Long-Term Outcomes After Corneal Cross-linking for Progressive Keratoconus and Corneal Ectasia: A 10-Year Follow-Up of the Pivotal Study.

OBJECTIVES: To report on the topographic and visual outcomes 10 years after corneal cross-linking in patients with progressive keratoconus and corneal ectasia after refractive surgery. METHODS: Cross-sectional cohort study of an original, prospective, randomized, clinical trial. Patients treated in a single center cornea and refractive surgery practice as part of the U.S. pivotal trials, which led to the Food and Drug Administration approval of corneal cross-linking, were recruited for a 10-year follow-up examination. LogMar lines (LL) of uncorrected visual acuity (UCVA) and best spectacle--corrected visual acuity (BSCVA), maximum keratometry, and thinnest pachymetry were evaluated. In addition, the Belin ABCD progression display was used to determine progression (95% confidence interval) of the anterior curvature, posterior curvature, and corneal thickness of each individual eye included. RESULTS: Nineteen eyes of 13 patients treated with standard cross-linking returned for a 10-year follow-up examination. Mean maximum keratometry changed from 58.2±12.0 diopters (D) to 58.3±10.1 D, thinnest pachymetry changed from 440.6±51.6 µm to 442.3±54.4 µm, UCVA changed from 0.79±0.42 LL to 0.86±0.46 LL, and BSCVA changed from 0.38±0.26 LL to 0.33±0.34 LL, 10 years after cross-linking. Individually, 68.5% of the entire cohort, 81.8% of keratoconus eyes, and 50% of eyes with corneal ectasia remained topographically stable 10 years after standard cross-linking. CONCLUSIONS: In the entire cohort, visual acuity and topography remained stable 10 years after cross-linking. Over the long-term, eyes with keratoconus seem to be more stable than those with corneal ectasia.

Results of corneal collagen cross-linking in patients with corneal ectasia after laser refractive surgery-A prospective study.

PURPOSE: To evaluate the safety and efficacy of epithelium-off (epi­off) corneal cross-linking (CXL) in patients with post-LASIK corneal ectasia (PLE) SETTING: Private clinical practice DESIGN: Prospective clinical trial METHODS: 82 eyes of adult patients post-LASIK, ages 21-67, with a topography pattern consistent with corneal ectasia, corrected distance visual acuity (CDVA) worse than 20/20, and minimum corneal pachymetry > 400 µm underwent epi­off CXL. Exclusion criteria were patients with corneas that were thinner than 400 µm or demonstrated central corneal scarring, history of herpetic eye disease, pregnancy or nursing. Follow up examinations of spherical equivalent, uncorrected distance visual acuity (UDVA), CDVA, steep keratometry (KSteep) and minimum pachymetry occurred on different but highly overlapping subsets of the operated eyes yearly until 5 years post-CXL. RESULTS: Over the 5 years of follow up, spherical equivalent did not significantly change while UCVA and CDVA stabilized or improved to a non-significant degree. KSteep and minimum pachymetry continued to be decreased to a statistically significant degree (p < 0.05 at 5 years). CONCLUSIONS: CXL in PLE patients is safe and efficacious: it halts progression of PLE and may improve visual function. KSteep and minimum pachymetry decrease post-CXL. Patients with PLE should be encouraged to stop progression of the disease by undergoing epi­off CXL once progression is established.

Therapeutic non-ectasia applications of cornea cross-linking.

Corneal cross-linking is a photopolymerization technique traditionally used to strengthen corneal tissue. Corneal cross-linking utilizes riboflavin (vitamin B2) as a photosensitizer and ultraviolet-A light (UVA) to create strong covalent bonds within the corneal stroma, increasing tissue stiffness. Multiple studies have demonstrated corneal cross-linking's effectiveness in treating corneal ectasia, a progressive, degenerative, and non-inflammatory thinning disorder, as quantified by key tomographic, refractive, and visual parameters. Since its introduction two decades ago, corneal cross-linking has surpassed its original application in halting corneal ectatic disease and its application has expanded into several other areas. Corneal cross-linking also possesses antibacterial, antienzymolytic and antioedematous properties, and has since become a tool in treating microbial keratitis, correcting refractive error, preventing iatrogenic ectasia, stabilising bullous keratopathy and controlling post keratoplasty ametropia. This review provides an overview of the current evidence base for the therapeutic non-ectasia applications of cornea cross-linking and looks at future developments in the field.

Subjective and objective evaluation of corneal haze after accelerated corneal crosslinking for corneal ectasias.

PURPOSE: To evaluate the relationship between subjective (slit lamp examination [SLE]) and objective (densitometry) measurements of corneal haze after accelerated corneal crosslinking (aCXL), assess the relationship between densitometry and corrected distance visual acuity (CDVA), and determine the effect of baseline characteristics on densitometry after aCXL in eyes with progressive keratoconus and other ectasias. SETTING: Kensington Eye Institute and Bochner Eye Institute, Toronto, Canada. DESIGN: Retrospective analysis of a prospective interventional cohort study. METHODS: Scheimpflug-derived corneal densitometry, CDVA, maximum keratometry (Kmax ), and central corneal thickness were measured preoperatively and up to 1 year after aCXL, and post-operative haze was estimated with SLE (n = 483 eyes). A random effect model was used to examine the relationship between post-operative subjective haze with SLE and densitometry. Linear mixed models were used to examine the relationship between densitometry, pre-operative baseline characteristics, and CDVA. RESULTS: There was a significant association between subjective haze with SLE and densitometry (p < 0.001). There was a significant relationship between CDVA and densitometry: for every 10 GSUs of increased densitometry in the 0-2 mm zone, CDVA worsened by approximately half a Snellen line (p < 0.001). Age and pre-operative Kmax were significant predictors of densitometry. For every 10 years of age, densitometry increased by 0.68 GSUs (95% CI [0.27 to 1.07], p < 0.001). For every 10 D of increased preoperative Kmax , densitometry increased by 0.69 GSUs (95% CI [0.41 to 0.98], p < 0.001). CONCLUSIONS: Subjective haze after aCXL estimated with SLE, is significantly associated with densitometry. Increased densitometry after aCXL is associated with a reduction in CDVA.

National survey of corneal cross-linking (CXL) practice patterns in the United Kingdom during 2019.

OBJECTIVE: To provide an insight into trends in corneal cross-linking (CXL) practice in the UK, including criteria for progression of corneal ectasia, identification of patients for CXL, the CXL procedure itself and post-operative management. METHODS: All ophthalmologist members of the UK Cross-linking (UK-CXL) Consortium were invited to complete an online survey about CXL practice for the year 2019. The data collected was anonymised by site and analysed with descriptive statistics. RESULTS: Responses were received from 16 individual CXL centres (16/38; 42% response rate) and the data represented ~2,000 CXL procedures performed in the UK in 2019. The commonest indication for CXL was progressive keratoconus. Between centres, there were variations in diagnostic evaluation, patient selection for CXL, the CXL procedure and the pre- and post-operative monitoring of patients. CONCLUSION: Consistent with the wide number of CXL treatment techniques described in the published literature world-wide, variations in the monitoring of corneal ectasia, indications for CXL, CXL practice and post-CXL follow-up were found to exist between UK-based CXL centres.

Three-Year Outcomes of Under-flap Stromal Bed CXL for Early Post-LASIK Ectasia.

PURPOSE: To investigate the 36-month clinical outcomes of under-flap stromal bed CXL (ufCXL) and report on its ability to stabilize post-laser in situ keratomileusis (LASIK) ectasia. METHODS: This case series included 20 eyes with diagnosed early post-LASIK ectasia treated with ufCXL. Inclusion criteria were early, mild post-LASIK ectasia, defined as new-onset postoperative manifest refraction cylinder of 1.50 diopters (D) or less, with new topographic inferior steepening consistent with ectasia, uncorrected distance visual acuity of 20/40 or better, and corrected distance visual acuity of 20/25 or better. The existing LASIK flap was lifted, 0.25% isotonic riboflavin was applied directly to the stromal bed, the flap was repositioned, and 18 mW/cm2 ultraviolet light was applied for 5 minutes to the corneal flap surface. Post-ufCXL ophthalmic data were compared to pre-ufCXL baseline measurements. RESULTS: Visual outcomes were maintained pre-ufCXL to 36 months post-ufCXL, with preserved safety index (P = .6545), efficacy index (P = .4980), spherical equivalent accuracy (P = .1536), defocus equivalent accuracy (P = .1032), central corneal thickness (P = .5196), and corneal irregularity indices at 3 mm (P = .8548) and 5 mm (P = .3399). Refractive astigmatism significantly decreased from 0.83 to 0.55 D pre-ufCXL to post-ufCXL (P = .0439), as did maximum keratometry from 42.40 to 42.00 D pre-ufCXL to post-ufCXL (P = .0420). The ufCXL demarcation line depth was 336 ± 21 µm post-ufCXL, with normal endothelial cell density (2,574 ± 203 cells/mm2). Only 1 of 20 eyes showed evidence of progression of 1.00 D in maximum keratometry. CONCLUSIONS: The ufCXL procedure shows promise in stabilizing early post-LASIK ectasia. Visual function, refractive astigmatism, maximum keratometry, and corneal irregularity indices were statistically maintained at 36 months postoperatively. [J Refract Surg. 2022;38(8):511-519.].

Dual Antiplatelet Therapy Versus Antiplatelet Monotherapy Plus Oral Anticoagulation in Patients with Acute Coronary Syndrome and Coronary Artery Ectasia: Design and Rationale of OVER-TIME Randomized Clinical Trial.

INTRODUCTION: The optimal anti-thrombotic therapy to prevent recurrent ischemic events in patients with acute coronary syndrome and coronary artery ectasia (CAE) remains unclear. AIM: To assess the efficacy and safety of antiplatelet plus anticoagulant therapy versus dual antiplatelet therapy in patients with acute coronary syndromes and coronary artery ectasia. METHODS: OVER-TIME is an investigator initiated, exploratory, open label, single center, randomized clinical trial comparing dual antiplatelet therapy (acetyl-salicylic acid plus a P2Y12 inhibitor) with the combination of an antiplatelet monotherapy (a P2Y12 inhibitor) plus a low dose anticoagulant (rivaroxaban, 15mg oral dose) for the prevention of recurrent ischemic events among patients with CAE. We aim to enroll approximately 60 patients with CAE and acute coronary syndromes. After recruitment, patients are randomized to (a) standard of care (dual antiplatelet regimen) or (b) the combination of antiplatelet monotherapy and low dose anticoagulant. Patients will be followed for at least 12 months. The OVER-TIME study aims to assess the efficacy of the regimen in prevention of major cardiovascular events and its security in bleeding events in acute coronary syndromes among patients with CAE. Expected results and conclusions: OVER-TIME is the first randomized controlled trial to assess different antithrombotic strategies in patients with CAE and acute coronary syndrome, and its results will offer preliminary data for the prevention of major cardiovascular events and bleeding events in this group of patients. TRIAL REGISTRATION NUMBER: NCT05233124 (ClinicalTrials.gov), date of registration: February 10, 2022.

Corneal Crosslinking for Progressive Keratoconus and Corneal Ectasia: Summary of US Multicenter and Subgroup Clinical Trials.

Purpose: The multicenter studies reviewed were designed to evaluate the safety and efficacy of corneal collagen crosslinking (CXL) for the treatment of progressive keratoconus and corneal ectasia after laser refractive surgery. The results of these studies led to approval by the United States Food and Drug Agency for both conditions in 2016. This paper reviews these studies, as well as single-center substudies investigating other aspects of crosslinking outcomes. Methods: As part of prospective, randomized, controlled clinical trials, the treatment group received standard CXL, and the sham control group received only riboflavin ophthalmic solution. The primary efficacy criterion was maximum keratometry (Kmax) 1 year after CXL. Secondary outcomes were corrected distance visual acuity (CDVA) and uncorrected distance visual acuity (UDVA). Safety and adverse events were analyzed. In single-center substudies, corneal topography, ocular aberrations, corneal haze measurements, corneal thickness, corneal biomechanics, subjective visual function, and outcomes predictors were also investigated. This paper presents a general review of the design and outcomes of crosslinking in these studies. Results: In the crosslinking treatment group, Kmax flattened by 1.6 diopters (D) and 0.7 D in eyes with keratoconus and ectasia, respectively. In both studies, there was continued progression in the control group. The CDVA improved by an average of 5.7 logMAR letters (LL) in the keratoconus treatment group and by 5.0 LL in the ectasia group. In both studies, corneal haze was the most frequently reported crosslinking-related adverse finding. This was most prominent at 1 month and generally returned to baseline between 3 and 12 months. In general, corneal topography, ocular aberrations, and subjective visual function improved after crosslinking. Conclusions: In the US multicenter trials, CXL was shown to be safe and effective in stabilizing Kmax, CDVA, and UDVA in eyes with progressive keratoconus or corneal ectasia. Translational Relevance: Corneal crosslinking was originally developed in the laboratory at the University of Dresden in the late 1990s. The combination of ultraviolet-A light and riboflavin was found to be the most effective of a number of different modalities tested to increase the biomechanical strength of the cornea. The clinical study design for the US multicenter clinical trials of crosslinking demonstrated the safety and effectiveness of this technique for treatment of progressive keratoconus and corneal ectasia, bringing this important advancement to patients in the United States.

Medical Therapies for Marfan Syndrome and Other Thoracic Aortic Dilatation in Adults: A Contemporary Review.

Thoracic aortic dilatation often has an asymptomatic course but may present with lethal complications such as aortic rupture or dissection, particularly when the thoracic aorta is aneurysmally enlarged; therefore, appropriate diagnosis, surveillance, and management are vital. Recommendations regarding imaging and surgical management are outlined in contemporary clinical practice guidelines. Dedicated guidelines regarding medical therapies for the management of thoracic aortic dilatation are lacking. Most of the medical treatment strategies, especially recommendations regarding pharmacological medical therapies related to ß-blockade and angiotensin receptor blockers, are derived from data on patients with Marfan syndrome. The main aims of medical therapies for the management of thoracic aortic dilatation are (1) to control the progression of the disease, and (2) to prevent complications related to the disease (such as aortic dissection and mortality). This paper reviews the contemporary evidence and highlights the gaps in evidence to be investigated in further studies.

Clinical outcomes of KeraVio using violet light: emitting glasses and riboflavin drops for corneal ectasia: a pilot study.

BACKGROUND/AIMS: We developed a novel technology consisting of violet light (VL)-emitting glasses and defined the combination of VL irradiation and riboflavin treatment as KeraVio. Our goal was to evaluate the clinical results of KeraVio in patients with progressive corneal ectasia. METHODS: Eyes were exposed to VL (375 nm, irradiance 310 µW/cm2)-emitting glasses for 3 hours daily for 6 months, and a riboflavin solution was administered onto the corneal epithelium six times during each 3-hour VL irradiation. The primary end point was a change in the maximum keratometry (Kmax) value over 6 months compared with that over the 1 year before baseline. RESULTS: The efficacy of KeraVio was evaluated in 20 eyes with severe progression, and its safety was evaluated in all 40 eyes. The mean changes in Kmax over the 1 year before baseline and during the 6-month observation period were 6.03±3.41 dioptres (D) and -0.81±3.34 D, respectively (p=0.002). At 6 months, the Kmax value decreased by more than 2 D in 4 eyes (20%), remained within 2 D in 13 eyes (65%), and increased by 2 D or more in 3 eyes (15%). The corneal stromal demarcation line was identified in 16 eyes (80%), and its depth was 206.3±54.9 µm at 1 month. No significant decrease in endothelial cell density, lenticular opacity or transient corneal haze was noted. CONCLUSION: Based on our 6-month results, daily treatment of progressive corneal ectasia with KeraVio can halt disease progression without any safety concerns. CLINICAL TRIAL REGISTRATION NUMBER: jRCTs032180217.

Effect of Losartan or Atenolol on Children and Young Adults With Bicuspid Aortic Valve and Dilated Aorta.

Bicuspid aortic valve aortopathy is defined by dilation of the aortic root (AoRt) and/or ascending aorta (AsAo), and increases risk for aortic aneurysm and dissection. The effects of medical prophylaxis on aortic growth rates in moderate to severe bicuspid aortopathy have not yet been evaluated. This was a single-center retrospective study of young patients (1 day to 29 years) with bicuspid aortopathy (AoRt or AsAo z-score ≥ 4 SD, or absolute dimension ≥ 4 cm), treated with either losartan or atenolol. Maximal diameters and BSA-adjusted z-scores obtained from serial echocardiograms were utilized in a mixed linear effects regression model. The primary outcome was the annual rate of change in AoRt and AsAo z-scores during treatment, compared with before treatment. The mean ages (years) at treatment initiation were 14.2 ± 5.1 (losartan; n = 27) and 15.2 ± 4.9 (atenolol; n = 18). Median treatment duration (years) was 3.1 (IQR 2.4, 6.0) for losartan, and 3.7 (IQR 1.4, 6.6) for atenolol. Treatment was associated with decreases in AoRt and AsAo z-scores (SD/year), for both losartan and atenolol (pre- vs post-treatment): losartan/AoRt: +0.06 ± 0.02 vs -0.14 ± 0.03, p < 0.001; losartan/AsAo: +0.20 ± 0.03 vs -0.09 ± 0.05, p < 0.001; atenolol/AoRt: +0.07 ± 0.03 vs -0.02 ± 0.04, p = 0.04; atenolol/AsAo: +0.21 ± 0.04 vs -0.06 ± 0.06, p < 0.001. Treatment was also associated with decreases in absolute growth rates (cm/year) for all comparisons (p ≤ 0.02). Medical prophylaxis reduced proximal aortic growth rates in young patients with at least moderate and progressive bicuspid aortopathy.

Transepithelial versus Epithelium-off Corneal Collagen Cross-linking for Corneal Ectasia: A Systematic Review and Meta-analysis.

TOPIC: To evaluate the safety and efficacy of transepithelial corneal cross-linking in comparison with the established epithelium-off technique for corneal ectasia. CLINICAL RELEVANCE: Considerable debate exists regarding whether transepithelial and epithelium-off cross-linking are comparable in their safety and efficacy. METHODS: We searched 16 electronic databases, including Medline, Embase, Web of Science, and the grey literature, current to July 8, 2020, for randomized controlled trials comparing transepithelial and epithelium-off cross-linking for corneal ectasia. We excluded studies evaluating cross-linking for nonectatic indications, as well as non-randomized controlled trials. Our primary outcome was the change in maximal keratometry (Kmax) at 12 months after cross-linking, and we considered additional topographic, visual, and safety outcomes. We summarized our analyses by calculating weighted mean differences (MDs) with associated 95% confidence intervals (CIs) for continuous outcomes and relative risks (RRs) with corresponding 95% CIs for dichotomous outcomes. We conducted trial sequential analysis to determine whether the required information size was met for each outcome. The quality of individual trials was evaluated using the Cochrane Collaboration's risk of bias assessment tool, and the evidence was assessed at an outcome level using the Grading of Recommendations Assessment, Development, and Evaluation methodology. RESULTS: Twelve studies totaling 966 eyes were eligible. A significant difference was found between transepithelial and epithelium-off cross-linking groups in the change in Kmax at 12 months (MD, 0.75; 95% CI, 0.23-1.28; P = 0.004; primary outcome) and at longest follow-up (MD, 1.20; 95% CI, 0.62-1.77; P < 0.001; secondary outcome) after treatment. No significant difference was found between the 2 groups when examining uncorrected distance visual acuity (MD, 0.04; 95% CI, -0.06 to 0.14; P = 0.386) or corrected distance visual acuity (MD, 0.01; 95% CI, -0.06 to 0.09; P = 0.732). Transepithelial cross-linking was associated with significantly fewer complications than the epithelium-off approach (RR, 0.22; 95% CI, 0.06-0.79; P = 0.020), although it was associated with an increased rate of disease progression at 12 months after treatment (RR, 4.49; 95% CI, 1.24-16.25; P = 0.022). The required information size was met for our primary outcome and trial sequential analysis supported the conventional meta-analysis. The quality of evidence was rated as moderate using the Grading of Recommendations Assessment, Development, and Evaluation methodology. DISCUSSION: The efficacy of transepithelial cross-linking remains inferior to the epithelium-off approach, although it is significantly safer.

The effects of losartan versus beta-blockers on cardiovascular protection in marfan syndrome: A systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Variable effects of beta-blockers (BB) and/or angiotensin receptor blockers (ARB) were reported to retard aortic root growth in Marfan syndrome (MFS). This study aimed to compare the effects of BB therapy and ARB-related therapies on cardiovascular protection in MFS. METHODS: Studies of randomized control trials comparing the efficacy of only-BB and ARB-related (only-ARB or ARB-plus-BB) therapies for MFS published before July 31, 2018 in PubMed, Embase, and the Cochrane Library were selected. The outcomes included changes in aortic growth and cardiovascular events. RESULTS: Eight trials involving 1381 patients were included. Patients received only-BB and ARB-related therapies did not differ significantly in changes in aortic growth (aortic root diameter: standardized mean difference [SMD] = 0.04, 95% confidence interval [CI]: -0.11-0.19, p = 0.63) or cardiovascular events (aortic dissection: Peto odds ratio [OR] = 1.67, 95% CI: 0.42-6.72, p = 0.47; aortic surgery: risk ratio = 0.97, 95% CI: 0.66-1.41, p = 0.86; death: Peto OR = 2.78, 95% CI: 0.39-19.82, p = 0.31). Subgroup analysis revealed that ARB-plus-BB therapy exhibited nonsignificantly better outcomes than only-BB therapy (aortic root diameter: SMD = 0.11, 95% CI: -0.22-0.45, p = 0.52; ascending aorta diameter: SMD = 0.10, 95% CI: -0.07-0.27, p = 0.26; aortic surgery: Peto OR = 1.10, 95% CI: 0.75-1.61, p = 0.62). CONCLUSION: For cardiovascular protection in MFS, only-ARB therapy is not inferior to only-BB therapy. Moreover, the outcomes of ARB-plus-BB therapy seemed to be favourable to those of only-BB therapy.

Corneal Scarring and Hyperopic Shift After Corneal Cross-linking for Corneal Ectasia After SMILE.

PURPOSE: To report a case of severe corneal scarring and hyperopic shift after corneal cross-linking (CXL) for the treatment of ectasia following small incision lenticule extraction (SMILE). METHODS: Case report and literature review. RESULTS: A 35-year-old man was referred with severe unilateral corneal haze that developed after CXL. The patient had undergone SMILE 4 years earlier in both eyes. Nineteen months postoperatively, the patient presented with bilateral decrease in vision and corneal topography revealed corneal ectasia in the right eye. CXL was performed in the right eye and a deep stromal haze was observed 1 year later. Comparative maps showed progressive corneal thinning with corresponding flattening that induced hypermetropization and astigmatism. CONCLUSIONS: CXL after SMILE in this original case resulted in severe deep corneal haze and corneal flattening with hyperopic shift. [J Refract Surg. 2018;34(11):779-782.].

Transepithelial versus epithelium-off corneal crosslinking for corneal ectasia.

This review compared the clinical results of transepithelial corneal crosslinking (CXL) to epithelium-off (epi-off) CXL in progressive corneal ectasia using a metaanalysis. The Cochrane databases and Medline were searched for randomized controlled trials (RCTs). Seven RCTs involving 505 eyes that met the eligibility criteria were identified. The epi-off CXL group showed significantly better outcomes in postoperative changes in maximum keratometry (K) during 1-year observation periods. Transepithelial CXL resulted in significantly greater post-treatment central corneal thickness and best spectacle-corrected visual acuity (BSCVA). The presence of a postoperative demarcation line was significantly more frequent after epi-off CXL than that after transepithelial CXL. No statistically significant difference was found between other parameters. Although patients in the transepithelial CXL group demonstrated a greater improvement in BSCVA compared with patients in the epi-off CXL group at the 1 year follow-up, transepithelial CXL had less impact on halting progressive corneal ectasia in terms of maximum K than epi-off CXL.