asymmetry (IVA), Index of Height Decentration (IHD), Keratoconus Index (KI) and Center of Keratoconus Index (CKI) (a total of 6 parameters). Root mean square (RMS) of coma, lower order (LOA) and higher order aberrations (HOA) along with defocus and spherical aberration (SA) of the anterior and posterior corneal surface (a total of 10 parameters). These aberrations were evaluated for the central 6 mm cornea using a Zernike order up to order 6. Scores A, B and C of ABCD score in Pentacam. We did not consider D in the analyses as it was related to visual acuity only. In this study, the difference in tomography parameters between the 1 st and latest visit was calculated. Then, the data was sub-divided into progression vs. no-progression based on change in Kmax by 0.75D, 1.0D and 1.25D. This initial classification was used as test data in the AI model 16 to determine which eyes had progressed globally (true instance) despite the use of anti-inflammatory eye drops and which eyes showed only local progression (stable). Additional technical details of the AI model are described in our earlier study. 16 Statistical analysis The performance of the AI model was evaluated using several parameters, including area under the curve (AUC), classification accuracy (CA), precision (Pr), recall (Rec), and F1-score. The Orange3 version 3.25.0 data mining package (University of Ljubljana, Slovenia) was used. Statistical tests were conducted with MedCalc v19 (MedCalc Inc, Belgium). Mean±standard deviation was calculated for each parameter after confirming normality of distribution. Results A total of 362 eyes of 181 patients were analyzed, which included 98 males and 83 females with an average age of 26 ± 3.6 years. After assessing the quality of the scans, a total of 724 Pentacam scans of 362 eyes were included in the study. The mean follow-up time was 10.8 ± 6.01 months (range: 6 to 36 months). Table 1 shows the mean values of all parameters at visit 1 and visit 2 (latest follow-up after initiation of topical eye drops) for the whole group. Among all parameters, central corneal thickness, thinnest corneal thickness, BAD-D, defocus and spherical aberration changed significantly between the visits (p < 0.05). However, none of these changes were clinically significant. Table 1 Mean and standard deviation of tomographic parameters at both visits. Visit 1 Visit 2 p-value from paired t-test Anterior Keratometry Indices Kmax (D) 51.1 ± 4.81 51.09 ± 4.71 0.11 CCT (µm) 480.8 ± 37.1 478 ± 37.2 < 0.0001* TCT (µm) 471.6 ± 37.2 468.2 ± 37.5 < 0.0001* K1 F (D) 44.7 ± 2.39 44.73 ± 2.38 0.28 K2 F (D) 47.8 ± 3.3 47.79 ± 3.29 0.63 Pentacam Derived Indices BAD D 5.82 ± 2.59 5.91 ± 2.62 0.0014* IHA 25.71 ± 20.75 25.66 ± 21.01 0.95 IHD 0.069 ± 0.04 0.068 ± 0.04 0.64 ISV 53.14 ± 25.3 52.9 ± 24.9 0.38 IVA 0.52 ± 0.3 0.51 ± 0.3 0.20 KI 1.12 ± 0.07 1.12 ± 0.08 0.20 CKI 1.03 ± 0.03 1.03 ± 0.03 0.12 Anterior Zernike Coefficients Defocus (µm) -0.97 ± 2.45 -0.88 ± 2.35 0.004* RMS COMA (µm) 1.34 ± 0.87 1.34 ± 0.88 0.45 RMS LOA (µm) 6.42 ± 3.72 6.35 ± 3.62 0.04* RMS HOA (µm) 1.59 ± 0.93 1.58 ± 0.92 0.70 PSA (µm) -0.2 ± 0.49 -0.18 ± 0.47 0.004* Statistical analysis was performed between 2 visits; p*<0.05 is statistically significant; Paired t test; Kmax (D)- Maximum anterior sagittal curvature, CCT (µm)—central corneal thickness, TCT (µm)-thinnest corneal thickness, K1 F (D)- Flat Keratometry, K2 F (D)-Steep keratometry, BAD-D- Belin-Ambrosia enhanced ectasia display, IHA-Index of Height Asymmetry, IHD- Index of Height Decentration, ISV- Index of Surface Variance, IVA- Index of Vertical Asymmetry,KI- Keratoconus Index,CKI- Centre of Keratoconus Index, RMS COMA (µm)- Root mean square of Coma, RMS LOA (µm)-Root mean square of lower order aberration, RMS HOA (µm)- Root mean square of higher order aberration, PSA (µm)-Primary spherical aberration. Based on a change in Kmax by 0.75D, 331 and 31 eyes were classified as non-progressed and progressed, respectively. When the AI model was used, 326 out of the 331 eyes (98.5%) were confirmed as stable. However, 13 out of 31 (41.9%) eyes were reclassified from progressed to stable (or local progression only) by the AI, while the remaining 18 eyes were maintained as progressed (or global progression). The AUC, CA, Pr, Rec and F1-score of the model were 0.93, 0.95, 0.95, 0.95 and 0.95, respectively. Based on a change in Kmax by 1D, 343 and 19 eyes were classified as non-progressed and progressed, respectively. When the AI model was used, 342 out of the 343 eyes (99.4%) were confirmed as stable. However, 9 out of 19 (52.6%) eyes were reclassified from progressed to stable (or local progression only) by the AI, while the remaining 10 eyes were maintained as progressed (or global progression). The AUC, CA, Pr, Rec and F1-score of the model were 0.96, 0.97, 0.96, 0.97 and 0.96, respectively. Based on a change in Kmax by 1.25D, 346 and 16 eyes were classified as non-progressed and progressed, respectively. When the AI model was used, all 346 eyes (100%) were confirmed as stable. However, 9 out of 16 (56.2%) eyes were reclassified from progressed to stable (or local progression only) by the AI, while the remaining 6 eyes were maintained as progressed (or global progression). The AUC, CA, Pr, Rec and F1-score of the model were 0.94, 0.98, 0.98, 0.98 and 0.97, respectively. Thus, both the change in Kmax and the AI model showed that most of the eyes were stable upon long-term follow-up with the use of cyclosporine and trehalose. Further, the AI helped in identifying eyes that showed only local progression based on change in Kmax and stability of other Pentacam tomography parameters. Interestingly, a combination of change in Kmax and the AI showed that overall, 339 to 355 eyes were stable depending on the cut-off criteria for change in Kmax. An example of why this combinational strategy of assessing progression works better than using the change in Kmax is shown in Table 2 . Table 2 The mean ± standard deviation of change in tomographic parameters of the eyes. The eyes were grouped based on 2×2 confusion matrix. Here, the initial classification was based on change in Kmax by 1D. Initial classification No-progression No-progression Progression Progression Predicted classification by AI Local progression Global progression Local Progression Global progression Anterior Keratometry Indices Kmax (D) -0.182 ± 0.71 0.5 ± 0.55 1.51 ± 0.41 1.92 ± 1.12 CCT (µm) -2.42 ± 6.94 -6.66 ± 6.92 -5.3 ± 9.81 -11.2 ± 8.29 TCT (µm) -3.02 ± 7.89 -6 ± 6.92 -4.5 ± 7.38 -11.9 ± 8.09 K1 F (D) -0.001 ± 0.29 0.566 ± 0.3 0.08 ± 0.27 0.44 ± 0.87 K2 F (D) -0.071 ± 0.39 0.6 ± 0.6 0.67 ± 0.20 1.11 ± 1.4 Pentacam Derived Indices BAD-D 0.036 ± 0.415 0.55 ± 0.30 0.35 ± 0.38 1.15 ± 0.97 IHA -0.53 ± 24.3 1.4 ± 19.3 6.65 ± 15.99 9.74 ± 24.08 IHD -0.001 ± 0.008 -0.006 ± 0.028 0.014 ± 0.012 0.015 ± 0.015 ISV -0.64 ± 3.3 1 ± 7.81 5 ± 4.59 10 ± 7.86 IVA -0.08 ± 0.052 -0.09 ± 0.26 0.043 ± 0.08 0.103 ± 0.10 KI 0.005 ± 0.092 -0.01 ± 0.05 0.016 ± 0.016 0.024 ± 0.02 CKI -0.001 ± 0.007 0.01 ± 0.01 0.002 ± 0.007 0.010 ± 0.011 Anterior Zernike Coefficients Defocus (µm) -0.019 ± 0.161 -0.85 ± 1.04 0.10 ± 0.177 0.21 ± 0.17 RMS COMA (µm) 0.154 ± 0.114 0.49 ± 0.43 0.06 ± 0.04 0.46 ± 0.28 RMS LOA (µm) -0.14 ± 0.58 0.073 ± 1.45 0.16 ± 0.28 1.46 ± 0.85 RMS HOA (µm) -0.02 ± 0.15 -0.03 ± 0.42 0.22 ± 0.19 0.42 ± 0.28 PSA (µm) 0.02 ± 0.18 -0.14 ± 0.17 -0.05 ± 0.05 -0.16 ± 0.18 Kmax (D)- Maximum anterior sagittal curvature, CCT (µm)—central corneal thickness, TCT (µm)-thinnest corneal thickness, K1 F (D)- Flat Keratometry, K2 F (D)-Steep keratometry, BAD-D- Belin-Ambrosia enhanced ectasia display, IHA-Index of Height Asymmetry, IHD- Index of Height Decentration, ISV- Index of Surface Variance, IVA- Index of Vertical Asymmetry,KI- Keratoconus Index,CKI- Centre of Keratoconus Index, RMS COMA (µm)- Root mean square of Coma, RMS LOA (µm)-Root mean square of lower order aberration, RMS HOA (µm)- Root mean square of higher order aberration, PSA (µm)-Primary spherical aberration. Table 2 shows the mean ± standard deviation of tomographic parameters of eye groups based on the initial classification of the eyes as no-progression and progression based on a change in Kmax by 1D. The AI reclassified the no-progression eyes as local progression (or stable; column 2 of Table 1 ) and global progression (true progression; column 3 in Table 1 ). The change in Kmax was less than 1D in both groups but note the difference between the change in BAD-D, i.e., a mean of 0.036 vs. a mean of 0.55. Similarly, the eyes with initial classification of progression and reclassification by the AI mode to local progression (or stable) had a mean change in BAD-D of 0.35 (column 4 in Table 1 ) despite a mean change in Kmax of 1.51D (column 4 in Table 1 ). This highlights the differential change in tomographic parameters with progression of disease. The more the number of tomographic parameters undergoing a change, the more confidence is associated with the diagnosis of true progression. Discussion Conventional management of KC is driven by laser treatments 18 , scleral contact lenses 19 , intracorneal rings 20 , tissue addition 21 , and corneal crosslinking 22 . These methods are expensive and sometimes invasive but capable of providing significant visual benefits to the patient. For example, significant reductions in higher-order aberrations were observed after topography-guided laser ablation of KC eyes 23 . However, non-surgical methods of prevention of KC progression haven’t received much attention. A recent study showed that the time of eye rubbing could have a mechanical bearing on the stiffness of the cornea, leading to progression of KC. 24 Both eye rubbing and environmental factors can act as feedforward instigators to promote inflammation in KC eyes, leading to progression of the disease. 24,25 Therefore, it is clear that therapeutic management of inflammation could be a useful strategy to manage KC patients who do not have access to more expensive methods or wish to avoid surgery. Few studies have investigated oral supplementation for management of KC progression. Oral supplementation with a highly-concentrated docosahexaenoic acid (DHA) triglyceride was investigated in a randomized controlled trial of 34 patients over 3 months. 26 The study showed that inflammatory markers were reduced due to supplementation, and statistically significant differences were in a few tomography parameters. 26 Another study investigated the effects of Vitamin D supplementation on disease progression, systemic inflammation, collagen degradation, and oxidative stress in 40 patients with a follow-up time of 12 months. 27 Overall, 75% of the eyes remained stable after 12 months.17 Furthermore, these patients (75% cohort) exhibited a downregulation in inflammatory and platelet activation pathways and an upregulation of proteoglycan metabolism/biosynthesis enrichment. 27 Select tomography parameters such as Kmax and thickness remained stable in these eyes. 27 A similar outcome was obtained in another study where Vitamin D supplementation was given to 20 patients (age range of 16–19 years). 28 Nearly 72% of the eyes remained stable after a 12 month follow-up. 28 These studies showed that molecular strategies of KC management may have a clinical role and require further long-term studies. Most studies rely on Kmax and corneal thickness to evaluate the progression of KC. Both Kmax and corneal thickness are local parameters, i.e., measure at a point. Thus, they may not be true descriptors of extensive disease-driven remodeling of the entire cornea. Our earlier study showed that not all tomography parameters indicated progression when Kmax increased by 1D. 16 Thus, combining all tomography parameters in an AI model provided a more efficient differentiator between local and global progression. 16 In this study, more than 91% of the eyes were stable based on both Kmax and parameters evaluated by the AI. However, ~ 50% of the remaining eyes, which were indicated as progressed based on change in Kmax, were reclassified as stable (or having only local progression) by the AI. Thus, a more refined evaluation of the efficacy of topical application of cyclosporine and trehalose was enabled by the AI. Table 1 showed that overall, the eyes exhibited minimal tomography change over the course of follow-up. This study extended the findings of an earlier study on 20 patients who were topically treated with cyclosporine. 29 The study showed that MMP9 levels decreased, and in some eyes, corneal curvature also showed a decrease after 6 months of topical application. 29 One of the limitations of this study is the lack of a control group of eyes. In a study, more than 80% of the children showed progression when followed longitudinally. 29 In another on adult eyes, 23.4% of the eyes progressed over an average follow-up period of 74.38 ± 42.21 months. 30 Progression was more severe in young patients (age from 19–24) compared to young adults (age from 25–30). 31 Interestingly, the progression percentage varied depending on the choice of metric of progression, e.g., Kmax and ABC parameters showed a progression proportion of 14.9% and 12%, respectively while E-Staging showed a progression proportion of 16.4% in young adults. 31 In this study, the progression proportion was less than 5% and therefore, indicated an improved clinical outcome compared to Vitamin D and DHA supplementation. Another limitation of this study is the lack of randomized controlled design and inclusion of primarily a young adult population. Future studies need to investigate whether pediatric population can equally benefit with simultaneous application of cyclosporine and trehalose. The impact of these eye drops on the thickness maps of epithelium also needs to be evaluated in future studies. Another avenue of research could be to investigate the anti-inflammatory effects of this combination of eye drops to manage inflammation and adverse responses in KC patients after surgical interventions. Conclusions Simultaneous application of topical cyclosporine and trehalose appeared to arrest progression of KC in young adult eyes. A combination of change in Kmax and other parameters evaluated with AI showed that less than 5% of the eyes progressed over the follow-up period. Declarations Acknowledgement s: None. Author contributions : R.S., P.K, G.K., P.S., D.H., A.S., R.N. and A.S.R: analyses and writing of the manuscript; R.S., P.K., G.K. and A.S.R: conception, writing and critical review of the manuscript Competing interests : The authors declare no competing interests. Data availability statement: The data for this study was collected from the research database of Narayana Nethralaya eye hospital in Bangalore, India with permission. Due to patient privacy protection, the availability of the data is restricted and not publicly accessible. For any data access requests, contact Dr. Abhijit Sinha Roy at [email protected] . Financial Disclosure/Funding : None References Rabinowitz, Y.S. Keratoconus. Surv Ophthalmol . 41 , 297-319 (1998). Lema, I. & Durán, J.A. Inflammatory molecules in the tears of patients with keratoconus. Ophthalmology . 112 , 654–9 (2005). Balasubramanian, S.A., Pye, D.C. & Willcox, M.D.P. 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J., Fernández-López, E. & Domingo, J. C. Antioxidant and Anti-Inflammatory Effects of Oral Supplementation with a Highly Concentrated Docosahexaenoic Acid (DHA) Triglyceride in Patients with Keratoconus: A Randomized Controlled Preliminary Study. Nutrients . 15, 1300 (2023). Bartolomeo, N., Pederzolli, M., Palombella, S., Fonteyne, P., Suanno, G., Tilaro, G., de Pretis, S., Borgo, F., Bertuzzi, F., Senni, C., De Micheli, M., Bandello, F. & Ferrari, G. The Effects of Vitamin D on Keratoconus Progression. Am J Ophthalmol . 276, 235-251 (2025). Shetty, R., Ghosh, A., Lim, R. R., Subramani, M., Mihir, K., Reshma, A. R., Ranganath, A., Nagaraj, S., Nuijts, R. M., Beuerman, R., Shetty, R., Das, D., Chaurasia, S. S., Sinha-Roy, A. & Ghosh, A. Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A. Invest Ophthalmol Vis Sci . 56, 738-50 (2015). Aslan, M. G., Fındık, H., Okutucu, M., Aydın, E., Oruç, Y., Arpa, M. & Uzun, F. Serum 25-Hydroxy Vitamin D, Vitamin B12, and Folic Acid Levels in Progressive and Nonprogressive Keratoconus. Cornea . 40, 334-341 (2021). Jamali, A., Hashemi, H., Nabovati, P. & Khabazkhoob, M. Progression and regression of keratoconus in an Iranian population. Sci Rep. 15, 28525 (2025). Kosekahya, P., Flockerzi, E., Munteanu, C., Sideroudi, H. & Seitz, B. Comparison of Keratoconus Progression Rate between Adolescents Aged 19-24 Years and Young Adults: Impact on Indication for Crosslinking. Curr Eye Res . 50, 572-578 (2025). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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08:57:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":781826,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7607476/v1/c2a92c09-f835-4fed-a3f4-5118554a76c0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Simultaneous topical application of cyclosporine and trehalose appears to keep keratoconus eyes stable: a prospective, longitudinal case series evaluated with artificial intelligence methods","fulltext":[{"header":"Introduction","content":"\u003cp\u003eKeratoconus (KC) is a progressive corneal ectasia characterized by stromal thinning and conical protrusion that can lead to visual impairment if left untreated [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Inflammation, oxidative stress, and impaired autophagy play a significant role in the disease pathogenesis [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. In progressive KC, corneal crosslinking (CXL) is the first-line intervention to halt biomechanical weakening of the cornea [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Both CXL and corneal transplantation can be performed in advanced KC patients. However, there remains a therapeutic void in early or mild disease, particularly in patients without definitive progression. Adjunct medical therapy with anti-inflammatory eye drops may overcome this limitation. Elevated levels of pro-inflammatory cytokines, e.g., interleukin-6 (IL-6), tumor necrosis alpha-α (TNF- α), and matrix metalloproteinase-9 (MMP-9), have been identified in the tears of patients with KC, reflecting chronic inflammation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Mechanical factors, such as eye rubbing, further promote inflammatory responses and protease release, contributing to corneal degradation [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Simultaneously, oxidative stress markers, such as lipid peroxidation products and nitrites, are elevated in KC corneas, while antioxidants like glutathione and total antioxidant capacity are diminished [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. KC corneas also demonstrate abnormal enzyme profiles, including increased catalase and cathepsin V/L2 and reduced tissue inhibitors of metalloproteinases (TIMP-1), reflecting an imbalance in matrix remodeling [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Fibroblasts derived from KC corneas produce more reactive oxygen species (ROS) and undergo higher rates of apoptosis under oxidative challenge compared to healthy corneas [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAdditionally, the dysregulation of autophagy may also drive progression of KC. The KC corneas exhibit elevated levels of autophagy-related markers, such as LC3, particularly in the epithelium overlying the cone apex [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. This suggests stress-induced autophagy activation, but studies also point to a dysfunctional response due to an incomplete autophagic flux [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Impaired autophagy can lead to accumulation of toxic protein aggregates and uncontrolled inflammation, creating a feedback loop that exacerbates corneal thinning and degradation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eTrehalose, a naturally occurring disaccharide composed of two glucose molecules linked via an α,α-1,1-glycosidic bond, acts as a cytoprotective, antioxidant, anti-inflammatory, and autophagy-enhancing agent [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Trehalose stabilizes cellular proteins and membranes under extreme stress, such as dehydration and heat [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recently, trehalose has demonstrated efficacy in protecting corneal epithelial cells from desiccation-induced death and in managing dry eye disease [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. It promotes autophagic flux through activation of the Keap1-Nrf2 antioxidant pathway, suppresses inflammatory cytokine production, and mitigates apoptosis in corneal cells exposed to oxidative stress [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Thus, trehalose may serve as a novel adjunctive option for modifying disease progression in early keratoconus. In this study, we evaluated the effect of a topical trehalose 3% eye drop (administered four times daily) in combination with cyclosporine 0.05% (twice daily) in patients with early to moderate keratoconus and low-moderate risk of progression. Cyclosporine, an anti-inflammatory immunomodulator, was used to address ocular surface inflammation potentially stemming from allergic eye disease or mechanical irritation. An artificial intelligence (AI)-based random forest model previously validated on longitudinal Pentacam tomography data was used to objectively assess progression status over time [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. We aimed to determine whether this pharmacologic regimen could promote disease stability and reduce tomographic signs of progression over a follow-up period of at least six months.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis was a prospective, longitudinal case series of KC patients visiting the out-patient department of Narayana Nethralaya eye hospital, Bangalore, India. The study was approved by the ethics committee of the hospital. The study adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from the patient. All the eyes were confirmed cases of KC. All eyes were put on topical medications: cyclosporine 0.05% eye drops twice daily and 3% trehalose mixed with sodium hyaluronate four times per day for at least 6 months. The change in maximum curvature of the anterior surface (Kmax) between 2 visits (at least 6 months apart) was observed. Exclusion criteria were eyes that underwent cross-linking, other ectatic conditions such as keratoglobus, pellucid marginal degeneration, post-refractive surgery ectasia, autoimmune disorders, any ocular or corneal surgery prior to the 1st visit of the patient or during the course of disease follow-up, patients on topical drops other than the above specified drops, patients with corneal scarring, and patients using contact lenses. All eyes underwent Pentacam imaging (OCULUS Optikgerate Gmbh, Germany). Only those images unaffected by blinking or eyelashes were used. These images were automatically classified as \u0026ldquo;OK\u0026rdquo; by the Pentacam software. Further, the detected anterior and posterior edges of the corneal scans were manually confirmed so that no missing portions of the detected edges confounded the tomography of the cornea.\u003csup\u003e17\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eWe used our recently published AI model, which used the tomography parameters of the cornea from the 1\u003csup\u003est\u003c/sup\u003e and latest follow-up visits of the patient.\u003csup\u003e16\u003c/sup\u003e Generally, the maximum anterior curvature (Kmax) is used for evaluating progression, such as an increase by 1D. However, the anterior surface of the cornea is very fluid and undergoes dynamic topology changes due to epithelium remodeling, eye rubbing, and inflammation in KC. Hence, we devised an AI model that evaluated multiple tomography parameters from Pentacam so that a distinction between \u003cem\u003elocal\u003c/em\u003e and \u003cem\u003eglobal\u003c/em\u003e progression could be ascertained.\u003csup\u003e16\u003c/sup\u003e Here, \u003cem\u003elocal\u003c/em\u003e progression could be simply a change in Kmax (a point or local measure) with no concomitant change in other tomography parameters, whereas \u003cem\u003eglobal\u003c/em\u003e would indicate simultaneous change in both Kmax and other parameters. Here, the former can be interpreted as stable, and the latter can be considered a true instance of progression.\u003csup\u003e16\u003c/sup\u003e The Pentacam parameters were exported from each measurement as a comma-separated value (csv) file. The average of parameters from repeat scans was used if multiple image sessions were available at the same time point. The following Pentacam parameters were used to calculate the difference data\u003csup\u003e16\u003c/sup\u003e:\u0026nbsp;\u003c/p\u003e\n\u003col style=\"list-style-type: lower-alpha;\"\u003e\n \u003cli\u003eFlat and steep axis curvature, mean curvature, axis and magnitude of astigmatism, and asphericity (Q-factor) of the anterior and posterior corneal surface (a total of 12 parameters).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCentral and minimum corneal thickness, Belin-Ambrosio overall deviation (BAD-D) index (a total of 3 parameters). The BAD-D index is an aggregate parameter of all the D indices calculated by Pentacam.\u003c/li\u003e\n \u003cli\u003eIndex of surface variance (ISV), Index of Height Asymmetry (IHA), Index of Vertical Asymmetry (IVA), Index of Height Decentration (IHD), Keratoconus Index (KI) and Center of Keratoconus Index (CKI) (a total of 6 parameters).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eRoot mean square (RMS) of coma, lower order (LOA) and higher order aberrations (HOA) along with defocus and spherical aberration (SA) of the anterior and posterior corneal surface (a total of 10 parameters). These aberrations were evaluated for the central 6 mm cornea using a Zernike order up to order 6.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eScores A, B and C of ABCD score in Pentacam. We did not consider D in the analyses as it was related to visual acuity only.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eIn this study, the difference in tomography parameters between the 1\u003csup\u003est\u003c/sup\u003e and latest visit was calculated. Then, the data was sub-divided into progression vs. no-progression based on change in Kmax by 0.75D, 1.0D and 1.25D. This initial classification was used as test data in the AI model\u003csup\u003e16\u003c/sup\u003e to determine which eyes had progressed \u003cem\u003eglobally\u003c/em\u003e (true instance) despite the use of anti-inflammatory eye drops and which eyes showed only \u003cem\u003elocal\u0026nbsp;\u003c/em\u003eprogression (stable).\u003csup\u003e\u0026nbsp;\u003c/sup\u003eAdditional technical details of the AI model are described in our earlier study.\u003csup\u003e16\u003c/sup\u003e \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cu\u003eStatistical analysis\u003c/u\u003e\u003c/p\u003e\n\u003cp\u003eThe performance of the AI model was evaluated using several parameters, including area under the curve (AUC), classification accuracy (CA), precision (Pr), recall (Rec), and F1-score. The Orange3 version 3.25.0 data mining package (University of Ljubljana, Slovenia) was used. Statistical tests were conducted with MedCalc v19 (MedCalc Inc, Belgium). Mean\u0026plusmn;standard deviation was calculated for each parameter after confirming normality of distribution.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 362 eyes of 181 patients were analyzed, which included 98 males and 83 females with an average age of 26\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6 years. After assessing the quality of the scans, a total of 724 Pentacam scans of 362 eyes were included in the study. The mean follow-up time was 10.8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.01 months (range: 6 to 36 months). Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows the mean values of all parameters at visit 1 and visit 2 (latest follow-up after initiation of topical eye drops) for the whole group. Among all parameters, central corneal thickness, thinnest corneal thickness, BAD-D, defocus and spherical aberration changed significantly between the visits (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). However, none of these changes were clinically significant.\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\u003eMean and standard deviation of tomographic parameters at both visits.\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\u003eVisit 1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eVisit 2\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value from\u003c/p\u003e\u003cp\u003epaired t-test\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eAnterior Keratometry Indices\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\u003cp\u003e51.1\u0026thinsp;\u0026plusmn;\u0026thinsp;4.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e51.09\u0026thinsp;\u0026plusmn;\u0026thinsp;4.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.11\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCCT (\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e480.8\u0026thinsp;\u0026plusmn;\u0026thinsp;37.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e478\u0026thinsp;\u0026plusmn;\u0026thinsp;37.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.0001*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTCT (\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e471.6\u0026thinsp;\u0026plusmn;\u0026thinsp;37.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e468.2\u0026thinsp;\u0026plusmn;\u0026thinsp;37.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.0001*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eK1\u0026nbsp;F\u0026nbsp;(D)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.7\u0026thinsp;\u0026plusmn;\u0026thinsp;2.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e44.73\u0026thinsp;\u0026plusmn;\u0026thinsp;2.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eK2\u0026nbsp;F\u0026nbsp;(D)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e47.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e47.79\u0026thinsp;\u0026plusmn;\u0026thinsp;3.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.63\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePentacam Derived Indices\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBAD\u0026nbsp;D\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5.82\u0026thinsp;\u0026plusmn;\u0026thinsp;2.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5.91\u0026thinsp;\u0026plusmn;\u0026thinsp;2.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.0014*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIHA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.71\u0026thinsp;\u0026plusmn;\u0026thinsp;20.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25.66\u0026thinsp;\u0026plusmn;\u0026thinsp;21.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.95\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIHD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.069\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.068\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.64\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eISV\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53.14\u0026thinsp;\u0026plusmn;\u0026thinsp;25.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e52.9\u0026thinsp;\u0026plusmn;\u0026thinsp;24.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIVA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.12\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.20\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCKI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAnterior Zernike Coefficients\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDefocus\u0026nbsp;(\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.97\u0026thinsp;\u0026plusmn;\u0026thinsp;2.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.88\u0026thinsp;\u0026plusmn;\u0026thinsp;2.35\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.004*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRMS COMA\u0026nbsp;(\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.34\u0026thinsp;\u0026plusmn;\u0026thinsp;0.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRMS\u0026nbsp;LOA\u0026nbsp;(\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.42\u0026thinsp;\u0026plusmn;\u0026thinsp;3.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.35\u0026thinsp;\u0026plusmn;\u0026thinsp;3.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.04*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRMS\u0026nbsp;HOA\u0026nbsp;(\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.59\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.58\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.70\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePSA\u0026nbsp;(\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.2\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.004*\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"4\"\u003eStatistical analysis was performed between 2 visits; p*\u0026lt;0.05 is statistically significant; Paired t test; Kmax (D)- Maximum anterior sagittal curvature, CCT (\u0026micro;m)\u0026mdash;central corneal thickness, TCT (\u0026micro;m)-thinnest corneal thickness, K1 F (D)- Flat Keratometry, K2 F (D)-Steep keratometry, BAD-D- Belin-Ambrosia enhanced ectasia display, IHA-Index of Height Asymmetry, IHD- Index of Height Decentration, ISV- Index of Surface Variance, IVA- Index of Vertical Asymmetry,KI- Keratoconus Index,CKI- Centre of Keratoconus Index, RMS COMA (\u0026micro;m)- Root mean square of Coma, RMS LOA (\u0026micro;m)-Root mean square of lower order aberration, RMS HOA (\u0026micro;m)- Root mean square of higher order aberration, PSA (\u0026micro;m)-Primary spherical aberration.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eBased on a change in Kmax by 0.75D, 331 and 31 eyes were classified as non-progressed and progressed, respectively. When the AI model was used, 326 out of the 331 eyes (98.5%) were confirmed as stable. However, 13 out of 31 (41.9%) eyes were reclassified from progressed to stable (or \u003cem\u003elocal\u003c/em\u003e progression only) by the AI, while the remaining 18 eyes were maintained as progressed (or \u003cem\u003eglobal\u003c/em\u003e progression). The AUC, CA, Pr, Rec and F1-score of the model were 0.93, 0.95, 0.95, 0.95 and 0.95, respectively.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eBased on a change in Kmax by 1D, 343 and 19 eyes were classified as non-progressed and progressed, respectively. When the AI model was used, 342 out of the 343 eyes (99.4%) were confirmed as stable. However, 9 out of 19 (52.6%) eyes were reclassified from progressed to stable (or \u003cem\u003elocal\u003c/em\u003e progression only) by the AI, while the remaining 10 eyes were maintained as progressed (or \u003cem\u003eglobal\u003c/em\u003e progression). The AUC, CA, Pr, Rec and F1-score of the model were 0.96, 0.97, 0.96, 0.97 and 0.96, respectively.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eBased on a change in Kmax by 1.25D, 346 and 16 eyes were classified as non-progressed and progressed, respectively. When the AI model was used, all 346 eyes (100%) were confirmed as stable. However, 9 out of 16 (56.2%) eyes were reclassified from progressed to stable (or \u003cem\u003elocal\u003c/em\u003e progression only) by the AI, while the remaining 6 eyes were maintained as progressed (or \u003cem\u003eglobal\u003c/em\u003e progression). The AUC, CA, Pr, Rec and F1-score of the model were 0.94, 0.98, 0.98, 0.98 and 0.97, respectively.\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eThus, both the change in Kmax and the AI model showed that most of the eyes were stable upon long-term follow-up with the use of cyclosporine and trehalose. Further, the AI helped in identifying eyes that showed only local progression based on change in Kmax and stability of other Pentacam tomography parameters. Interestingly, a combination of change in Kmax and the AI showed that overall, 339 to 355 eyes were stable depending on the cut-off criteria for change in Kmax. An example of why this combinational strategy of assessing progression works better than using the change in Kmax is shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eThe mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation of change in tomographic parameters of the eyes. The eyes were grouped based on 2\u0026times;2 confusion matrix. Here, the initial classification was based on change in Kmax by 1D.\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=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInitial classification\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNo-progression\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eNo-progression\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eProgression\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eProgression\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePredicted classification by AI\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eLocal progression\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGlobal progression\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eLocal Progression\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGlobal progression\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eAnterior Keratometry Indices\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\u003cp\u003e-0.182\u0026thinsp;\u0026plusmn;\u0026thinsp;0.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.92\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCCT (\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-2.42\u0026thinsp;\u0026plusmn;\u0026thinsp;6.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-6.66\u0026thinsp;\u0026plusmn;\u0026thinsp;6.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-5.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-11.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTCT (\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-3.02\u0026thinsp;\u0026plusmn;\u0026thinsp;7.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-6\u0026thinsp;\u0026plusmn;\u0026thinsp;6.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-4.5\u0026thinsp;\u0026plusmn;\u0026thinsp;7.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-11.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.09\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eK1\u0026nbsp;F\u0026nbsp;(D)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.001\u0026thinsp;\u0026plusmn;\u0026thinsp;0.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.566\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eK2\u0026nbsp;F\u0026nbsp;(D)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.071\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.11\u0026thinsp;\u0026plusmn;\u0026thinsp;1.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePentacam Derived Indices\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBAD-D\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.036\u0026thinsp;\u0026plusmn;\u0026thinsp;0.415\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.30\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIHA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.53\u0026thinsp;\u0026plusmn;\u0026thinsp;24.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;19.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6.65\u0026thinsp;\u0026plusmn;\u0026thinsp;15.99\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e9.74\u0026thinsp;\u0026plusmn;\u0026thinsp;24.08\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIHD\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.001\u0026thinsp;\u0026plusmn;\u0026thinsp;0.008\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.006\u0026thinsp;\u0026plusmn;\u0026thinsp;0.028\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.014\u0026thinsp;\u0026plusmn;\u0026thinsp;0.012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.015\u0026thinsp;\u0026plusmn;\u0026thinsp;0.015\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eISV\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.64\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e10\u0026thinsp;\u0026plusmn;\u0026thinsp;7.86\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eIVA\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.08\u0026thinsp;\u0026plusmn;\u0026thinsp;0.052\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.043\u0026thinsp;\u0026plusmn;\u0026thinsp;0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.103\u0026thinsp;\u0026plusmn;\u0026thinsp;0.10\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eKI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.005\u0026thinsp;\u0026plusmn;\u0026thinsp;0.092\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.016\u0026thinsp;\u0026plusmn;\u0026thinsp;0.016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.024\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eCKI\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.001\u0026thinsp;\u0026plusmn;\u0026thinsp;0.007\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.002\u0026thinsp;\u0026plusmn;\u0026thinsp;0.007\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.010\u0026thinsp;\u0026plusmn;\u0026thinsp;0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cb\u003eAnterior Zernike Coefficients\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDefocus\u0026nbsp;(\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.019\u0026thinsp;\u0026plusmn;\u0026thinsp;0.161\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.85\u0026thinsp;\u0026plusmn;\u0026thinsp;1.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.10\u0026thinsp;\u0026plusmn;\u0026thinsp;0.177\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRMS COMA\u0026nbsp;(\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.154\u0026thinsp;\u0026plusmn;\u0026thinsp;0.114\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.49\u0026thinsp;\u0026plusmn;\u0026thinsp;0.43\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRMS\u0026nbsp;LOA\u0026nbsp;(\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.073\u0026thinsp;\u0026plusmn;\u0026thinsp;1.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e1.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eRMS\u0026nbsp;HOA\u0026nbsp;(\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.22\u0026thinsp;\u0026plusmn;\u0026thinsp;0.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.28\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003ePSA\u0026nbsp;(\u0026micro;m)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.02\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.05\u0026thinsp;\u0026plusmn;\u0026thinsp;0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e-0.16\u0026thinsp;\u0026plusmn;\u0026thinsp;0.18\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eKmax (D)- Maximum anterior sagittal curvature, CCT (\u0026micro;m)\u0026mdash;central corneal thickness, TCT (\u0026micro;m)-thinnest corneal thickness, K1 F (D)- Flat Keratometry, K2 F (D)-Steep keratometry, BAD-D- Belin-Ambrosia enhanced ectasia display, IHA-Index of Height Asymmetry, IHD- Index of Height Decentration, ISV- Index of Surface Variance, IVA- Index of Vertical Asymmetry,KI- Keratoconus Index,CKI- Centre of Keratoconus Index, RMS COMA (\u0026micro;m)- Root mean square of Coma, RMS LOA (\u0026micro;m)-Root mean square of lower order aberration, RMS HOA (\u0026micro;m)- Root mean square of higher order aberration, PSA (\u0026micro;m)-Primary spherical aberration.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation of tomographic parameters of eye groups based on the initial classification of the eyes as no-progression and progression based on a change in Kmax by 1D. The AI reclassified the no-progression eyes as local progression (or stable; column 2 of Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) and global progression (true progression; column 3 in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The change in Kmax was less than 1D in both groups but note the difference between the change in BAD-D, i.e., a mean of 0.036 vs. a mean of 0.55. Similarly, the eyes with initial classification of progression and reclassification by the AI mode to local progression (or stable) had a mean change in BAD-D of 0.35 (column 4 in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) despite a mean change in Kmax of 1.51D (column 4 in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). This highlights the differential change in tomographic parameters with progression of disease. The more the number of tomographic parameters undergoing a change, the more confidence is associated with the diagnosis of true progression.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eConventional management of KC is driven by laser treatments\u003csup\u003e18\u003c/sup\u003e, scleral contact lenses\u003csup\u003e19\u003c/sup\u003e, intracorneal rings\u003csup\u003e20\u003c/sup\u003e, tissue addition\u003csup\u003e21\u003c/sup\u003e, and corneal crosslinking\u003csup\u003e22\u003c/sup\u003e. These methods are expensive and sometimes invasive but capable of providing significant visual benefits to the patient. For example, significant reductions in higher-order aberrations were observed after topography-guided laser ablation of KC eyes\u003csup\u003e23\u003c/sup\u003e. However, non-surgical methods of prevention of KC progression haven\u0026rsquo;t received much attention. A recent study showed that the time of eye rubbing could have a mechanical bearing on the stiffness of the cornea, leading to progression of KC.\u003csup\u003e24\u003c/sup\u003e Both eye rubbing and environmental factors can act as feedforward instigators to promote inflammation in KC eyes, leading to progression of the disease.\u003csup\u003e24,25\u003c/sup\u003e Therefore, it is clear that therapeutic management of inflammation could be a useful strategy to manage KC patients who do not have access to more expensive methods or wish to avoid surgery.\u003c/p\u003e\u003cp\u003eFew studies have investigated oral supplementation for management of KC progression. Oral supplementation with a highly-concentrated docosahexaenoic acid (DHA) triglyceride was investigated in a randomized controlled trial of 34 patients over 3 months.\u003csup\u003e26\u003c/sup\u003e The study showed that inflammatory markers were reduced due to supplementation, and statistically significant differences were in a few tomography parameters.\u003csup\u003e26\u003c/sup\u003e Another study investigated the effects of Vitamin D supplementation on disease progression, systemic inflammation, collagen degradation, and oxidative stress in 40 patients with a follow-up time of 12 months.\u003csup\u003e27\u003c/sup\u003e Overall, 75% of the eyes remained stable after 12 months.17 Furthermore, these patients (75% cohort) exhibited a downregulation in inflammatory and platelet activation pathways and an upregulation of proteoglycan metabolism/biosynthesis enrichment.\u003csup\u003e27\u003c/sup\u003e Select tomography parameters such as Kmax and thickness remained stable in these eyes.\u003csup\u003e27\u003c/sup\u003e A similar outcome was obtained in another study where Vitamin D supplementation was given to 20 patients (age range of 16\u0026ndash;19 years).\u003csup\u003e28\u003c/sup\u003e Nearly 72% of the eyes remained stable after a 12 month follow-up.\u003csup\u003e28\u003c/sup\u003e These studies showed that molecular strategies of KC management may have a clinical role and require further long-term studies.\u003c/p\u003e\u003cp\u003eMost studies rely on Kmax and corneal thickness to evaluate the progression of KC. Both Kmax and corneal thickness are local parameters, i.e., measure at a point. Thus, they may not be true descriptors of extensive disease-driven remodeling of the entire cornea. Our earlier study showed that not all tomography parameters indicated progression when Kmax increased by 1D.\u003csup\u003e16\u003c/sup\u003e Thus, combining all tomography parameters in an AI model provided a more efficient differentiator between \u003cem\u003elocal\u003c/em\u003e and \u003cem\u003eglobal\u003c/em\u003e progression.\u003csup\u003e16\u003c/sup\u003e In this study, more than 91% of the eyes were stable based on both Kmax and parameters evaluated by the AI. However, ~\u0026thinsp;50% of the remaining eyes, which were indicated as progressed based on change in Kmax, were reclassified as stable (or having only local progression) by the AI. Thus, a more refined evaluation of the efficacy of topical application of cyclosporine and trehalose was enabled by the AI. Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e showed that overall, the eyes exhibited minimal tomography change over the course of follow-up. This study extended the findings of an earlier study on 20 patients who were topically treated with cyclosporine.\u003csup\u003e29\u003c/sup\u003e The study showed that MMP9 levels decreased, and in some eyes, corneal curvature also showed a decrease after 6 months of topical application.\u003csup\u003e29\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eOne of the limitations of this study is the lack of a control group of eyes. In a study, more than 80% of the children showed progression when followed longitudinally.\u003csup\u003e29\u003c/sup\u003e In another on adult eyes, 23.4% of the eyes progressed over an average follow-up period of 74.38\u0026thinsp;\u0026plusmn;\u0026thinsp;42.21 months.\u003csup\u003e30\u003c/sup\u003e Progression was more severe in young patients (age from 19\u0026ndash;24) compared to young adults (age from 25\u0026ndash;30).\u003csup\u003e31\u003c/sup\u003e Interestingly, the progression percentage varied depending on the choice of metric of progression, e.g., Kmax and ABC parameters showed a progression proportion of 14.9% and 12%, respectively while E-Staging showed a progression proportion of 16.4% in young adults.\u003csup\u003e31\u003c/sup\u003e In this study, the progression proportion was less than 5% and therefore, indicated an improved clinical outcome compared to Vitamin D and DHA supplementation. Another limitation of this study is the lack of randomized controlled design and inclusion of primarily a young adult population. Future studies need to investigate whether pediatric population can equally benefit with simultaneous application of cyclosporine and trehalose. The impact of these eye drops on the thickness maps of epithelium also needs to be evaluated in future studies. Another avenue of research could be to investigate the anti-inflammatory effects of this combination of eye drops to manage inflammation and adverse responses in KC patients after surgical interventions.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eSimultaneous application of topical cyclosporine and trehalose appeared to arrest progression of KC in young adult eyes. A combination of change in Kmax and other parameters evaluated with AI showed that less than 5% of the eyes progressed over the follow-up period.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003es: None.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e: R.S., P.K, G.K., P.S., D.H., A.S., R.N. and A.S.R: analyses and writing of the manuscript; R.S., P.K., G.K. and A.S.R: conception, writing and critical review of the manuscript\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u0026nbsp;\u003c/strong\u003eThe data for this study was collected from the research database of Narayana Nethralaya eye hospital in Bangalore, India with permission. Due to patient privacy protection, the availability of the data is restricted and not publicly accessible. For any data access requests, contact Dr. Abhijit Sinha Roy at [email protected].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinancial Disclosure/Funding\u003c/strong\u003e: None\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eRabinowitz, Y.S. Keratoconus. \u003cem\u003eSurv Ophthalmol\u003c/em\u003e. \u003cstrong\u003e41\u003c/strong\u003e, 297-319 (1998).\u003c/li\u003e\n \u003cli\u003eLema, I. \u0026amp; Dur\u0026aacute;n, J.A. Inflammatory molecules in the tears of patients with keratoconus. \u003cem\u003eOphthalmology\u003c/em\u003e. \u003cstrong\u003e112\u003c/strong\u003e, 654\u0026ndash;9 (2005).\u003c/li\u003e\n \u003cli\u003eBalasubramanian, S.A., Pye, D.C. \u0026amp; Willcox, M.D.P. 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New insights on trehalose: a multifunctional molecule. \u003cem\u003eGlycobiology\u003c/em\u003e. 13, 17-27 (2003).\u003c/li\u003e\n \u003cli\u003eCejka, C., Kubinova, S. \u0026amp; Cejkova, J. Trehalose in ophthalmology. \u003cem\u003eHistol Histopathol\u003c/em\u003e. 34, 611-8 (2019).\u003c/li\u003e\n \u003cli\u003eMatsuo, T. Trehalose protects corneal epithelial cells from death by drying. \u003cem\u003eBr J Ophthalmol\u003c/em\u003e. 85, 610-2 (2001).\u003c/li\u003e\n \u003cli\u003ePanigrahi, T., Shivakumar, S., Shetty, R., D\u0026apos;souza, S., Nelson, E. J. R., Sethu, S., Jeyabalan, N. \u0026amp; Ghosh, A. Trehalose augments autophagy to mitigate stress-induced inflammation in human corneal cells. \u003cem\u003eOcul Surf\u003c/em\u003e. 17, 699-713 (2019).\u003c/li\u003e\n \u003cli\u003eShetty, R., Kundu, G., Narasimhan, R., Khamar, P., Gupta, K., Singh, N., Nuijts, R. M. M. A. \u0026amp; Sinha Roy, A. Artificial Intelligence Efficiently Identifies Regional Differences in the Progression of Tomographic Parameters of Keratoconic Corneas. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 37, 240-8 9 (2021).\u003c/li\u003e\n \u003cli\u003eMatalia, H., Narasimhan, R., Chinnappaiah, N., Kumar, V. \u0026amp; Sinha Roy, A. An interesting case of data gaps in measurement of corneal curvature with Scheimpflug tomography. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 36, 350-1 (2020).\u003c/li\u003e\n \u003cli\u003eAchiron, A., Yahalomi, T., Knyazer, B., Hecht, I., Elbaz, U., Spierer, O., Livny, E., Akowuah, P. K., Tuuminen, R. \u0026amp; Avadhanam, V. S. Efficacy comparison of combining cross-linking and refractive laser ablation in progressive keratoconus: systematic review and meta-analysis. \u003cem\u003eCan J Ophthalmol\u003c/em\u003e. 59, e661-e672 (2024).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGindina, S., Kang, J. J. \u0026amp; Jacobs, D. S. Scleral lenses for correction of irregular astigmatism: advances and limitations. \u003cem\u003eCurr Opin Ophthalmol\u003c/em\u003e. 36, 282-7 (2025).\u003c/li\u003e\n \u003cli\u003eMorales, P. \u0026amp; Dur\u0026aacute;n, J. A. Advances in Intracorneal Ring Segment (ICRS) Implantation for Keratoconus: A Comprehensive Literature Review, Clinical Insights, and Future Prospects. \u003cem\u003eJ Clin Med\u003c/em\u003e. 14, 4454 (2025).\u003c/li\u003e\n \u003cli\u003eLiu, Y., He, Y., Deng, Y. \u0026amp; Wang, L. Lenticule addition keratoplasty for the treatment of keratoconus: A systematic review and critical considerations. \u003cem\u003eIndian J Ophthalmol\u003c/em\u003e. 72 S167-S175 (2024).\u003c/li\u003e\n \u003cli\u003eRaiskup, F., Herber, R., Lenk, J., Pillunat, L. E. \u0026amp; Spoerl, E. Crosslinking with UV-A and riboflavin in progressive keratoconus: From laboratory to clinical practice - Developments over 25 years. \u003cem\u003eProg Retin Eye Res\u003c/em\u003e. 102, 101276 (2024).\u003c/li\u003e\n \u003cli\u003eKundu, G., Khamar, P., Modak, D., Mukherji, R., Bhatkal, A., Sinha Roy, A. \u0026amp; Shetty, R. Simultaneous Topography-guided Custom Ablation with Corneal Cross-linking for Keratoconus: 10-Year Prospective Outcomes. \u003cem\u003eJ Refract Surg\u003c/em\u003e. 39, 759-766 (2023).\u003c/li\u003e\n \u003cli\u003eYang, K., Tu, R., Xu, L., Gu, Y., Fan, Q., Yin, S., Yuan, Y., Chang, A., Wang, Y., Yin, C., Zang, Y., Pang, C., Oehring, D., Hao, Y. \u0026amp; Ren, S. Mediating roles of corneal biomechanical and topographic parameters in eye rubbing and keratoconus based on the Chinese keratoconus cohort study. \u003cem\u003eFront Bioeng Biotechnol\u003c/em\u003e. 13, 1595671 (2025).\u003c/li\u003e\n \u003cli\u003eShirzadeh, E., Shomoossi, N. \u0026amp; Hasani, H. On the urgency of air pollution control to manage chronic eye rubbing and probable risk of keratoconus. \u003cem\u003eJ Optom\u003c/em\u003e. 18, 100554 (2025).\u003c/li\u003e\n \u003cli\u003ePeris-Mart\u0026iacute;nez, C., Pi\u0026aacute;-Lude\u0026ntilde;a, J. V., Rog-Revert, M. J., Fern\u0026aacute;ndez-L\u0026oacute;pez, E. \u0026amp; Domingo, J. C. Antioxidant and Anti-Inflammatory Effects of Oral Supplementation with a Highly Concentrated Docosahexaenoic Acid (DHA) Triglyceride in Patients with Keratoconus: A Randomized Controlled Preliminary Study. \u003cem\u003eNutrients\u003c/em\u003e. 15, 1300 (2023).\u003c/li\u003e\n \u003cli\u003eBartolomeo, N., Pederzolli, M., Palombella, S., Fonteyne, P., Suanno, G., Tilaro, G., de Pretis, S., Borgo, F., Bertuzzi, F., Senni, C., De Micheli, M., Bandello, F. \u0026amp; Ferrari, G. The Effects of Vitamin D on Keratoconus Progression. \u003cem\u003eAm J Ophthalmol\u003c/em\u003e. 276, 235-251 (2025).\u003c/li\u003e\n \u003cli\u003eShetty, R., Ghosh, A., Lim, R. R., Subramani, M., Mihir, K., Reshma, A. R., Ranganath, A., Nagaraj, S., Nuijts, R. M., Beuerman, R., Shetty, R., Das, D., Chaurasia, S. S., Sinha-Roy, A. \u0026amp; Ghosh, A. Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A. \u003cem\u003eInvest Ophthalmol Vis Sci\u003c/em\u003e. 56, 738-50 (2015).\u003c/li\u003e\n \u003cli\u003eAslan, M. G., Fındık, H., Okutucu, M., Aydın, E., Oru\u0026ccedil;, Y., Arpa, M. \u0026amp; Uzun, F. Serum 25-Hydroxy Vitamin D, Vitamin B12, and Folic Acid Levels in Progressive and Nonprogressive Keratoconus. \u003cem\u003eCornea\u003c/em\u003e. 40, 334-341 (2021).\u003c/li\u003e\n \u003cli\u003eJamali, A., Hashemi, H., Nabovati, P. \u0026amp; Khabazkhoob, M. Progression and regression of keratoconus in an Iranian population. \u003cem\u003eSci Rep.\u003c/em\u003e 15, 28525 (2025).\u003c/li\u003e\n \u003cli\u003eKosekahya, P., Flockerzi, E., Munteanu, C., Sideroudi, H. \u0026amp; Seitz, B. Comparison of Keratoconus Progression Rate between Adolescents Aged 19-24 Years and Young Adults: Impact on Indication for Crosslinking. \u003cem\u003eCurr Eye Res\u003c/em\u003e. 50, 572-578 (2025).\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7607476/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7607476/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eA prospective, longitudinal case series on keratoconus (KC) eyes was studied where the eyes were treated with topical cyclosporine and trehalose. The study included 362 eyes of 181 patients. The eyes were followed up for a minimum period of 6 months. Corneal tomography was evaluated with Pentacam (OCULUS Optikgerate Gmbh, Germany) at 1st visit and at the last follow-up. Progression was initially evaluated based on change in maximum keratometry (Kmax). Then, this initial classification was assessed with an artificial intelligence model of 31 tomography variables of Pentacam to confirm the inference of progression based on Kmax alone. Based on a change in Kmax of 0.75, 1.0 and 1.25D criteria, more than 90% of the eyes were stable for each criteria at the last follow-up (initial classification). Further analysis with the AI revealed that less than 5% of the eyes had progressed at the last follow-up (final classification). Hence, topical cyclosporine and trehalose appeared to effectively stabilize KC and provide a suitable non-surgical option to manage the inflammation driving the disease.\u003c/p\u003e","manuscriptTitle":"Simultaneous topical application of cyclosporine and trehalose appears to keep keratoconus eyes stable: a prospective, longitudinal case series evaluated with artificial intelligence methods","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-20 13:18:03","doi":"10.21203/rs.3.rs-7607476/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"5ebd9d03-08a3-4625-a10d-999af08a35af","owner":[],"postedDate":"October 20th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":56517508,"name":"Health sciences/Diseases"},{"id":56517509,"name":"Health sciences/Health care"},{"id":56517510,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2026-02-26T08:55:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-20 13:18:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7607476","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7607476","identity":"rs-7607476","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}