Case of Progressive Keratoconus With Newly Diagnosed Pellucid Marginal Degeneration After Corneal Cross-Linking.

PURPOSE: The purpose of this study was to document, to our knowledge, the first reported case of keratoconus progression accompanied with newly diagnosed pellucid marginal degeneration after corneal cross-linking (CXL). METHODS: A novel case of further keratoconus progression plus development of pellucid marginal degeneration in the same eye after CXL was documented with supporting evidence from Scheimpflug and optical coherence tomography imaging. RESULTS: A male patient was diagnosed with progressive keratoconus in the left eye and treated with CXL when aged 25 years. Although strongly cautioned not to rub his eyes, he admitted that he continued eye rubbing in association with atopic disease. At a follow-up examination 3.5 years after CXL, progressive keratoconus was detected and pellucid marginal degeneration was newly diagnosed in the left eye. The eye was retreated with CXL. CONCLUSIONS: This case illustrates that progressive keratoconus and pellucid marginal degeneration can occur in the same eye after CXL and demonstrates the deleterious effects that can develop with continued eye rubbing.

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.

The histopathological findings in excised upper eyelids of patients with dermatochalasis following collagen cross-linking treatment.

PURPOSE: To evaluate the histopathological effects of collagen cross-linking (CCL) on excised skin samples of patients undergoing upper eyelid blepharoplasty due to dermatochalasis. METHODS: This study examined 74 excised eyelid skin samples from 37 dermatochalasis patients. Following an upper eyelid blepharoplasty, CCL with hypotonic riboflavin (0.1%) was applied. Both treated (right eyelid, CCL group) and untreated eyelid specimen (left eyelid, non-CCL group) sections were stained with hematoxylin-eosin and Masson's trichrome. The sections were evaluated for the following parameters: the collagen status (parallel, oblique, and perpendicular), the distance between collagen fibers, the diameter of collagen fibers, and the length of collagen fibers. RESULTS: There were no statistically significant differences in the collagen status, the distance between collagen fibers, the diameter of collagen fibers, and the length of collagen fibers between the CCL and non-CCL groups (p > 0.05 for all). Although the lack of statistically significant differences, the structure of the treated eyelid collagen fibers was more parallel in 48% of the participants than in the untreated ones. For male patients, a statistically significant shorter distance between collagen fibers was observed in the CCL group (8.05 ± 2.04 µm) compared to the non-CCL group (9.97 ± 2.33 µm) (p = 0.042). CONCLUSION: In this study, more parallel collagen structures and tightly packed collagen fibers were detected in eyelid samples following CCL treatment. The authors note that the results of this study may be promising for further research, so the effect of CCL therapy on the eyelid may be an interesting subject for the treatment of non-severe or surgically inadequately corrected dermatochalasis.

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.

Decreased Riboflavin Impregnation Time Does Not Increase the Risk for Endothelial Phototoxicity During Corneal Cross-Linking.

Purpose: To evaluate the riboflavin (RF) concentration and distribution in the corneal stroma and the risk for endothelial photodamage during corneal crosslinking (CXL) following 10- and 30-minute impregnation. Methods: De-epithelialized rabbit corneas were subjected to impregnation for 10 and 30 minutes with different RF formulations. Human corneal endothelial cells (HCECs) were subjected to different RF concentrations and ultraviolet A (UVA) dosages. Assays included fluorescence imaging, absorption spectroscopy of corneal buttons and anterior chamber humor, and cell viability staining. Results: After 10 and 30 minutes of impregnation, respectively, anterior chamber fluid showed an RF concentration of (1.6 ± 0.21)•10-4% and (5.4 ± 0.21)•10-4%, and trans-corneal absorption reported an average corneal RF concentration of 0.0266% and 0.0345%. This results in a decrease in endothelial RF concentration from 0.019% to 0.0056%, whereas endothelial UVA irradiance increases by 1.3-fold when changing from 30 to 10 minutes of impregnation. HCEC viability in cultures exposed to UVA illumination and RF concentrations as concluded for the endothelium after 10- and 30-minute impregnation was nonstatistically different at 51.0% ± 3.9 and 41.3 ± 5.0%, respectively. Conclusions: The risk for endothelial damage in CXL by RF/UVA treatment does not increase by shortened impregnation because the 30% increase in light intensity is accompanied by a 3.4-fold decrease of the RF concentration in the posterior stroma. This is substantiated by similar endothelial cell toxicity seen in vitro, which in fact appears to favor 10-minute impregnation. Translational Relevance: This study offers compelling arguments for (safely) shortening RF impregnation duration, reducing patients' burden and costly operation room time.

Corneal cross-linking versus standard care in children with keratoconus - a randomised, multicentre, observer-masked trial of efficacy and safety (KERALINK): a statistical analysis plan.

BACKGROUND: The KERALINK trial tests the hypothesis that corneal cross-linking (CXL) treatment reduces the progression of keratoconus in comparison to standard care in patients aged 10-16 years. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written before the end of the patient follow-up, while the outcome of the trial is still unknown. DESIGN AND METHODS: KERALINK is a randomised controlled, observer-masked, multicentre trial in progressive keratoconus comparing epithelium-off CXL with standard care, including spectacles or contact lenses as necessary for best-corrected acuity. Keratoconus is a disorder of the shape of the cornea in which the normally round dome-shaped clear front window of the eye (cornea) thins progressively leading to a cone-like bulge. This impairs the ability of the eye to focus properly, causing reduced vision which requires spectacle or contact lens wear or, in a minority of patients, eventually corneal replacement by a transplant for best vision. The primary outcome measure is the between-group difference in K2 at 18 months adjusted for K2 at baseline examination. K2 is the value of the steepest corneal meridian as measured on Pentacam topography. Secondary outcomes are keratoconus progression, time to keratoconus progression, visual acuity, refraction, apical corneal thickness and adverse events. Patient-reported effects will be explored by questionnaires. We describe in detail the statistical aspects of KERALINK: the outcome measures, the sample size calculation, general analysis principles, the planned descriptive statistics and statistical models, and planned subgroup and sensitivity analyses. DISCUSSION: The KERALINK statistical analysis will provide comprehensive and precise information on the relative effectiveness of the two treatments. The plan will be implemented in May 2020 when follow-up for the trial is completed. TRIAL REGISTRATION: EudraCT, 2016-001460-11. Registered on 19 May 2016.

The effects of chemical crosslinking manners on the physical properties and biocompatibility of collagen type I/hyaluronic acid composite hydrogels.

It is necessary to use chemical crosslinking to regulate the mechanical properties, biodegradability and biocompatibility of hydrogels. In this study, three kinds of collagen type I (Col I)/hyaluronic acid (HA) hydrogels with the same ratio and different chemical crosslinking manners were designed and fabricated, and the effects of chemical crosslinking manners on the physical properties and biocompatibility of hydrogels were investigated. The gelation time, mechanical property, swelling and degradability of hydrogels were characterized. Chondrocytes were encapsulated into these hydrogels to detect their effects on cell survival, proliferation, morphology and ECM secretion. Furthermore, the hydrogels were implanted into the back of SD rats to evaluate their biodegradability and biocompatibility in vivo. The results showed that chemical crosslinking manners of hydrogels could affect their physical properties to some extent. Chondrocytes encapsulated into these hydrogels showed a round or oval shape. ECM secretion of cells encapsulated in hydrogels increased with the elongation of culture duration, and cells encapsulated in hydrogels HA-sNHS/Col I (HSC) and HA-CHO/Col I (HCC) secreted more ECM than others. In vivo studies demonstrated that these hydrogels showed similar and acceptable inflammatory reaction.

Carboplatin-related acute interstitial nephritis in a patient with pancreatic neuroendocrine tumor.

Carboplatin is characterized by low nephrotoxicity, including acute tubular necrosis (ATN), compared to a conventional platinum complex due to its low accumulative property in the renal tubules. Therefore, there are extremely few reports of carboplatin-induced kidney injury and only one case has been histologically examined. Herein, we describe the case of a 53-year-old man who presented with acute kidney injury (AKI) that occurred after carboplatin administration and was diagnosed with biopsy-proven acute interstitial nephritis (AIN). To our knowledge, this is the second case report of carboplatin-related AIN. The patient was diagnosed with a pancreatic neuroendocrine tumor, and chemotherapy consisting of cisplatin and irinotecan was initiated. However, 1 week later, he was admitted to our institution with fever, fatigue and an increase in C-reactive protein (CRP) level. The chemotherapy regimen was altered to carboplatin and etoposide, but high fever occurred on the first day, and CRP re-elevation and AKI became apparent 9 days later. Renal biopsy revealed prominent inflammatory cell infiltration into the interstitium, which lead to the pathological diagnosis of AIN. On immunostaining for surface markers, CD3- and CD68-positive cells were found to be predominant, and CD20-positive cells were relatively few. Although the serum creatinine level increased to 6.81 mg/dL, it decreased to 1.43 mg/dL 15 days after steroid therapy. This case demonstrated that carboplatin-related kidney injury includes not only ATN but also AIN. Appropriate pathological diagnosis including renal biopsy and indications for steroid treatment should be carefully considered.

Severe focal stromal degeneration up to Descemet membrane after corneal collagen cross-linking.

Corneal collagen cross-linking (CXL) is an effective treatment for arresting progression in keratoconus cases. It is considered safe despite a few complications that have been recorded earlier. In this case series, we report a rare and late complication caused due to severe stromal thinning up to Descemet's membrane in three patients who underwent CXL 3 to 6 years back for keratoconus. Deep anterior lamellar keratoplasty (DALK) was then done for the affected eye with good outcomes. This case series highlights the possible late effects of UVA irradiation post CXL.

A randomised, controlled, observer-masked trial of corneal cross-linking for progressive keratoconus in children: the KERALINK protocol.

INTRODUCTION: The KERALINK trial tests the hypothesis that corneal cross-linking (CXL) treatment reduces the progression of keratoconus in comparison to standard care in patients under 17 years old. KERALINK is a randomised controlled, observer-masked, multicentre trial in progressive keratoconus comparing epithelium-off CXL with standard care, including spectacles or contact lenses as necessary for best-corrected acuity. METHODS AND ANALYSIS: A total of 30 participants will be randomised per group. Eligible participants aged 10-16 years with progressive keratoconus in one or both eyes will be recruited. Following randomisation, participants will be followed up 3-monthly for 18 months. The effect on progression will be determined by K2 on corneal topography. The primary outcome measure is between-group difference in K2 at 18 months adjusted for K2 at baseline examination. Secondary outcomes are the effect of CXL on (1) keratoconus progression, (2) time to keratoconus progression, (3) visual acuity, (4) refraction, (5) apical corneal thickness and (6) adverse events. Patient-reported effects will be explored by questionnaires. ETHICS AND DISSEMINATION: Research Ethics Committee Approval was obtained on 30 June 2016 (ref: 14/LO/1937). Current protocol: V.5.0 (08/11/2017). Study findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: European Union clinial trials register (EudraCT) 2016-001460-11.

Corneal Perforation After Corneal Cross-Linking in Keratoconus Associated With Potentially Pathogenic ZNF469 Mutations.

PURPOSE: To report a case of bilateral and repetitive corneal perforations after corneal cross-linking (CXL) for keratoconus in a woman harboring potentially pathogenic variants in the ZNF469 gene and to characterize the keratoconus phenotype in this woman and her daughter who shared the same ZNF469 mutations. METHODS: Clinical characterization of the proband and her daughter followed by sequencing of the genes associated with brittle cornea syndrome, ZNF469 and PRDM5, in both individuals. RESULTS: An Ashkenazi Jewish woman in her sixth decade presented with diffuse corneal thinning and progressive steepening consistent with keratoconus. After CXL, epithelium-off in the first eye and epithelium-on in the second, she developed spontaneous corneal perforations in each eye. Her daughter in her fourth decade demonstrated a similar pattern of diffuse corneal thinning and progressive corneal steepening but did not undergo CXL and did not develop corneal perforation. Screening of the ZNF469 and PRDM5 genes revealed 3 missense ZNF469 variants (c.2035G>A, c.10244G>C, and c.11119A>G) in cis arrangement on 1 allele of ZNF469 in both proband and her daughter. Although the 3 variants share low (<0.01) global minor allele frequencies, each has significantly higher minor allele frequencies (0.01-0.03) in the Ashkenazi Jewish population, leading to uncertainty regarding a pathogenic role for the identified variants. CONCLUSIONS: CXL may be associated with the development of corneal perforation in particular at-risk individuals with keratoconus. Identifying clinical and genetic risk factors, including screening of ZNF469 and PRDM5, may be useful in the prevention of significant complications after CXL.

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.].