EpiSmart Crosslinking for Keratoconus: A Phase 2 Study.

PURPOSE: The aim of this study was to assess changes in visual acuity after epithelium-on ("epi-on") corneal crosslinking after a diagnosis of keratoconus. METHODS: Subjects with corneal ectatic diseases were enrolled in a prospective, randomized, controlled, open-label, multicenter trial. Subjects were randomized to 1 of 3 treatment groups and treated with an epi-on crosslinking system including riboflavin/sodium iodide and pulsed UVA exposure (EpiSmart, CXL Ophthalmics, Encinitas, CA). The UVA treatment groups were 2.4 J/cm 2 over 20 minutes, 3.6 J/cm 2 over 20 minutes, and 3.6 J/cm 2 over 30 minutes. The primary end point was logarithm of the minimum angle of resolution corrected distance visual acuity (CDVA). Secondary end points were logarithm of the minimum angle of resolution uncorrected distance visual acuity (UCVA), maximum corneal curvature (Kmax), and minimum corneal thickness. Data were assessed 6 and 12 months post-operatively, using t -tests for differences from baseline. RESULTS: Two thousand two hundred twenty-eight subjects were treated with epi-on crosslinking. One thousand nine hundred twenty-two subjects had a diagnosis of keratoconus; other treated eyes had postsurgical and other ectasias. At 6 and 12 months, the subjects with keratoconus demonstrated significant improvements in CDVA, UCVA, and Kmax; minimum corneal thickness was unchanged. One hundred ninety-five subjects (8.7%) reported at least 1 adverse event (AE). A mild corneal epithelial defect was reported in 31 cases (1.4%) and was the only AE reported in >1% of subjects. There were no serious AEs related to the treatment. CONCLUSIONS: EpiSmart epi-on crosslinking resulted in mean improvements in CDVA, UCVA, and Kmax at both 6 and 12 months and an excellent safety and efficacy profile in subjects with keratoconus, with few significant side effects. Differences between UVA treatment groups were not significant.

Pachymetric Assessment After EpiSmart® Epithelium-on Cross-Linking for Keratoconus and Post-Surgical Ectasia.

Purpose: To assess the change in corneal pachymetry after a novel epithelium-on (EpiSmart®) corneal crosslinking procedure (CXL). Methods: Eyes treated as part of the open-label, non-controlled arm of the study "Collagen Crosslinking with Ultraviolet-A in Asymmetric Corneas" (NCT01097447) were examined at baseline, 3-, 6- and 12-months post-CXL. Thinnest pachymetry readings based on Pentacam (OCULUS GmbH, Wetzlar, Germany) were recorded. Results: A total of 101 eyes met the study inclusion criteria. Thinnest pachymetric readings at baseline averaged 451 ± 50 microns. The mean (± SD) minimum thickness was 450 ± 46 microns at 3 months, 452 ± 47 microns at 6 months, and 451 ± 48 microns at 12 months post-CXL. The changes from baseline (mean ± SE) at 3, 6, and 12 months post-CXL were -1.2 ± 1.5 microns, 0.5 ± 1.6 microns, and 0.4 ± 1.6 microns, respectively. Student's t-tests showed no statistically significant change in pachymetry from baseline for any exam period. Conclusion: This study demonstrated that, after EpiSmart® epithelium-on CXL, there was no substantial corneal thinning observable on Scheimpflug tomography out to 12 months.

The Effect of Sodium Iodide on Stromal Loading, Distribution and Degradation of Riboflavin in a Rabbit Model of Transepithelial Corneal Crosslinking.

PURPOSE: To evaluate effects of sodium iodide (NaI) on riboflavin concentration in corneal stroma before and during ultraviolet A (UVA) light exposure using a novel transepithelial corneal collagen crosslinking (CXL) procedure (EpiSmart CXL system, CXL Ophthalmics, Encinitas CA). METHODS: Riboflavin solutions with NaI (Ribostat, CXL Ophthalmics, Encinitas CA) and without NaI were used for CXL in rabbits using EpiSmart. A pilot study determined sufficient riboflavin loading time. Four rabbits were dosed and monitored. Riboflavin fluorescence intensity was assessed from masked slit-lamp photos. A 12 min loading time was selected. Sixteen additional rabbits received the two formulae in contralateral eyes for CXL. Riboflavin uptake was assessed at 0, 10, 15, 20, 25, and 30 min of UVA exposure using a scale for riboflavin fluorescence previously validated against stromal concentration. Post sacrifice, corneal stromal samples were analyzed for concentrations of riboflavin and riboflavin 5'-phosphate. RESULTS: Eyes dosed with NaI riboflavin had higher riboflavin grades compared to eyes dosed with the NaI-free riboflavin formulation immediately after riboflavin loading and persisting throughout UVA exposure, with significantly higher (P < 0.01 to < 0.05) riboflavin grades from 15 through 25 min of UVA exposure. Riboflavin grades decreased more slowly in eyes dosed with NaI riboflavin through 25 minutes of UVA exposure. Minor conjunctival irritation was noted with or without NaI. CONCLUSION: The addition of NaI to riboflavin solution is associated with increased riboflavin concentration in corneal stroma throughout a clinically relevant time course of UVA exposure. This effect may be a combination of enhanced epithelial penetration and reduced riboflavin photodegradation and should enhance intrastromal crosslinking.

Outcomes of Conductive Keratoplasty Combined with Corneal Crosslinking in Advanced Ectatic Corneal Disease.

PURPOSE: To assess the effectiveness of a novel treatment for patients with advanced corneal ectasia and loss of visual acuity (VA). Conductive keratoplasty (CK) is performed to improve VA followed by epithelium-on (epi-on) corneal crosslinking (CXL) to stabilize the cornea after CK. METHODS: Retrospective, exploratory cohort study. Patients with keratoconus or postsurgical ectasia and best spectacle-corrected distance VA (CDVA) ≤ 20/40 were included. Conductive keratoplasty was performed (ViewPoint CK System, Refractec, Inc., Bloomington, MN); followed a day later by epi-on CXL (CXLUSA/CXLO, Bethesda, MD/CXLO Encinitas, CA). Measures included uncorrected distance visual acuity (UDVA) and CDVA, as well as refractive and tomographic measures and tomographic indices. RESULTS: Data from 50 eyes of 45 patients were analyzed. Mean follow-up was 15.1 ± 12.2 months (range: 2 to 51). Overall, UDVA and CDVA improved postoperatively. Subjective refraction and tomographic metrics did not show consistent changes, but changes in tomographic indices were associated with treatment follow-up time. At the 1-year visit, mean UDVA significantly improved over baseline (P = 0.009) by approximately 3 lines; mean CDVA improved significantly (P = 10-5) by approximately 2 lines. No eye lost lines of CDVA. Change in the Index of Surface Variance (ISV) was associated with treatment, and the D-Index trended over follow-up time. CONCLUSION: Conductive keratoplasty with a proprietary epi-on CXL treatment improved vision in patients with advanced ectasia This CK/epi-on CXL treatment offers the possibility of improved VA for patients with compromised vision due to ectasia.

Corneal Cross-Linking: The Science Beyond the Myths and Misconceptions.

PURPOSE: There has been a recent explosion in the variety of techniques used to accomplish corneal cross-linking (CXL) for the treatment of ectatic corneal diseases. To understand the success or failure of various techniques, we review the physicochemical basis of corneal CXL and re-evaluate the current principles and long-standing conventional wisdom in the light of recent, compelling, and sometimes contradictory research. METHODS: Two clinicians and a medicinal chemist developed a list of current key topics, controversies, and questions in the field of corneal CXL based on information from current literature, medical conferences, and discussions with international practitioners of CXL. RESULTS: Standard corneal CXL with removal of the corneal epithelium is a safe and efficacious procedure for the treatment of corneal ectasias. However, the necessity of epithelium removal is painful for patients, involves risk and requires significant recovery time. Attempts to move to transepithelial corneal CXL have been hindered by the lack of a coherent understanding of the physicochemistry of corneal CXL. Misconceptions about the applicability of the Bunsen-Roscoe law of reciprocity and the Lambert-Beer law in CXL hamper the ability to predict the effect of ultraviolet A energy during CXL. Improved understanding of CXL may also expand the treatment group for corneal ectasia to those with thinner corneas. Finally, it is essential to understand the role of oxygen in successful CXL. CONCLUSIONS: Improved understanding of the complex interactions of riboflavin, ultraviolet A energy and oxygen in corneal CXL may provide a successful route to transepithelial corneal CXL.

Diffuse lamellar keratitis after epi-off corneal crosslinking: An under-recognized complication?

PURPOSE: To report diffuse lamellar keratitis (DLK) occurring in an eye that underwent epithelium-off (epi-off) corneal cross-linking (CXL) as a treatment for post-surgical ectasia and the successful treatment of progressive ectasia with a novel epi-on CXL and conductive keratoplasty (CK) treatment. OBSERVATIONS: A 42-year-old man presented with corneal ectasia in his right eye 3 years after laser in situ keratomileusis (LASIK) surgery. He underwent epi-off corneal CXL using the Dresden protocol. Grade II DLK was diagnosed within days of CXL. Despite successful treatment of DLK, best-corrected visual acuity in the right eye deteriorated over the next 4 months due to progression of ectasia and remained worse than the patient's pre-operative baseline 1 year after epi-off CXL. Because of apparent disease progression, despite his CXL treatment, the patient underwent a novel, transepithelial CXL (TE-CXL) treatment combined with conductive keratoplasty (CK). This treatment improved his vision and stabilized his ectasia without subsequent DLK. Approximately 3 years after CK and TE-CXL, his eye remains stable with 4 Snellen lines of improved vision and no progression of ectasia. CONCLUSION AND IMPORTANCE: Epithelium-off CXL is used increasingly to treat post-LASIK ectasia. First, in this case, DLK occurred after epi-off CXL. We suggest careful scrutiny of such cases as DLK is difficult to identify after epi-off CXL. Second, the epi-off CXL was unsuccessful in stopping the post-LASIK ectasia. Transepithelial CXL successfully treated the ongoing ectasia after resolution of the DLK with no subsequent re-occurrence of DLK. We suggest that TE-CXL may provide a successful initial treatment for post-LASIK ectasia that also minimizes the epithelial disruption that can lead to DLK.

Corneal crosslinking without epithelial removal.

PURPOSE: To evaluate the effect of riboflavin-ultraviolet (UV)-A corneal crosslinking (CXL) without epithelial removal on ectatic corneal disease. SETTING: Woolfson Eye Institute, Atlanta, Georgia, USA. DESIGN: Prospective observational study. METHODS: Patients were treated with a new riboflavin formulation without epithelial removal, then exposed to UV light (365 nm) at 4 mW/cm2 with on-off cycling for 30 minutes. Uncorrected (UDVA) and corrected (CDVA) distance visual acuities, maximum corneal curvature (maximum keratometry [Kmax]), total higher-order aberrations (HOAs), and coma were measured at 3, 6, 12, and 24 months postoperatively. Progression was defined as an increase of more than 1 diopter (D) in Kmax and loss of more than 1 line of CDVA. RESULTS: Five hundred twelve eyes of 308 patients with keratoconus or forme fruste keratoconus and 80 eyes of 55 patients with ectasia after laser in situ keratomileusis (LASIK) were treated with the new riboflavin formulation without epithelial removal; 229 patients received bilateral treatments, 95 of which were simultaneous. The mean UDVA and CDVA improved by 1 to 1.5 Snellen lines at 1 and 2 years postoperatively (P < .0001). Mean Kmax decreased by 0.48 D at 2 years postoperatively (P = .0002). Mean total HOAs and coma decreased by 36% (P < .0001) and 37% (P = .0002), respectively, at 2 years postoperatively. Kmax decreased more than 1 D in three times as many eyes as it increased more than 1 D (P < .0001). No eyes progressed, and there was no loss of effect between 1 and 2 years postoperatively. No vision-threatening events were observed. Pain typically resolved within 24 hours, and visual acuity returned to preoperative levels in 1 to 2 days. CONCLUSION: Epithelium-on CXL using this new protocol halted the progression of keratoconus and ectasia after LASIK. It was safer and provided more rapid visual recovery than CXL with epithelial removal, allowing routine bilateral, simultaneous treatment.

Quantitative analysis of corneal stromal riboflavin concentration without epithelial removal.

PURPOSE: To compare the corneal stromal riboflavin concentration and distribution using 2 transepithelial corneal crosslinking (CXL) systems. SETTING: Absorption Systems, San Diego, California, USA. DESIGN: Experimental study. METHODS: The stromal riboflavin concentration of 2 transepithelial CXL systems was compared in rabbit eyes in vivo. The systems were the Paracel/Vibex Xtra, comprising riboflavin 0.25% solution containing TRIS and ethylenediaminetetraacetic acid and an isotonic solution of riboflavin 0.25%, (Group 1) and the CXLO system (Group 2). Manufacturers' Instructions For Use were followed. The intensity of riboflavin fluorescence by slitlamp observation 10, 15, and 20 minutes after instillation was graded on a scale of 0 to 5. The animals were humanely killed and the corneal stromal samples analyzed with liquid chromatography and mass spectrometry. RESULTS: The mean riboflavin fluorescence intensity grades in Group 1 (4 eyes) were 3.8, 4.8, and 4.8 at 10, 15, and 20 minutes, respectively. The mean grades in Group 2 (3 eyes) were 2.0, 2.3, and 2.0, respectively. The riboflavin distribution was uniform in Group 1 but not in Group 2. The mean riboflavin concentration by liquid chromatography and mass spectrometry was 27.0 µg/g stromal tissue in Group 1 and 6.7 µg/g in Group 2. A stromal riboflavin concentration theoretically adequate for CXL, 15 µg/g, was achieved in all eyes in Group 1 and no eyes in Group 2. Slitlamp grading correlated well with liquid chromatography and mass spectrometry concentration (R2 = 0.940). CONCLUSIONS: The system used in Group 1 produced corneal riboflavin concentrations that were theoretically adequate for effective transepithelial CXL (≥15 µg/g), while the system in Group 2 did not. Slitlamp grading successfully estimated the corneal riboflavin concentration and can be used to ensure an adequate concentration of riboflavin in the cornea for transepithelial CXL.

Transepithelial crosslinking retreatment of progressive corneal ectasia unresponsive to classic crosslinking.

A 41-year-old man presented 10 years after uneventful laser in situ keratomileusis (LASIK) with symptomatic post-LASIK ectasia. He had treatment with the classic Dresden epithelium-off technique and presented 4 years later with progression of the ectasia. He was subsequently retreated with conductive keratoplasty (CK) followed by a new proprietary epithelium-on corneal collagen crosslinking (CXL) procedure using a proprietary transepithelial riboflavin formulation and delivery system on the following day. One year after retreatment, the patient noted stable vision in the treated eye with a corrected distance visual acuity (CDVA) of 20/60+. Thus, epithelium-on CXL, if performed with appropriate formulations and delivery technology as well as careful attention to appropriate riboflavin loading of the stroma, can stabilize an ectatic cornea. In addition, when performed prior to CXL, CK can induce a significant, lasting improvement in corneal shape and CDVA. This technique merits further study.

Vertical D: a novel topographic pattern in some keratoconus suspects.

PURPOSE: To describe a novel topographic curvature pattern, vertical D, which was present in some keratoconus suspects. This pattern was detected retrospectively in 2 patients who developed post-LASIK ectasia and prospectively in 4 patients who had other corneal abnormalities suggestive of keratoconus. DESIGN: Retrospective interventional case series and prospective cross-sectional study. PARTICIPANTS: After vertical D topographic curvature patterns were noted in 2 patients (3 eyes) who developed post-LASIK ectasia, 1168 consecutive potential refractive surgical candidates (2336 eyes) evaluated at a refractive center were screened to detect this vertical D pattern. METHODS: Placido disc-based curvature topography, ultrasound pachymetry, and elevation-based Scheimpflug topography were performed on these patients. MAIN OUTCOME MEASURES: Corneal curvature topographic patterns, central keratometry, inferior-superior and nasal-temporal ratios, skewed radial axis value, Humphrey Atlas PathFinder corneal analysis, corneal thickness, and corneal anterior and posterior elevation. RESULTS: Four additional patients (7 eyes) with vertical D patterns were found (prevalence, 0.34%). In addition to this vertical D pattern, these patients had central corneal thickness < 500 microm and/or posterior corneal protrusion > 20 microm or positive results on keratoconus detection analyses. The 10 eyes with the vertical D pattern had more horizontal (nasal-temporal ratio) than vertical (inferior-superior ratio) curvature asymmetry: 0.98+/-0.04 diopters versus 0.44+/-0.2 diopters (paired t test, P<0.001). CONCLUSIONS: We propose that vertical D is a novel corneal curvature pattern reflecting horizontal asymmetry that was present in keratoconus suspect patients even if standard keratoconus analyses' results were negative.

Methicillin-resistant Staphylococcus aureus infectious keratitis following refractive surgery.

PURPOSE: To elucidate risk factors, clinical course, visual outcomes, and treatment of culture-proven methicillin-resistant Staphylococcus aureus (MRSA) infectious keratitis following refractive surgery. DESIGN: Interventional case series. METHODS: Multicenter chart review of 13 cases of MRSA keratitis following refractive surgery and literature review. RESULTS: Thirteen eyes of 12 patients, nine of whom were either healthcare workers or exposed to a hospital surgical setting, developed MRSA keratitis following refractive surgery. All patients presented with a decrease in visual acuity and complaints of pain or irritation in the affected eye. Common signs on slit-lamp biomicroscopy were corneal epithelial defects, focal infiltrates with surrounding edema, conjunctival injection, purulent discharge, and hypopyon. All patients were diagnosed with infectious keratitis on presentation and treated with two antibiotics. All eyes were culture-positive for MRSA. CONCLUSIONS: According to a computerized MEDLINE literature search, this is the first case series of MRSA infectious keratitis following refractive surgery, the first reports of MRSA keratitis after refractive surgery in patients with no known exposure to a healthcare facility, the first report of MRSA keratitis after a laser in situ keratomileusis (LASIK) enhancement, and the first reports of MRSA keratitis after prophylaxis with fourth-generation fluoroquinolones. MRSA keratitis is a serious and increasing complication following refractive surgery. Patients with exposure to a healthcare environment should be considered at additional risk for developing MRSA keratitis. However, in addition, surgeons should now be vigilant for community-acquired MRSA. Prompt identification with culturing and appropriate treatment of MRSA keratitis after refractive surgery is important to improve visual rehabilitation.

To lift or recut: changing trends in LASIK enhancement.

PURPOSE: To report serious complications caused by recutting laser in situ keratomileusis (LASIK) flaps for enhancement and reconsider the current preferred method of LASIK enhancement. SETTING: Multiple surgeon practices. METHODS: This retrospective noncomparative nonconsecutive case series comprised LASIK patients in the private practices of 9 experienced refractive surgeons and those reported in a survey of refractive surgeons. Case histories, refractions, corneal topographies, slitlamp photographs, and measurements of uncorrected and best corrected (BCVA) visual acuity after recutting LASIK flaps were collected. Surveys of refractive surgeons and an analysis of changing practice trends among the authors and these surgeons were assessed. RESULTS: In 12 cases, significant loss of BCVA and subjective visual difficulties resulted from recutting LASIK flaps. Most surveyed surgeons had changed their practice from recutting to lifting flaps even 9 to 10 years postoperatively with good results. CONCLUSION: Recutting flaps for enhancement should be avoided unless other alternatives are unavailable.

Histologic and ultrastructural findings in human corneas after successful laser in situ keratomileusis.

OBJECTIVE: To examine the histologic and ultrastructural features of human corneas after successful laser in situ keratomileusis (LASIK) in 2 patients post mortem. METHODS: Portions of 4 corneas were processed for histology, transmission electron microscopy, and scanning electron microscopy. RESULTS: Case 1 had undergone LASIK 3 months prior to death and case 2 had undergone LASIK 20 months prior to death. A Hansatome (Bausch & Lomb Surgical Inc, Clarement, Calif) microkeratome with a 180-microm plate had been used for case 1 and an Automated Corneal Shaper (Chiron Corporation, Munich, Germany) with a 160-microm plate had been used for case 2. Histologically, the LASIK flap measured 160 microm and 150 microm in thickness in case 1 and case 2, respectively. Corneas from both cases exhibited minor epithelial ingrowth into the wound, reactive keratocytes at the wound margin, irregular collagen fibrils in the wound bed, and severed collagen bundles at the flap hinge. These findings were more pronounced in case 1 than in case 2, and the wound interface was virtually imperceptible in case 2. Additionally, the corneas from case 1 contained periodic acid-Schiff--positive electron dense material and wide-spaced collagen at the wound interface, and there was an absence of corneal nerves. CONCLUSIONS: These findings show that changes caused by wound repair that are present at 3 months are minor 20 months after LASIK.