A comparison of keratoconus progression following collagen cross-linkage using standard or personalised keratometry thresholds.

OBJECTIVE: To define how estimates of keratoconus progression following collagen cross-linking (CXL) vary according to the parameter selected to measure corneal shape. MATERIALS AND METHODS: We estimated progression following CXL in 1677 eyes. We compared standard definitions of keratoconus progression based on published thresholds for Kmax, front K2, or back K2, or progression of any two of these three parameters, with the option of an increased threshold for Kmax values ≥ 55D. As corneal thickness reduces unpredictably after CXL, it was excluded from the principal analysis. We then repeated the analysis using novel adaptive estimates of progression for Kmax, front K2, or back K2, developed separately using 6463 paired readings from keratoconus eyes, with a variation of the Bland-Altman method to determine the 95% regression-based limits of agreement (LoA). We created Kaplan-Meier survival plots for both standard and adaptive thresholds. The primary outcome was progression five years after a baseline visit 9-15 months following CXL. RESULTS: Progression rates were 8% with a standard (≥ 1.5D) threshold for K2 or 6% with the static multi-parameter definition. With a ≥ 1D threshold for Kmax, the progression was significantly higher at 29%. With adaptive Kmax or K2, the progression rates were similar (20%) but less than with the adaptive multi-parameter method (22%). CONCLUSIONS: Estimates of keratoconus progression following CXL vary widely according to the reference criteria. Using adaptive thresholds (LoA) to define the repeatability of keratometry gives estimates for progression that are markedly higher than with the standard multi-parameter method.

Laser-assisted cataract surgery versus standard ultrasound phacoemulsification cataract surgery.

BACKGROUND: Cataract is the leading cause of blindness in the world and, as such, cataract surgery is one of the most commonly performed operations globally. Surgical techniques have changed dramatically over the past half century with associated improvements in outcomes and safety. Femtosecond lasers can be used to perform the key steps in cataract surgery, such as corneal incisions, lens capsulotomy and fragmentation. The potential advantage of femtosecond laser-assisted cataract surgery (FLACS) is greater precision and reproducibility of these steps compared to manual techniques. The disadvantages are the costs associated with FLACS technology. OBJECTIVES: To compare the effectiveness and safety of FLACS with standard ultrasound phacoemulsification cataract surgery (PCS) by gathering evidence from randomised controlled trials (RCTs). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; which contains the Cochrane Eyes and Vision Trials Register; 2022, Issue 5); Ovid MEDLINE; Ovid Embase; LILACS; the ISRCTN registry; ClinicalTrials.gov; the WHO ICTRP and the US Food and Drug Administration (FDA) website. We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 10 May 2022. SELECTION CRITERIA: We included RCTs where FLACS was compared to PCS. DATA COLLECTION AND ANALYSIS: Three review authors independently screened the search results, assessed risk of bias and extracted data using the standard methodological procedures expected by Cochrane. The primary outcome for this review was intraoperative complications in the operated eye, namely anterior capsule, and posterior capsule tears. The secondary outcomes included corrected distance visual acuity (CDVA), quality of vision (as measured by any validated patient-reported outcome measure (PROM)), postoperative cystoid macular oedema complications, endothelial cell loss and cost-effectiveness. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 42 RCTs conducted in Europe, North America, South America and Asia, which enrolled a total of 7298 eyes of 5831 adult participants. Overall, the studies were at unclear or high risk of bias. In 16 studies the authors reported financial links with the manufacturer of the laser platform evaluated in their studies. Thirteen of the studies were within-person (paired-eye) studies with one eye allocated to one procedure and the other eye allocated to the other procedure. These studies were reported ignoring the paired nature of the data. There was low-certainty evidence of little or no difference in the odds of developing anterior capsular tears when comparing FLACS and PCS (Peto odds ratio (OR) 0.83, 95% confidence interval (CI) 0.40 to 1.72; 5835 eyes, 27 studies) There was one fewer anterior capsule tear per 1000 operations in the FLACS group compared with the PCS group (95% CI 4 fewer to 3 more).  There was low-certainty evidence of lower odds of developing posterior capsular tears with FLACS compared to PCS (Peto OR 0.50, 95% CI 0.25 to 1.00; 5767 eyes, 26 studies). There were four fewer posterior capsule tears per 1000 operations in the FLACS group compared with the PCS group (95% CI 6 fewer to same).  There was moderate-certainty evidence of a very small advantage for the FLACS arm with regard to CDVA at six months or more follow-up, (mean difference (MD) -0.01 logMAR, 95% CI -0.02 to 0.00; 1323 eyes, 7 studies). This difference is equivalent to 1 logMAR letter between groups and is not thought to be clinically important. From the three studies (1205 participants) reporting a variety of PROMs (Cat-PROMS, EQ-5D, EQ-SD-3L, Catquest9-SF and patient survey) up to three months following surgery, there was moderate-certainty evidence of little or no difference in the various parameters between the two treatment arms. There was low-certainty evidence of little or no difference in the odds of developing cystoid macular oedema when comparing FLACS and PCS (Peto OR 0.84, 95% CI 0.56 to 1.28; 4441 eyes, 18 studies). There were three fewer cystoid macular oedema cases per 1000 operations in the FLACS group compared with the PCS group (95% CI 10 fewer to 6 more).  In one study the incremental cost-effectiveness ratio (ICER) (cost difference divided by quality-adjusted life year (QALY) difference) was GBP £167,620 when comparing FLACS to PCS. In another study, the ICER was EUR €10,703 saved per additional patient who had treatment success with PCS compared to FLACS. Duration ranged from three minutes in favour of FLACS to eight minutes in favour of PCS (I2 = 100%, 11 studies) (low-certainty evidence).  There was low-certainty evidence of little or no important difference in endothelial cell loss when comparing FLACS with PCS (MD 12 cells per mm2 in favour of FLACS, 95% CI -40 to 64; 1512 eyes, 10 studies).  AUTHORS' CONCLUSIONS: This review of 42 studies provides evidence that there is probably little or no difference between FLACS and PCS in terms of intraoperative and postoperative complications, postoperative visual acuity and quality of life. Evidence from two studies suggests that FLACS may be the less cost-effective option. Many of the included studies only investigated very specific outcome measures such as effective phacoemulsification time, endothelial cell count change or aqueous flare, rather than those directly related to patient outcomes. Standardised reporting of complications and visual and refractive outcomes for cataract surgery would facilitate future synthesis, and guidance on this has been recently published.

ANTECEDENTES: La catarata es la principal causa de ceguera en el mundo y, como tal, la cirugía de cataratas es una de las operaciones más realizadas en todo el mundo. Las técnicas quirúrgicas han cambiado radicalmente en el último medio siglo, con las consiguientes mejoras en los desenlaces y la seguridad. Los láseres de femtosegundo se pueden utilizar para realizar los pasos clave de la cirugía de cataratas, como las incisiones corneales, la capsulotomía y la fragmentación del cristalino. La ventaja potencial de la cirugía de cataratas asistida por láser de femtosegundo (FLACS por sus siglas en inglés) es la mayor precisión y reproducibilidad de estos pasos en comparación con las técnicas manuales. Las desventajas son los costes asociados con la tecnología FLACS. OBJETIVOS: Comparar la eficacia y la seguridad de la FLACS con la cirugía de cataratas estándar por facoemulsificación (PCS) con ultrasonido mediante la recopilación de evidencia de ensayos controlados aleatorizados (ECA). MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en el Registro Cochrane central de ensayos controlados (Cochrane Central Register of Controlled Trials [CENTRAL]; que contiene el Registro de ensayos del Grupo Cochrane de Salud ocular y de la visión [Cochrane Eyes and Vision]; 2022, número 5); en Ovid MEDLINE; Ovid Embase; LILACS; el registro ISRCTN; ClinicalTrials.gov; la ICTRP de la OMS y el sitio web de la Food and Drug Administration (FDA) de los EE. UU. No se aplicaron restricciones de fecha ni de idioma en las búsquedas electrónicas de ensayos. La última búsqueda en las bases de datos electrónicas se realizó el 10 de mayo de 2022. CRITERIOS DE SELECCIÓN: Se incluyeron los ECA en los que la FLACS se comparó con la PCS. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Tres autores de la revisión examinaron de forma independiente los resultados de la búsqueda, evaluaron el riesgo de sesgo y extrajeron los datos mediante los procedimientos metodológicos estándar previstos por Cochrane. El desenlace principal de esta revisión fueron las complicaciones intraoperatorias en el ojo operado, concretamente, desgarros de la cápsula anterior y posterior. Los desenlaces secundarios incluyeron la agudeza visual corregida a distancia (AVCD), la calidad de la visión (medida por cualquier medida de desenlace notificada por el paciente [PROM] validada), las complicaciones posoperatorias del edema macular cistoide, la pérdida de células endoteliales y la coste­efectividad. La certeza de la evidencia se evaluó mediante el método GRADE. RESULTADOS PRINCIPALES: Se incluyeron 42 ECA realizados en Europa, Norteamérica, Sudamérica y Asia, que reclutaron un total de 7298 ojos de 5831 participantes adultos. En general, los estudios tuvieron riesgo de sesgo incierto o alto. En 16 estudios, los autores informaron vínculos financieros con el fabricante de la plataforma láser evaluada en sus estudios. Trece de los estudios fueron estudios intrapersonales (ojo pareado) con un ojo asignado a un procedimiento y el otro ojo asignado al otro procedimiento. El informe de estos estudios no consideró la naturaleza pareada de los datos. Hubo evidencia de certeza baja de poca o ninguna diferencia en las probabilidades de desarrollar desgarros de la cápsula anterior al comparar FLACS y PCS (odds ratio [OR] de Peto 0,83; intervalo de confianza [IC] del 95%: 0,40 a 1,72; 5835 ojos, 27 estudios). Hubo un desgarro de la cápsula anterior menos por cada 1000 cirugías en el grupo de FLACS en comparación con el grupo de PCS (IC del 95%: 4 menos a 3 más).  Hubo evidencia de certeza baja de menores probabilidades de desarrollar desgarros de la cápsula posterior con FLACS en comparación con PCS (OR de Peto 0,50; IC del 95%: 0,25 a 1,00; 5767 ojos, 26 estudios). Hubo cuatro desgarros de la cápsula posterior menos por cada 1000 cirugías en el grupo de FLACS en comparación con el grupo de PCS (IC del 95%: 6 menos a igual).  Hubo evidencia de certeza moderada de una ventaja muy pequeña en el grupo de FLACS con respecto a la AVCD a los seis meses o más de seguimiento, (diferencia de medias [DM] ­0,01 logMAR; IC del 95%: ­0,02 a 0,00; 1323 ojos, siete estudios). Esta diferencia equivale a 1 letra logMAR entre los grupos y no se considera clínicamente importante. De los tres estudios (1205 participantes) que informaron sobre una variedad de PROM (Cat­PROMS, EQ­5D, EQ­SD­3L, Catquest9­SF y encuesta de pacientes) hasta tres meses después de la cirugía, hubo evidencia de certeza moderada de poca o ninguna diferencia en los diversos parámetros entre los dos grupos de tratamiento. Hubo evidencia de certeza baja de poca o ninguna diferencia en las probabilidades de desarrollar edema macular cistoide al comparar FLACS y PCS (OR de Peto 0,84; IC del 95%: 0,56 a 1,28; 4441 ojos, 18 estudios). Hubo tres casos menos de edema macular cistoide por cada 1000 cirugías en el grupo de FLACS en comparación con el grupo de PCS (IC del 95%: 10 menos a 6 más).  En un estudio, el cociente coste­efectividad incremental (ICER) (diferencia de coste dividida por la diferencia de años de vida ajustados por la calidad [AVAC]) fue de 167 620 GBP al comparar FLACS con SCP. En otro estudio, el ICER fue de 10 703 euros ahorrados por paciente adicional que tuvo un tratamiento exitoso con PCS en comparación con FLACS. La duración varió entre tres minutos a favor de FLACS y ocho minutos a favor de PCS (I 2 = 100%, 11 estudios) (evidencia de certeza baja).  Hubo evidencia de certeza baja de poca o ninguna diferencia importante en la pérdida de células endoteliales al comparar la FLACS con la PCS (DM 12 células por mm 2 a favor de la FLACS; IC del 95%: ­40 a 64; 1512 ojos, 10 estudios).  CONCLUSIONES DE LOS AUTORES: Esta revisión de 42 estudios aporta evidencia de que probablemente haya poca o ninguna diferencia entre la FLACS y la PCS en cuanto a las complicaciones intraoperatorias y posoperatorias, la agudeza visual posoperatoria y la calidad de vida. La evidencia de dos estudios indica que la FLACS podría ser la opción menos coste­efectiva. Muchos de los estudios incluidos solo investigaron medidas de desenlace muy específicas, como el tiempo efectivo de facoemulsificación, el cambio en el recuento de células endoteliales o el brote acuoso, en lugar de las directamente relacionadas con los desenlaces de los pacientes. La notificación estandarizada de las complicaciones y los desenlaces visuales y refractarios de la cirugía de cataratas facilitaría la síntesis futura, y recientemente se han publicado guías al respecto.

Personalized Model to Predict Keratoconus Progression From Demographic, Topographic, and Genetic Data.

PURPOSE: To generate a prognostic model to predict keratoconus progression to corneal crosslinking (CXL). DESIGN: Retrospective cohort study. METHODS: We recruited 5025 patients (9341 eyes) with early keratoconus between January 2011 and November 2020. Genetic data from 926 patients were available. We investigated both keratometry or CXL as end points for progression and used the Royston-Parmar method on the proportional hazards scale to generate a prognostic model. We calculated hazard ratios (HRs) for each significant covariate, with explained variation and discrimination, and performed internal-external cross validation by geographic regions. RESULTS: After exclusions, model fitting comprised 8701 eyes, of which 3232 underwent CXL. For early keratoconus, CXL provided a more robust prognostic model than keratometric progression. The final model explained 33% of the variation in time to event: age HR (95% CI) 0.9 (0.90-0.91), maximum anterior keratometry 1.08 (1.07-1.09), and minimum corneal thickness 0.95 (0.93-0.96) as significant covariates. Single-nucleotide polymorphisms (SNPs) associated with keratoconus (n=28) did not significantly contribute to the model. The predicted time-to-event curves closely followed the observed curves during internal-external validation. Differences in discrimination between geographic regions was low, suggesting the model maintained its predictive ability. CONCLUSIONS: A prognostic model to predict keratoconus progression could aid patient empowerment, triage, and service provision. Age at presentation is the most significant predictor of progression risk. Candidate SNPs associated with keratoconus do not contribute to progression risk.

Accelerated Pulsed High-Fluence Corneal Cross-Linking for Progressive Keratoconus.

PURPOSE: To report on 2-year results of accelerated corneal collagen cross-linking (CXL) in progressive ectasia using the Avedro KXL system. DESIGN: Prospective interventional case series. METHODS: A total of 870 patients (1,192 eyes) attending Moorfields Eye Hospital after CXL were included. All patients undergoing CXL had progressive keratoconus. Corneas with a minimum stromal thickness <375 µm were excluded. Riboflavin 0.1% soak duration was 10 minutes. High-fluence pulsed UVA was delivered at 30 mW/cm2 for 4 minutes, with a 1.5-second on/off cycle (total energy 7.2 J/cm2). Subjective refractive, corneal tomography, and specular microscopy were performed at baseline, 6, 12, and 24 months postoperatively. The primary outcome measure was a change in maximum keratometry (Kmax) at 24 months. RESULTS: Twelve- and 24-month follow-up data were available on 543 and 213 patients, respectively (mean age 25.4 ± 6.6 years). In mild cones (Kmax < 55 diopter [D]), mean keratometry remained unchanged at 24 months. In more advanced disease, we observed modest corneal flattening compared to baseline (Kmax 63.2 ± 6.5 D vs 61.9 ± 8.1 D, P = .02), but no significant changes in central keratometry (K1 or K2). Keratometric stabilization was confirmed in 98.3% of eyes. Mean CDVA, manifest refraction and endothelial cell density did not change. Overall, 2.7% of eyes lost more than 2 lines of CDVA. CONCLUSION: Accelerated pulsed CXL is a safe, effective, and refractively neutral intervention (at 2 years) to halt disease progression in keratoconus.

Corneal transplantation after failed grafts: Options and outcomes.

Corneal transplantation is the most commonly performed human tissue transplantation procedure worldwide. Because of the large number of transplants, corneal graft failure has become one of the most common indications for corneal transplantation. The relatively recently developed lamellar transplant techniques have brought about specific potential complications leading to graft failure that may require different approaches to repeat transplantation other than penetrating keratoplasty. On the other hand, these new lamellar techniques also provide novel ways of rescuing failed penetrating grafts, with potential advantages over successive penetrating keratoplasties, such as reduced intraoperative risks and faster visual rehabilitation. We summarize the incidence and risk factors of graft failure for penetrating and lamellar (stromal and endothelial) corneal transplants and discuss the various surgical alternatives currently available to rescue such failed grafts, with a focus on the reported outcomes and limitations.

Femtosecond Laser-Assisted Deep Anterior Lamellar Keratoplasty for Keratoconus: Multi-surgeon Results.

PURPOSE: To compare the clinical outcomes in femtosecond laser-assisted deep anterior lamellar keratoplasty (F-DALK) to manual non-laser deep anterior lamellar keratoplasty (M-DALK) for keratoconus in a multi-surgeon public healthcare setting. DESIGN: Single-center, comparative, retrospective interventional case series. METHODS: Population: Consecutive cases of keratoconus treated with big-bubble F-DALK from August 1, 2015, to September 1, 2018 and big-bubble M-DALK from September 1, 2012, to September 30, 2016. SETTING: Moorfields Eye Hospital, London. OBSERVATIONS: Data on preoperative status, operative details, intraoperative and postoperative complications, secondary interventions, and visual outcomes were archived on a customized spreadsheet for analysis. MainOutcomeMeasures: Rate of intraoperative perforation and conversion to penetrating keratoplasty (PK) and the percentage of patients, post removal of sutures (ROS), with corrected distance visual acuity (CDVA) ≥20/40. RESULTS: We analyzed 58 eyes of 55 patients who underwent F-DALK and 326 eyes of 309 patients who underwent M-DALK. Intraoperative perforation of Descemet membrane occurred in 15 of 58 (25.9%) F-DALK cases compared to 148 of 326 (45.4%) M-DALK cases (P = .006). Intraoperative conversion to PK was carried out in 2 of 58 (3.4%) F-DALK cases compared to 80 of 326 (24.5%) M-DALK cases (P = .001). Post ROS, 86.5% of F-DALK eyes had a CDVA of ≥20/40 (15 ± 7.3 months after surgery) compared to 83.7% of M-DALK eyes (24.9 ± 10.6 months) (P = .825). CONCLUSION: Laser automation of some steps in DALK for keratoconus may reduce the rate of intraoperative Descemet perforation and the conversion to PK in a multi-surgeon setting.

Technique for pediatric corneal crosslinking under general anesthesia.

Corneal cross-linking (CXL) is typically performed under topical anesthesia, which may be unsuitable in children and individuals with severe anxiety, poor cooperation, or neurodevelopmental issues. We describe a technique of CXL under general anesthesia that uses sevoflurane and propofol with laryngeal airway or nasal oxygen cannulas, and forceps or microsponges to stabilize the eye position intraoperatively. We also developed a simple and time-saving technique of bilateral simultaneous CXL, whereby the second eye can undergo CXL concurrently with the first in a staggered fashion. Using this technique, we have been able to eliminate up to 25% of surgical time required in standard bilateral procedures. Postoperatively, multimodal analgesia was administered to ensure patient comfort and prevent excessive eye rubbing. In total, 21 eyes of 13 subjects ≤18 years of age were treated. During a median follow-up of 14.5 months (range, 4-43), the only complication observed was sterile corneal infiltrate in 1 eye that resolved with a short course of corticosteroids.

Royston-Parmar flexible parametric survival model to predict the probability of keratoconus progression to corneal transplantation.

PURPOSE: To assess a Royston-Parmar flexible parametric survival model to generate a personalised risk profile for keratoconus progression. METHODS: We re-analysed a historic database of 2723 individuals with keratoconus. A Royston-Parmar survival model was fitted to predict the likelihood of the worse eye progressing to corneal transplantation. We used a backwards selection multivariable fractional polynomial procedure to assist with selection of covariates and identify appropriate transformation(s) to retain in the final model. Time-dependent receiver operating characteristic (ROC) curves from censored survival data using the Kaplan-Meier (KM) method were computed to visually assess how well the model identified eyes likely to progress. RESULTS: In all, 5020 eyes from 2581 patients were available for model development. This included 2378 worst affected eyes, and 313 eyes that progressed to transplantation. The best fitting model [df = 1: Bayes information criterion (BIC) = 1573] included three variables, keratometry [hazard ratio (HR) 0.36: 95% confidence limits (CI) 0.32-0.42], age at baseline [HR 0.97: CI 0.95-0.99] and ethnicity [HR 3.92: CI 2.58-5.95]. Specificity at 1 year was 92.8% (CI 90.4-95.2%) with a corresponding sensitivity of 64.6% (CI 58.9-60.0%). These three prognostic factors account for 41.3% (CI 33.6 - 48.2%) of the variation among the survival curves. CONCLUSION: Researchers should consider the Royston-Parmar model as an alternative to the Cox model. We illustrate the concepts and our results may lead to better tools that identify individuals at high risk of keratoconus progression.

Genetic Variants Associated With Corneal Biomechanical Properties and Potentially Conferring Susceptibility to Keratoconus in a Genome-Wide Association Study.

IMPORTANCE: Keratoconus is an important cause of visual loss in young adults, but little is known about its genetic causes. Understanding the genetic determinants of corneal biomechanical factors may in turn teach us about keratoconus etiology. OBJECTIVES: To identify genetic associations with corneal biomechanical properties and to examine whether these genetic variants are associated with keratoconus. DESIGN, SETTING, AND PARTICIPANTS: A stage 1 discovery and replication genome-wide association study (GWAS) of corneal biomechanical properties was performed in 2 cross-sectional populations (6645 participants from the European Prospective Investigation into Cancer and Nutrition [EPIC]-Norfolk Eye Study and 2384 participants from the TwinsUK study). In stage 2, the association of genetic determinants identified in stage 1 with keratoconus was examined in a case-control study. A total of 752 patients with keratoconus were compared with 974 TwinsUK participants (undergoing direct sequencing) or 13 828 EPIC-Norfolk participants (undergoing genotyping and imputation) who were not part of the stage 1 analysis. Data were collected from March 1, 1993, through March 13, 2017, and analyzed from November 1, 2015, through February 1, 2018. EXPOSURES: In stage 1, allele dosage at genome-wide single-nucleotide polymorphisms (SNPs); in stage 2, allele dosage at SNPs with genome-wide significance (P < 5 × 10-8) in stage 1 and not previously reported as associated with corneal disease. MAIN OUTCOMES AND MEASURES: In stage 1, corneal hysteresis (CH) and corneal resistance factor (CRF), measured with the Ocular Response Analyzer (ORA); in stage 2, association with keratoconus compared with controls. RESULTS: Among 6645 participants in the discovery cohort (3635 women (54.7%); mean age, 69 years [range, 48-92 years]), 7 genome-wide significant loci associated with CH or CRF were identified that were independently replicated. Two further suggestive loci were identified after meta-analysis. To date, 5 of the identified loci, at ANAPC1, ADAMTS8, ADAMTS17, ABCA6, and COL6A1, have not previously been reported as associated with corneal disease. The ABCA6 locus (rs77542162) was associated with keratoconus using the TwinsUK (odds ratio [OR], 0.50; 95% CI, 0.27-0.92; P = .03) and EPIC-Norfolk controls (OR, 0.39; 95% CI, 0.22-0.70; P = .002). The other loci were associated with keratoconus using TwinsUK (OR per effect allele for ADAMTS8, 0.51 [95% CI, 0.37-0.71; P = 7.9 × 10-5]; for COL6A1, 1.65 [95% CI, 1.05-2.59; P = .03]) or EPIC-Norfolk (OR per effect allele for ANAPC1, 0.78 [95% CI, 0.68-0.89; P = 3.7 × 10-4]; for ADAMTS17, 0.82 [95% CI, 0.68-0.99; P = .04]) controls. CONCLUSIONS AND RELEVANCE: Five loci that are associated with corneal biomechanical properties and that have suggestive associations with keratoconus were reported. These findings suggest the role of type VI collagen, extracellular matrix, and connective-tissue development for corneal biomechanics and keratoconus and the role of CH and CRF as biomarkers for keratoconus.

Corneal and Scleral Problems Caused by Skin-Lightening Creams.

PURPOSE: To present a case series of patients with corneal and scleral changes associated with the use of skin-lightening creams. This is the first report of corneal changes with these widely available creams. METHODS: Three patients of West African origin presented with strikingly similar skin, corneal, and scleral changes and were found to have all been using skin-lightening creams containing hydroquinone. Histopathology was obtained for 1 patient. RESULTS: Three patients were referred to the corneal clinics of 2 hospitals with corneal changes and a history of blurred vision for 1 to 3 years. There was a 60-year-old woman from Nigeria and a 68-year-old woman and a 73-year-old man both from Ghana. All 3 had been using skin-lightening lotions containing hydroquinone on their faces for between 3 and 15 years and had black-blue facial pigmentation of exogenous ochronosis, a recognized complication of these creams. Their corneas all had horizontal striae radiating across the posterior corneas with scleral thinning and plaques. Linear brown epithelial pigmentation was observed within the lower third of the corneas. Biopsy of the sclera in 1 patient showed ochronosis. CONCLUSIONS: We present previously unreported eye changes associated with the use of skin-lightening creams containing hydroquinone, with a triad of signs: posterior corneal striae radiating from 3 o'clock to 9 o'clock, thinning and plaques in the sclera, and a normal endothelial cell count. Similar pathological changes are seen in exogenous ochronosis, a recognized skin complication of hydroquinone, are seen in the sclera.

Keratoconus Natural Progression: A Systematic Review and Meta-analysis of 11 529 Eyes.

PURPOSE: We set out to describe the natural history of keratoconus. We included untreated patients, and our key outcome measures were vision, refraction, and corneal curvature. CLINICAL RELEVANCE: Keratoconus affects 86 in 100 000 people, causing visual loss due to increasing irregular corneal astigmatism, and the quality of life declines in patients. Interventions are used to stabilize the disease or improve vision, including corneal cross-linking (CXL) and grafting, but these carry risks. Detailed knowledge of the natural history of keratoconus is fundamental in making informed decisions on when their benefits outweigh these risks. METHODS: We included prospective or retrospective studies of pediatric or adult patients who reported 1 or more of visual acuity, refraction, and corneal curvature measures: steep keratometry (K2), mean keratometry (Kmean), or maximum keratometry (Kmax), thinnest pachymetry, corneal transplantation rates, corneal scarring incidence, and patient-reported outcome measures (PROMs). Databases analyzed included Medline, Embase, CENTRAL, and CINAHL. Searches were carried out until October 2018. Bias assessment was carried out using the Joanna Briggs Institute model of evidence-based healthcare. RESULTS: Our search yielded 3950 publication titles, of which 41 were included in our systematic review and 23 were incorporated into the meta-analysis. Younger patients and those with greater Kmax demonstrated more steepening of Kmax at 12 months. The meta-analysis for Kmax demonstrated a significant increase in Kmax of 0.7 diopters (D) at 12 months (95% confidence interval [CI], 0.31-1.14; P = 0.003). Our meta-regression model predicted that patients had 0.8 D less Kmax steepening over 12 months for every 10-year increase in age (P = 0.01). Patients were predicted to have 1 D greater Kmax steepening for every 5 D of greater baseline Kmax (P = 0.003). At 12 months, there was a significant increase in the average Kmean of 0.4 D (95% CI, 0.18-0.65; P = 0.004). CONCLUSIONS: We report the first systematic review and meta-analysis of keratoconus natural history data including 11 529 eyes. Younger patients and those with Kmax steeper than 55 D at presentation have a significantly greater risk of progression of keratoconus. Closer follow-up and a lower threshold for cross-linking should be adopted in patients younger than 17 years and steeper than 55 D Kmax.

Cytomegalovirus infection is not a major cause of corneal graft failure in the United Kingdom.

BACKGROUND: Cytomegalovirus (CMV) endotheliitis is a significant cause for acute corneal allograft rejection in East Asian populations, where there is a high CMV seroprevalence. To determine how frequently CMV is associated with corneal graft failure in the UK, we looked for the presence of CMV DNA in grafts that had failed and had been removed at repeat keratoplasty. We also looked for CMV DNA in corneal rims discarded after corneal transplantation. METHODS: In this retrospective study, we identified 54 cases of corneal graft failure following endothelial rejection and 38 control grafts that had failed without a history of endothelial rejection. For these groups archived formalin-fixed paraffin-embedded (FFPE) tissue samples were retrieved. We also prospectively examined 80 non-fixed cornea rims following transplantation surgery. In all samples nested quantitative PCR was used to identify CMV, herpes simplex virus (HSV) and varicella zoster virus (VZV) DNA. We also used in situ hybridisation to examine for CMV DNA in the FFPE samples. RESULTS: No CMV or VZV DNA was detected in any of the archived case or control FFPE tissues. One corneal rim from the control group was positive for HSV. In situ hybridisation for CMV was negative for CMV in all FFPE samples. No CMV, VZV or HSV DNA was detected in the donor corneal rim samples. CONCLUSION: CMV DNA was not identified in excised failed corneal tissue or from tissue prior to transplantation. We infer that CMV infection is not a significant factor risk for corneal graft failure in the United Kingdom.

Combined wavefront-guided transepithelial photorefractive keratectomy and corneal crosslinking for visual rehabilitation in moderate keratoconus.

PURPOSE: To present 24-month results from the transepithelial photorefractive keratectomy (PRK)-corneal crosslinking (CXL) trial using simultaneous accelerated CXL and a new tissue-saving ocular wavefront-guided transepithelial PRK algorithm aiming to reverse visual loss in early-stage keratoconus without compromise to stabilization of disease progression. SETTING: Moorfields Eye Hospital, London, United Kingdom. DESIGN: Prospective case series. METHOD: Patients with progressive grades I to III keratoconus and logarithm of the minimum angle of resolution (logMAR) corrected distance vision acuity (CDVA) worse than 0.00 (20/20) were included. Consecutive matched historical controls treated only with accelerated CXL were the control group. The main outcome measure was change in logMAR CDVA. RESULTS: The study group comprised 47 eyes of 47 patients (mean age 24.6 years ± 3.8 [SD]). The CDVA improved from 0.28 ± 0.21 logMAR (20/60) preoperatively to 0.15 ± 0.14 logMAR (20/30) 24 months after transepithelial PRK-CXL (P < .001). Twelve eyes gained and 1 eye lost 2 lines or more of CDVA. The mean stromal ablation depth at the cone apex was 35 ± 15 µm. Significant reductions in the maximum keratometry (K) reading and coma were evident in topographic comparison maps. The controls (n = 47) had no significant changes in CDVA, higher-order aberrations, or K values. The mean K values in both groups were stable from 6 months after treatment. CONCLUSION: Ocular wavefront-guided transepithelial PRK-CXL resulted in significant gains in CDVA without compromising CXL efficacy over a 24-month follow-up.

Laser-assisted cataract surgery versus standard ultrasound phacoemulsification cataract surgery.

BACKGROUND: Cataract is the leading cause of blindness in the world, and cataract surgery is one of the most commonly performed operations in the Western world. Preferred surgical techniques have changed dramatically over the past half century with associated improvements in outcomes and safety. Femtosecond laser platforms that can accurately and reproducibly perform key steps in cataract surgery, including corneal incisions, capsulotomy and lens fragmentation, are now available. The potential advantages of laser-assisted surgery are broad, and include greater safety and better visual outcomes through greater precision and reproducibility. OBJECTIVES: To compare the effectiveness of laser-assisted cataract surgery with standard ultrasound phacoemulsification cataract surgery by gathering evidence on safety from randomised controlled trials (RCTs). SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 4), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to May 2016), EMBASE (January 1980 to May 2016), Latin American and Caribbean Health Sciences Literature Database (LILACS) (January 1982 to May 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en) and the U.S. Food and Drugs Administration (FDA) website (www.fda.gov). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 10 May 2016. SELECTION CRITERIA: We included randomised controlled trials where laser-assisted cataract surgery was compared to standard ultrasound phacoemulsification cataract surgery. We graded the certainty of the evidence using GRADE. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the search results, assessed risk of bias and extracted data using the standard methodological procedures expected by Cochrane. The primary outcome for this review was intraoperative complications in the operated eye, namely anterior capsule and posterior capsule tears. The secondary outcomes were visual acuity (corrected distance visual acuity (CDVA) and uncorrected distance visual acuity (UDVA)), refractive outcomes, quality of vision (as measured by any validated visual function score), postoperative complications and cost-effectiveness. MAIN RESULTS: We included 16 RCTs conducted in Germary, Hungary, Italy, India, China and Brazil that enrolled a total of 1638 eyes of 1245 adult participants. Overall, the studies were at unclear or high risk of bias. In 11 of the studies the authors reported financial links with the manufacturer of the laser platform evaluated in their studies. Five of the studies were within-person (paired-eye) studies with one eye allocated to one procedure and the other eye allocated to the other procedure. These studies were reported ignoring the paired nature of the data.The number of anterior capsule and posterior capsule tears reported in the included studies for both laser cataract surgery and manual phacoemulsification cataract surgery were low. There were four anterior capsule tears and one posterior capsule tear in 1076 eyes reported in 10 studies (2 anterior capsule tears in laser arms, 2 anterior capsule tears and 1 posterior capsule tear in standard phacoemulsification arms). We are very uncertain as to the effect of laser-assisted surgery compared to standard phacoemulsification surgery with respect to these two outcomes. For postoperative cystoid macular oedema and elevated postoperative intraocular pressures, again the evidence was inconclusive (odds ratio (OR) 0.58, 95% confidence interval (CI) 0.20 to 1.68; 957 eyes, 9 studies, low certainty evidence; and OR 0.57, 95% CI 0.11 to 2.86; 903 eyes, 8 studies, low certainty evidence).We found little evidence of any important difference in postoperative visual acuity between laser-assisted and standard phacoemulsification arms. There was a small advantage for laser-assisted cataract surgery at six months in CDVA. However, the mean difference (MD) was -0.03 logMAR (95% CI -0.05 to -0.00; 224 eyes, 3 studies, low certainty evidence) which is equivalent to 1.5 logMAR letters and is therefore, clinically insignificant. No studies reported patient-reported outcome measures such as visual function.There were no data reported on costs or resource use but three studies reported the time taken to do the surgery. There was little evidence of any major difference between the two procedures in this respect (MD 0.1 minutes, 95% CI -0.02 to 0.21; 274 eyes, low certainty evidence). AUTHORS' CONCLUSIONS: The evidence from the 16 randomised controlled trials RCTs included in this review could not determine the equivalence or superiority of laser-assisted cataract surgery compared to standard manual phacoemulsification for our chosen outcomes due to the low to very low certainty of the evidence available from these studies. As complications occur rarely, large, adequately powered, well designed, independent RCTs comparing the safety and efficacy of laser-assisted cataract surgery with standard phacoemulsification cataract surgery are needed. Standardised reporting of complications and visual and refractive outcomes for cataract surgery would facilitate future synthesis. Data on patient-reported outcomes and cost-effectiveness are needed. Paired-eye studies should be analysed and reported appropriately.

A Comparison of Different Corneal Iontophoresis Protocols for Promoting Transepithelial Riboflavin Penetration.

PURPOSE: To measure corneal riboflavin penetration using different transepithelial iontophoresis protocols. METHODS: Freshly enucleated rabbit eyes were divided into nine treatment groups of 4 eyes. One group, in which 0.1% wt/vol riboflavin was applied for 30 minutes without iontophoresis after corneal epithelial debridement, acted as a control. The remaining groups were treated with an intact epithelium using different riboflavin formulations and varying iontophoresis current, soak, and rinse times. After riboflavin application, eyes were snap frozen in liquid nitrogen. Corneal cross sections 35 µm thick were then imaged immediately by two-photon fluorescence microscopy, using image processing software to quantify stromal riboflavin concentration at different corneal depths. RESULTS: In the epithelium-on iontophoresis treatment groups, greater stromal riboflavin penetration was achieved with higher-concentration riboflavin solutions, greater iontophoresis dosage, and longer solution contact times. A protocol utilizing 0.25% wt/vol riboflavin with benzalkonium chloride (BAC) 0.01% and two cycles of applied current and subsequent soaking (1 mA 5 minutes, soak 5 minutes; 0.5 mA 5 minutes, soak 5 minutes) achieved similar stromal riboflavin penetration to epithelium-off controls. The best-performing non-BAC-containing protocol produced stromal riboflavin penetration approximately 60% that of epithelium-off controls. Riboflavin solutions containing saline resulted in minimal stromal penetration. Riboflavin loading within the epithelium was equivalent to or higher than that in the subjacent stroma, despite rinsing the ocular surface with balanced salt solution. CONCLUSIONS: Modified iontophoresis protocols can significantly improve transepithelial riboflavin penetration in experimental corneal collagen cross-linking.

Transepithelial Riboflavin Absorption in an Ex Vivo Rabbit Corneal Model.

PURPOSE: To measure depth-specific riboflavin concentrations in corneal stroma using two-photon fluorescence microscopy and compare commercially available transepithelial corneal collagen cross-linking (CXL) protocols. METHODS: Transepithelial CXL riboflavin preparations--MedioCross TE, Ribocross TE, Paracel plus VibeX Xtra, and iontophoresis with Ricrolin+--were applied to the corneal surface of fresh postmortem rabbit eyes in accordance with manufacturers' recommendations for clinical use. Riboflavin 0.1% (VibeX Rapid) was applied after corneal epithelial debridement as a positive control. After riboflavin application, eyes were snap frozen in liquid nitrogen. Corneal cross sections 35-µm thick were cut on a cryostat, mounted on a slide, and imaged by two-photon fluorescence microscopy. Mean (SD) concentrations were calculated from five globes tested for each protocol. RESULTS: Peak riboflavin concentration of 0.09% (± 0.01) was observed within the most superficial stroma (stromal depth 0-10 µm) in positive controls (epithelium-off). At the same depth, peak stromal riboflavin concentrations for MedioCross TE, Ricrolin+, Paracel/Xtra, and Ribocross TE were 0.054% (± 0.01), 0.031% (0.003), 0.021% (± 0.001), and 0.015% (± 0.004), respectively. At a depth of 300 µm (within the demarcation zone commonly seen after corneal cross-linking), the stromal concentration in epithelium-off positive controls was 0.075% (± 0.006), while at the same depth MedioCross TE and Ricrolin+ achieved 0.018% (± 0.006) and 0.016% (0.002), respectively. None of the remaining transepithelial protocols achieved concentrations above 0.005% at this same 300-µm depth. Overall, MedioCross TE was the best-performing transepithelial formulation. CONCLUSIONS: Corneal epithelium is a significant barrier to riboflavin absorption into the stroma. Existing commercial transepithelial CXL protocols achieve relatively low riboflavin concentrations in the anterior corneal stroma when compared to gold standard epithelium-off absorption. Reduced stromal riboflavin concentration may compromise the efficacy of riboflavin/ultraviolet corneal CXL.

Acanthamoeba sclerokeratitis: epidemiology, clinical features, and treatment outcomes.

PURPOSE: To describe the epidemiology, clinical features, and treatment outcomes of Acanthamoeba sclerokeratitis (ASK). DESIGN: Retrospective case series. PARTICIPANTS: All cases of both Acanthamoeba keratitis (AK) and ASK identified between January 1, 2000, and January 8, 2011, at Moorfields Eye Hospital. METHODS: Acanthamoeba keratitis was defined as the presence of AK with concurrent ipsilateral scleral inflammation. Topical steroids and oral nonsteroidal anti-inflammatory drugs (NSAIDs) were used as the first line of treatment. In unresponsive cases, oral NSAIDs were replaced by oral prednisolone with cyclosporine, azathioprine, or mycophenolate as steroid-sparing agents. Cyclosporine was combined with azathioprine or mycophenolate in cases unresponsive to only 1 of these drugs alone. MAIN OUTCOME MEASURES: Epidemiology, clinical phenotype, response to therapy, resolution of inflammation, visual outcome, corneal transplantation, and enucleation rate. RESULTS: From a series of 178 patients with AK, 36 eyes of 33 patients (18.5%) developed ASK. A total of 25 of 33 patients (76%) with ASK were tertiary referrals. The incidence of the disease in greater London was 0.13 per million, and the incidence in this population of patients with AK was 33 of 178 (18.5%). Mild scleritis/limbitis responsive to topical steroids and oral NSAIDs was present in 11 of 36 eyes (31%), and moderate/severe scleritis, requiring systemic immunosuppressive therapy, was present in 25 eyes (69%). Before the initiation of ASK treatment, 2 of 36 eyes (6%) had corrected distance visual acuity (CDVA) ≥ 20/40. The length of ASK treatment was 15.3 ± 20.7 months. The follow-up after discontinuation of scleritis treatment was 27.2 ± 31.8 months. An improvement in visual acuity was recorded in 23 of 36 eyes (64%). At the final visit, 13 of 36 eyes (36%) had CDVA ≥ 20/40. Control of scleral inflammation and pain was achieved in all but 2 eyes (2 enucleations). Cataract developed in 10 of 36 eyes (28%), and 14 of 36 eyes (39%) developed a persistent epithelial defect. Keratoplasty was performed in 21 of 36 eyes (58%), 9 therapeutic/tectonic and 12 for visual rehabilitation. Six eyes had more than 1 keratoplasty. The mild scleritis group had better outcomes in terms of visual improvement and need for keratoplasty. CONCLUSIONS: Acanthamoeba sclerokeratitis is associated with poor clinical outcomes. Management of ASK with anti-inflammatory/immunosuppressive treatment is usually effective in reducing both scleral inflammation and symptoms and possibly reduces the number of enucleations.