Combined simultaneous photorefractive keratectomy and collagen cross-linking in keratoconus suspect patients.

PURPOSE: To evaluate the safety and efficacy of combined simultaneous photorefractive keratectomy (PRK) with collagen cross-linking (CXL) in keratoconus suspects (KCS). METHODS: This was a retrospective, non-randomized study of KCS patients who underwent combined simultaneous PRK with CXL. The efficacy, safety, refractive outcomes, and corneal wavefront aberration changes were assessed after the surgery and compared with existing preoperative data. RESULTS: Fifty-six eyes of 28 patients, including 20 females (71.4%), with a mean age of 30.92±4.09 years, were enrolled. The mean follow-up was 19.46±8.48 months (range: 7-35). At the conclusion of the study, mean uncorrected distance visual acuity LogMAR improved from 0.89±0.44 preoperatively to 0.04±0.09 postoperatively (P<0.001). In addition, a statistically significant corneal flattening was observed postoperatively, with a decrease in manifest refraction. A statistically significant increase was found in higher-order aberrations (P<0.001), horizontal coma (P<0.001), and spherical aberration (P<0.001) compared with preoperatively. Postoperatively, 41% exhibited refractive astigmatism of 0.50 diopter (D) or less; 83.8% showed 1.00 D or less. CONCLUSION: The results of our study indicate that combined simultaneous PRK with CXL can be a safe and effective method for treating refractive instability in KCS patients.

Twin Premature Infants With Riboflavin and Biotin Deficiency Presenting With Refractory Lactic Acidosis, Rash, and Multiorgan Failure During Prolonged Parenteral Nutrition.

We are reporting monochorionic, diamniotic twin premature infants born at 25 weeks and 6 days gestation with riboflavin (vitamin B2) and biotin (vitamin B7) deficiency, while on prolonged total parenteral nutrition (TPN) during vitamin shortage. They presented initially with skin rash, lactic acidosis, and thrombocytopenia. Both twins progressed to severe respiratory failure, severe lactic acidosis, with refractory vasodilatory shock, pancytopenia, ischemic bowel injury, acute kidney injury, liver injury, and capillary leak syndrome leading to death of twin A. The surviving twin B was diagnosed with riboflavin and biotin deficiency that presented with abnormal metabolic work up suggestive of maple syrup urine disease, glutaric acidemia type 2, and X-linked adrenoleukodystrophy. Twin B was started on riboflavin and biotin supplementation at 41 days of life, with rapid improvement in clinical findings and laboratory abnormalities within days of starting biotin and riboflavin supplementation. He was discharged home in stable condition at 49 weeks of postmenstrual age.

Efficacy and safety of the combined metabolic medication, containing inosine, nicotinamide, riboflavin and succinic acid, for the treatment of diabetic neuropathy: a multicenter randomized, double-blind, placebo-controlled parallel group clinical trial (CYLINDER).

INTRODUCTION: Antioxidants may have positive impact on diabetic polyneuropathy (DPN), presumably due to alleviation of oxidative stress. We aimed to evaluate the efficacy and safety of combination of antioxidants: succinic acid, inosine, nicotinamide, and riboflavin (SINR) in the treatment of DPN. RESEARCH DESIGN AND METHODS: In a double-blind, placebo-controlled clinical trial, men and women aged 45-74 years with type 2 diabetes and symptomatic DPN, with initial Total Symptom Score (TSS) ˃5, were randomized into experimental (n=109) or placebo (n=107) group. Patients received study medication/placebo intravenously for 10 days, followed by oral administration for 75 days. Statistical significance was defined as a two-tailed p<0.05. RESULTS: In SINR group, mean TSS change after 12 weeks was -2.65 (±1.46) vs -1.73 (±1.51) in the placebo group (p<0.0001; t-test). Reduction of symptoms in the SINR group was achieved regardless of hemoglobin A1c levels, but better results were observed in patients with initial TSS <7.5. The analysis of TSS subscores revealed statistically significant between-group differences by dynamics of the intensity of paresthesia and of numbness starting from day 11 (p=0.035 and p=0.001, respectively; mixed model); by day 57, statistically significant between-group differences were detected also by dynamics of burning intensity (p=0.005; mixed model). Study limitations are small effect size, moderate proportion of patients with severe DPN symptoms, subjective assessment of outcomes, exclusion of participants who received injectable glucose-lowering medications other than insulins, and patients with uncontrolled and type 1 diabetes. CONCLUSIONS: The combination of SINR effectively alleviates DPN symptoms in patients with type 2 diabetes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT04649203; Unique Protocol ID: CTF-III-DM-2019).

Adverse events after riboflavin/UV-A corneal cross-linking: a literature review.

BACKGROUND: Riboflavin/UV-A corneal cross-linking (CXL) for treating keratoconus and iatrogenic corneal ectasia has been well-established as first treatment option to stabilize corneal tissue biomechanical instability. Although the plethora of clinical studies has been published into the field, there is no systematic review assessing the type and frequency of adverse events after CXL. METHODS: A systemic literature review on clinical safety and adverse events after CXL in patients with keratoconus and corneal ectasia was performed using PubMed. A literature search was performed for relevant peer-reviewed publications. The main outcome measures extracted from the articles were adverse events, endothelial cell density, corrected distance visual acuity and maximum simulated keratometry. RESULTS: The most frequent adverse events after CXL were corneal haze and corneal edema, which were mild and transient. The severe adverse events were infrequent (cumulative incidence: < 1.3%) after CXL. The clinical benefits of CXL highly outweighed the risks for the treatment of keratoconus and corneal ectasia. CONCLUSIONS: The severe adverse events with permanent sequelae are infrequent after CXL and all are associated with corneal de-epithelialization, such as infectious keratitis and corneal scarring.

Diffuse Lamellar Keratitis in a Patient Undergoing Collagen Corneal Cross-Linking 18 Years After Laser In Situ Keratomileusis Surgery.

PURPOSE: To report a case of diffuse lamellar keratitis (DLK) after corneal collagen cross-linking in an eye with a remote history of laser in situ keratomileusis (LASIK) surgery. METHODS: This is a case report and literature review. RESULTS: This report describes the development of unilateral stage IV DLK in a patient who underwent bilateral corneal cross-linking for corneal ectasia 18 years after LASIK surgery. The patient was treated with high-dose topical steroids that were tapered over 1 month and multiple flap lifts. The ultimate best-corrected visual outcome was 20/60. CONCLUSIONS: DLK is a potential sight-threatening complication of refractive surgery that can occur at any time in the postoperative period, even years after the procedure. Undergoing a subsequent corneal procedure that may disrupt or promote inflammation within the surgical flap-stromal interface, such as corneal collagen cross-linking, is a recognized risk factor for the development of DLK. This case suggests that patients with any history of LASIK surgery undergoing corneal cross-linking or other lamellar corneal surgeries may benefit from closer follow-up (eg, daily) than patients with no history of LASIK.

Apoptosis as an underlying mechanism in lymphocytes induced by riboflavin and ultraviolet light.

Riboflavin plus UV light pathogen reduction technology (RF-PRT) is an effective method for inactivating donor-derived leukocytes (DDLs) in blood components. Literature data have shown that reactive oxygen species (ROS) increased in lymphocytes after RF-PRT treatment. Sustained high levels of ROS may abolish the endogenous antioxidant system, leading to damage to proteins, lipids, and nucleic acids, resulting in cell apoptosis. Nevertheless, whether riboflavin plus UV light can trigger leukocyte apoptosis remains obscure. In this study, a pool-and-split design, ABO/D-matched lymphocytes treated with RF-PRT or UV light or left untreated. After treatment, the level of ROS and intracellular calcium were measured in samples. Changes in the protein expression of cleaved PARP, Bax, and Bcl-2 and the activities of caspase-3 and caspase-9 were determined by immunoblot analysis or luminometer, respectively. Cell apoptosis was evaluated by flow cytometry. The effect of ROS on apoptosis was assessed. The RF-PRT treatment significantly augmented ROS production, intracellular calcium concentration. The pro-apoptotic proteins expression levels of Bax, but did not the anti-apoptotic protein Bcl-2, were markedly increased after the RF-PRT treatment. Furthermore, the percentage of apoptotic cells was increased in RF-PRT-treated lymphocytes compared to UV-treated cells or untreated cells. Moreover, the inhibition of ROS generation partially neutralized the apoptosis effects of riboflavin plus UV treatment. These findings revealed that RF-PRT-treated lymphocytes significantly increase the proportion of apoptotic cells by promoting ROS generation delineation of the biochemical processes influenced by RF-PRT are a necessary step to provide novel insights into the riboflavin pathogen inactivation technology.

Safety and Efficacy of Corneal Cross-linking in Pediatric Patients with Keratoconus and Vernal Keratoconjunctivitis.

PURPOSE: The purpose of the study is to determine the safety and efficacy of corneal collagen cross-linking for keratoconus in pediatric patients with and without vernal keratoconjunctivitis (VKC). METHODS: This is a retrospective analysis of 89 eyes of 58 patients <18 years of age that underwent corneal collagen cross-linking for progressive keratoconus; inclusion criteria included a minimum of 2-year follow-up after cross-linking. The main outcomes measures included keratometry, pachymetry, vision, and complications following epithelial-off cross-linking with the Dresden protocol. RESULTS: VKC patients were more likely to be male; 81.6% of the non-VKC patients and 96.3% of VKC patients were male (P = 0.038). Comparing pretreatment to the 2-year follow-up, there was no statistically significant change in the mean steep or flat keratometry, corneal thickness, and uncorrected visual acuity or best spectacle-corrected visual acuity in either group. There were no statistically significant differences in the mean visual, keratometric, or adverse event outcomes between the two groups. The proportion exhibiting progression of ectasia at 2 years was 18.5% in the VKC group and 16.7% in the non-VKC group (P = 0.83). CONCLUSIONS: Cross-linking appears to be as safe and effective in pediatric patients with vernal keratoconjunctivits as in those without, with similar outcomes, adverse events, and progression of keratoconus after treatment. The proportion of patients exhibiting progression appears to be higher in pediatric patients than adults, and there is an association between male sex and diagnosis of VKC.

Sterile keratitis following standard corneal collagen crosslinking: A case series and literature review.

Standard corneal collagen crosslinking (S-CXL) is a safe, approved procedure, but it may result in severe pain, early vision loss and possible complications, such as infectious or sterile keratitis, in some cases. We describe four cases of sterile infiltrates after uneventful S-CXL for keratoconus, from diagnosis to medical management with six months of follow-up, reporting their pathophysiological features, and comparing our findings with published reports. We discuss various possibilities for diagnosing sterile infiltration more rapidly. In terms of the pathophysiology of sterile infiltrate formation, we separated our patients into two types, one with sterile infiltrate from an antigen reaction and the other with sterile infiltrate due to excessive scarring. Early local steroid treatment resulted in a good visual outcome in our cases.

Late-Onset Sterile Peripheral Ulcerative Keratitis Post-Corneal Collagen Crosslinking.

PURPOSE: To report the incidence, characteristics, clinical presentations, risk factors, and the available treatment modalities of sterile peripheral ulcerative keratitis (PUK) post-corneal collagen crosslinking (CXL). METHODS: This study is a retrospective study including 771 eyes of 474 patients operated for keratoconus or ectasia after LASIK between January 2010 and June 2017 at Beirut Eye & ENT Specialist hospital. The average follow-up period was 4.2 years with a minimum of 1 year post-CXL. RESULTS: Eleven eyes (1.4%) of 8 patients developed late-onset PUK with or without corneal haze and sterile infiltrates. The complications occurred between 3 months and 6 years postoperatively. Their mean age of 39.6 ± 7.1 years was higher than the age of the noncomplicated patients 21.9 ± 8.8 years (P = 0.0001). Four affected patients had inflammatory and autoimmune conditions. Sex, presence of intrastromal ring segments, mean keratometry, and the thinnest pachymetry were found to be insignificantly different between groups, and photorefractive keratectomy was performed more in patients with keratitis. Duration of ultraviolet light exposure was related to sterile ulcerative keratitis development. All patients responded to steroid treatment, and only one had a relapse which resolved with topical cyclosporine 1% drops. CONCLUSIONS: PUK is a rare but serious complication after CXL. Long-term follow-up is necessary to detect late-onset PUK. It is a treatable condition associated with older age and autoimmune conditions but has a good visual outcome.

Sterile keratitis after uneventful corneal collagen cross-linking in a patient with Axenfeld-Rieger syndrome.

PURPOSE: To report on a keratoconus (KC) patient with Axenfeld-Rieger syndrome (ARS) who developed sterile keratitis after accelerated corneal collagen cross-linking (CXL). METHODS: An 18-year-old patient with ARS and KC who had previously undergone intrastromal ring segment implantation underwent accelerated CXL (9 mW/cm2 UVA intensity for 10 min). RESULTS: After uneventful surgery, the patient presented with severe photophobia, redness of the eye, and decreased vision 72 h following the procedure. Slit-lamp examination showed anterior multiple superficial stromal infiltrates in the central cornea with an overlying epithelium defect. Due to the lack of pain and absence of any pathogen from corneal samples, a diagnosis of sterile keratitis was considered. A combination of topical antibiotic and corticosteroid regimen was administered. Three months after CXL slit-lamp examination showed a mild stromal scar overlying the central cornea, which did not decrease visual acuity. CONCLUSIONS: The mechanism by which the sterile keratitis occurs following CXL remains unclear. For our case, the reason of post-CXL sterile keratitis could be considered as an immune response due to the staphylococcal antigens. Furthermore, the possible developmental disturbance of corneal stroma in ARS might have contributed to the development of post-CXL sterile keratitis.

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.].

Automated Detection and Classification of Corneal Haze Using Optical Coherence Tomography in Patients With Keratoconus After Cross-Linking.

PURPOSE: To evaluate a proposed technology for offering objective grading and mapping of corneal haze as detected by corneal spectral domain optical coherence tomography after corneal cross-linking. METHODS: This was a retrospective study to evaluate corneal optical coherence tomography images performed on 44 eyes of 44 patients who underwent corneal cross-linking between January 2014 and May 2015, at the American University of Beirut Medical Center. RESULTS: Overall average brightness of the cornea was markedly increased from 43.4% (±6.0) at baseline to 50.2% (±4.4) at 1 month, 47.9% (±4.4) at 3 months, and 46.4% (±5.7) at 6 months with P <0.001, <0.001, and 0.005, respectively. In the anterior stroma, the average brightness significantly increased at 1, 3, and 6 months with values of 54.8% (±3.9), 52.5% (±5.2), and 49.7% (±6.9) with P <0.001, <0.001, and 0.003, respectively. In the mid stroma, the change was clinically significant at 1 and 3 months, whereas in the posterior stroma, it was only significant at 1 month compared with baseline (P = 0.003). Overall, haze was mostly present at 1 month after surgery in all regions, especially in the anterior (32.1%; ±19.2) and mid stromal regions (9.1%; ±18.8), P <0.001 and 0.001, respectively. In contrast, haze in the posterior stromal region peaks at 3 and 6 months after surgery. CONCLUSIONS: Anterior stromal haze was the greatest in intensity and area and it was present for a longer time span than mid and posterior stromal haze. At 12 months, the anterior stroma had still more haze intensity than preoperatively. This image-based software can provide objective and valuable quantitative measurements of corneal haze, which may impact clinical decision-making after different corneal surgeries.

Clinical Study of Mitomycin C in Reducing Haze Formation After Ultraviolet A/Riboflavin Crosslinking for Keratoconus.

OBJECTIVES: To evaluate the safety and efficacy of mitomycin C (MMC) in haze formation after ultraviolet A/riboflavin corneal crosslinking (CXL) for progressive keratoconus. METHODS: A total of 60 keratoconic eyes of 48 patients were enrolled in this prospective comparative study after obtaining informed consent. In the CXL group, standard corneal CXL was performed, whereas in the CXL+MMC group, 0.02% MMC was used for 30 s soon after CXL. Comprehensive ophthalmologic examinations were performed on all patients before surgery and at 1, 3, 6, and 12 months after surgery. RESULTS: The epithelium recovered within 3 to 4 days after CXL, and the healing time was comparable in the two groups. There was no significant endothelial cell density loss after CXL in both groups. Eyes in both groups showed improvement of uncorrected distance visual acuity (Snellen) and best-corrected visual acuity (Snellen; P<0.05), and there was a decrease in K-max, cylinder degree, and central corneal thickness (CCT) (P<0.05). There was no significant statistical difference between the groups regarding postoperative K-max reduction, refraction, and CCT (P>0.05). Corneal haze scores were significantly higher in the CXL group at 1 and 3 months after CXL (P=0.012 and P=0.028, respectively), but were similar to the MMC group at 6 and 12 months after surgery (P=0.329 and P=0.543, respectively). CONCLUSIONS: Prophylactic intraoperative use of 0.02% MMC can significantly reduce CXL-associated haze formation, especially in the early postoperative period, and no signs of weakening CXL efficacy were observed.

Comparison of Changes in Central Corneal Thickness During Corneal Collagen Cross-Linking, Using Isotonic Riboflavin Solutions With and Without Dextran, in the Treatment of Progressive Keratoconus.

PURPOSE: To compare intraoperative changes in central corneal thickness (CCT) during corneal cross-linking, using 2 different isotonic riboflavin solutions either with dextran or with hydroxy propyl methylcellulose, in the treatment of progressive keratoconus. METHODS: In this retrospective study, we analyzed records of corneal thickness measurements, taken during various steps of cross-linking. Cross-linking was performed using either isotonic riboflavin with dextran (group A) or isotonic riboflavin with hydroxy propyl methylcellulose (without dextran) (group B). CCT measurements were recorded before and after epithelial removal, after saturation with respective isotonic riboflavin solution, after use of hypotonic riboflavin in selected cases, and after ultraviolet A (UV-A) application. A mixed-way analysis of variance was conducted on CCT readings within each group and between both groups, and p < 0.05 was considered significant. RESULTS: In group A (100 cases), after saturation with isotonic riboflavin, CCT was decreased by a mean of 51.4 µm (12.1%). In 64%, CCT was <400 µm and additional hypotonic riboflavin was used. After UV-A irradiation, CCT was decreased by a mean of 46.7 µm (11.4%). In group B (100 cases), after saturation with isotonic riboflavin, CCT was increased by a mean of 109.4 µm (26.1%). After UV-A exposure, CCT was increased by a mean of 59.2 µm (11.2%). There was a substantial main effect for time on CCT during corneal cross-linking (CXL), p < 0.001, within both groups. The main effect comparing CCT readings between groups A and B was also significant, p < 0.001. CONCLUSIONS: During cross-linking, isotonic riboflavin with dextran causes a significant decrease in corneal thickness, whereas dextran-free isotonic riboflavin causes a significant increase in corneal thickness, thus facilitating the procedure.

The comparative safety of genipin versus UVA-riboflavin crosslinking of rabbit corneas.

PURPOSE: To investigate, after 24 h, the safety of genipin or ultraviolet A (UVA)-riboflavin crosslinking of keratocytes and endothelial cells. METHODS: Fifteen New Zealand white rabbits were selected and divided into a PBS group (five rabbits), a 0.2% genipin crosslinking (GP-CXL) group (five rabbits), and a UVA-riboflavin crosslinking (UVA-CXL) group (five rabbits). In the GP-CXL and PBS groups, 0.2% genipin or PBS was applied to the corneal surface of the right eyes. In the UVA-CXL group, a clinical crosslinking procedure was used. Before and after surgery, the operated eyes of each group were characterized with confocal microscopy, and the corneal buttons were excised for endothelium staining and electron microscopy. RESULTS: The corneal endothelial cell density of the GP-CXL, UVA-CLX, and PBS groups changed. There was a statistically significant difference in thickness and changes in corneal endothelial cell density between the UVA-CXL group and the PBS group (p<0.05), and between the UVA-CXL group and the GP-CXL group (p<0.05), but no statistically significant difference between the GP-CXL group and the PBS group. Confocal microscopy, transmission electron microscopy, and hematoxylin and eosin staining showed that there was keratocyte apoptosis in the anterior and middle stroma and endothelial cell damage in the UVA-CXL group. In the GP-CXL group, only active keratocytes were found and minimal endothelial cell damage. CONCLUSIONS: Treatment of rabbit corneas with 0.2% genipin showed minimal toxicity toward keratocytes and endothelial cells. Genipin is safer than UVA-CXL for crosslinking of thin corneas.

Sterile infiltrates after cross-linking. / Infiltrados estériles tras cross-linking.

CASE REPORT: A 20 year-old woman presented with an asymmetric bilateral keratoconus. Cross-linking of the right eye was performed due of its topographic and pachymetric conditions. Three days after the procedure, the patient presented with some corneal infiltrates that where classified as sterile. DISCUSSION: Cross-linking is known for its efficacy and safety. Nevertheless, there can be complications. Sterile infiltrates have already been described, although their aetiology is still not clear.

[Complications and postoperative therapeutic strategies in cross-linking]. / Komplikationen und postoperative Therapiestrategien beim Crosslinking.

CLINICAL ISSUE: The reduced corneal mechanical stability in keratoconus and similar collagen diseases can lead to a progressive and irregular corneal shape and decrease of visual acuity. DIAGNOSTICS: A progression of keratectatic diseases can be shown with corneal topography. TREATMENT: Keratoconus can be treated by photo-oxidative cross-linking of the corneal collagen. In order to achieve a high absorption of irradiation energy in the cornea, riboflavin at a concentration of 0.1% and UVA light at a wavelength of 370 nm corresponding to the relative maximum absorption of riboflavin (vitamin B2) are used. Evidence for corneal cross-linking are the increase of biomechanical stiffness, the increased resistance against enzymatic degradation, a higher shrinkage temperature, a lower swelling rate and an increased diameter of collagen fibers. The currently available data demonstrate that the therapeutic cross-linking procedure is safe when respecting the important theoretical and clinical parameters and that a progression of the keratoconus can be avoided. In 80% of cases an average levelling of the curvature of approximately 2 dpt can be achieved, which leads not only to stabilization but also to an increase in visual acuity of approximately 1.2 lines. ASSESSMENT: In a Cochrane review from 2015 publications about complications and results were reviewed. Complication rates ranged from 1-10% depending on the initial situation, comorbidities and stage of the keratoconus. The most important complications are early epithelial wound healing problems as well as extremely rare perforations. PRACTICAL RECOMMENDATIONS: Corneal cross-linking is a well-established and safe procedure but is not free of complications.