Deep anterior lamellar keratoplasty versus penetrating keratoplasty for treating keratoconus

Published version made available following 12 month embargo from date of publication (22 July 2014) in accordance with publisher copyright policy.BACKGROUND: Keratoconus is an ectatic (weakening) disease of the cornea, which is the clear surface at the front of the eye. Approximately 10% to 15% of patients diagnosed with keratoconus require corneal transplantation. This may be full-thickness (penetrating) or partial-thickness (lamellar). OBJECTIVES: To compare visual outcomes after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty for keratoconus, and to compare additional outcomes relating to factors which may contribute to poor visual outcomes (e.g. astigmatism, graft rejection and failure). SEARCH METHODS: We searched a number of electronic databases including CENTRAL, PubMed and EMBASE without using any date or language restrictions. We last searched the electronic databases on 31 October 2013. We also handsearched the proceedings of several international ophthalmic conferences. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing the outcomes of DALK and penetrating keratoplasty in the treatment of keratoconus. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted data independently. For dichotomous data (graft failure, rejection, achievement of functional vision) results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). For continuous data (postoperative best corrected visual acuity (BCVA), uncorrected visual acuity (UCVA), keratometric astigmatism and spherical equivalent) results were expressed as mean differences (MDs) and 95% CIs. MAIN RESULTS: We identified two completed studies, with a total of 111 participants (n = 30 and n = 81), both conducted in Iran, that met our inclusion criteria. Participants had moderate to severe keratoconus pre-operatively and were randomly allocated to receive either DALK or penetrating keratoplasty. Only one eye of each participant was treated as part of the trials. The smaller study had 12 month follow-up data for all participants. For the larger study, four DALK surgeries had to be abandoned due to technical failure and visual and refractive outcomes were not measured in these participants. Follow-up length for the remaining 77 participants ranged from 6.8 to 36.4 months, with all 77 followed for at least three months post-suture removal. Details of the randomisation procedure were unavailable for the smaller study and so sensitivity analyses were conducted to determine if the results from this study had affected the overall results of the review.Neither of the included studies reported a difference between groups on any of the measures of post-graft visual achievement, keratometric astigmatism or spherical equivalent. A single case of graft failure in a penetrating keratoplasty was reported. No postoperative graft failures were reported in the DALK group of either study.Instances of graft rejection were reported in both groups, in both studies. The majority of these cases were successfully treated with steroids. The data, which related to all cases in each study - given that the four cases that did not go ahead as planned had already technically failed without presence of rejection - showed that rejection was less likely to occur in DALK (odds ratio (OR): 0.33, 95% confidence interval (CI) 0.14 to 0.81, GRADE rating: moderate).Results of the sensitivity analysis indicated that inclusion of the Razmju 2011 study did not bias the results with regards to rejection episodes. While sensitivity analysis showed altered results with regards to failure rates, the data available from the Javadi 2010 study alone had a very wide 95% CI, suggesting an imprecise estimate. Therefore, even after removal of the Razmju 2011 data, it is still difficult to draw conclusions regarding superiority of one technique over another with regards to graft failure.DALK was unable to be completed as planned in four cases and in a further three cases, complications during dissection required further intervention. Other adverse events, of varying severity, were reported in both intervention groups with similar frequency. For both types of surgery, these included postoperative astigmatism, steroid induced ocular hypertension and persistent epithelial defects. In recipients of DALK, one participant had interface neovascularisation (a proliferation of blood vessels where the host and donor cornea come together) and one had wrinkling of Descemet's membrane, the basement membrane separating the corneal stroma from the corneal endothelium. In the penetrating keratoplasty groups, one participant required graft resuturing and one had an atonic pupil, a condition in which the pupil dilates and is non-reactive.Overall, the quality of the evidence was rated as very low to moderate, with methodological limitations, incomplete data analysis and imprecision of findings, as well as high risk of bias in several areas for both studies. AUTHORS' CONCLUSIONS: We found no evidence to support a difference in outcomes with regards to BCVA at three months post-graft or at any of the other time points analysed (GRADE rating: very low). We also found no evidence of a difference in outcomes with regards to graft survival, final UCVA or keratometric outcomes. We found some evidence that rejection is more likely to occur following penetrating keratoplasty than DALK (GRADE rating: moderate). The small number of studies included in the review and methodological issues relating to the two, mean that the overall quality of the evidence in this review is low. There is currently insufficient evidence to determine which technique may offer better overall outcomes - final visual acuity and time to attain this, keratometric stabilisation, risk of rejection or failure, or both, and risk of other adverse events - for patients with keratoconus. Large randomised trials comparing the outcomes of penetrating keratoplasty and DALK in the treatment of keratoconus are needed

The outcome of corneal transplantation in infants, children, and adolescents

© 2011. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/OBJECTIVE: To examine factors affecting penetrating corneal graft survival and visual outcomes in patients aged less than 20 years. DESIGN: Large prospective, cohort study. PARTICIPANTS: Records of 14 865 followed penetrating corneal grafts in 11 929 patients were searched to identify 765 grafts in 640 patients aged younger than 20 years of age at the time of graft. METHODS: Records submitted to the Australian Corneal Graft Registry by 381 ophthalmic surgeons and 253 follow-up practitioners from May 1985 to June 2009 were analyzed using Kaplan-Meier survival plots and Cox proportional hazards regression analysis. MAIN OUTCOMES MEASURES: Probability of corneal graft survival and Snellen acuity at the time of most recent follow-up and at defined intervals post-graft. RESULTS: Infants (<5 years) exhibited poorer graft survival than children aged 5 to 12 years. Adolescents (13-19 years) exhibited better corneal graft survival than other age groups; 86% of grafts in adolescents were for keratoconus. Factors significantly affecting corneal graft survival in pediatric patients included indication for graft, graft inflammation, history of intraocular surgery, vascularization, rejection episodes, post-graft operative procedures, and refractive surgery. Fourteen percent of pediatric grafts failed, of which 65% failed within 2 years post-graft. Forty-four percent of failures were due to unknown causes (18) or irreversible rejection (30). CONCLUSIONS: Corneal grafts for keratoconus in adolescents show excellent survival. Infants exhibit poor graft survival and visual outcomes, especially those undergoing transplantation for Peters' anomaly. Corneal graft survival and visual outcomes vary more by indication for graft than recipient age. The major reason for graft failure is irreversible rejection. Corneal transplantation improves overall bilateral vision in pediatric patients

Predictive genetic testing experience for myocilin primary open-angle glaucoma using the Australian and New Zealand Registry of Advanced Glaucoma

Author version made available in accordance with publisher copyright policy.Purpose: Predictive genetic testing of relatives of known myocilin (MYOC) gene mutation carriers is an appropriate strategy to identify individuals at risk for glaucoma. It is likely to prevent irreversible blindness in this high-risk group because this treatable condition might otherwise be diagnosed late. The Australian and New Zealand Registry of Advanced Glaucoma has established genetic testing protocols for known glaucoma genes, including MYOC. Methods: Through the Australian and New Zealand Registry of Advanced Glaucoma, we investigated the experience of 40 unaffected individuals who had undergone predictive genetic testing for MYOC mutations through questionnaires. Results: The main motivations for being tested were (i) to make appropriate interventions and (ii) to reduce uncertainty. All our respondents perceived strong benefits, either medical or emotional, in being tested. However, different concerns were raised by the respondents that need to be addressed during counseling. Greater family awareness was reported by the majority of the respondents, and the ability to provide information to children was a strong motivation for being tested. Conclusion: This study provides valuable information on the personal and familial impacts of having predictive genetic testing for glaucoma, which will help health professionals to better address the issues faced by patients and provide them adequate support

The Australian Corneal Graft Registry 2015 Report

The Australian Corneal Graft Registry (ACGR) opened in May 1985 and has now been operating for 30 years. Over the years, we have collected information on more than 30,000 corneal grafts. At registration, we seek information on the donor, eye bank practices, the recipient, the surgeon, the graft type and the operative procedure. Follow-up then occurs at approximately yearly intervals for an indefinite period, and ceases upon graft failure, or the death or loss-to-follow-up of the patient. At each round of follow-up, we request information on the survival of the graft, the visual outcomes, and any relevant post-operative events and treatments. The data are entered into an Access database and checked for consistency. Descriptive, univariate and multivariate analyses are subsequently performed using SPSS and Stata software, and the report is eventually collated.Eye Bank of South Australia, Lions New South Wales Eye Bank, Lions Eye Bank of Western Australia, Lions Eye Donation Service, Victoria, Queensland Eye Bank, The Australian Government Organ and Tissue Authority (DonateLife

The Australian Corneal Graft Registry 2012 Report

The Australian Corneal Graft Registry (ACGR) opened in May 1985 and thus has now been in operation for over 26 years. However, the census dates for this report was 01/06/2010 for penetrating grafts and 12/10/2011 for lamellar grafts. Over the years, we have collected data on more than 23,000 corneal grafts. The majority of corneal grafts registered have been penetrating, but increasing numbers of lamellar grafts have also been registered over recent years, as patterns of surgical practice change. At registration, we seek information on the recipient, the donor, the eye bank practices and the operative procedure. Follow-up then occurs at approximately yearly intervals for an indefinite period, and ceases upon loss of the graft, or the death or loss-to-follow-up of the patient. At each round of follow-up, we request information on the graft and visual outcome, and upon relevant post-operative events and treatments. The data are entered into an Access database and checked for consistency. Descriptive, univariate and multivariate analyses are subsequently performed using SPSS and Stata software, and the report is eventually collated

A comparison of endothelial and penetrating keratoplasty outcomes following failed penetrating keratoplasty: a registry study

Author version made available in accordance with publisher copyright policy.Purpose To compare graft survival and visual outcomes for endothelial keratoplasty (EK) after a first penetrating keratoplasty (PK), with outcomes of repeat PK after a first PK. Methods 400 eyes with a second graft (65 EKs, 335 PKs) performed after failure of a primary PK were identified through the Australian Corneal Graft Registry, a national prospectively followed cohort. Grafts were performed after January 2008 (follow-up of the second graft extending to 6.75 years maximum). Kaplan–Meier graft survival plots were constructed and Cox proportional hazards regression was used to identify independent risk factors for graft failure. Best-corrected Snellen visual acuity (BCVA) at last follow-up was compared with pregraft acuity. Results Poor Kaplan–Meier graft survival was observed for PK-EK compared with PK-PK (log-rank=29.66, p<0.001). Variables retained in multivariate analysis as significantly influencing survival of the second graft included graft type (PK-EK or PK-PK, p<0.001), length of survival of the previous PK (global p=0.011), graft era (global p=0.018), occurrence of rejection in the second graft (p=0.005) and a history of raised intraocular pressure at any time ( p=0.048), but not indication for the first graft. BCVA improved in the majority of surviving grafts and attainment of 6/12 vision was similar for both PK-EK and PK-PK groups. Conclusions Our registry findings suggest that repeat PK may deliver a better outcome in terms of graft survival than EK after a failed PK that was performed initially for keratoconus or pseudophakic bullous keratopathy. For surviving grafts, visual outcomes appeared equivalent across groups

The Australian Corneal Graft Registry 2018 Report

Copyright, All rights reserved.The Australian Corneal Graft Registry (ACGR) opened in May 1985 and has now been operating for 33 years. Over the years, we have collected information on more than 35,000 corneal grafts. At registration, we seek information on the donor, eye bank practices, the recipient, the surgeon, the graft type and the operative procedure. Follow-up then occurs at approximately yearly intervals for an indefinite period, and ceases upon graft failure, or the death or loss-to-follow-up of the patient. At each round of follow-up, we request information on the survival of the graft, the visual outcomes, and any relevant post-operative events and treatments. The data are entered into an Access database and checked for consistency. Descriptive, univariate and multivariate analyses are subsequently performed using SPSS and Stata software, and the report is eventually collated

DNA methylation at the 9p21 glaucoma susceptibility locus is associated with normal-tension glaucoma

“This is an Accepted Manuscript of an article published by Taylor & Francis in Ophthalmic Genetics on 21 Dec 2017, available online: http://www.tandfonline.com/10.1080/13816810.2017.1413659” This author accepted manuscript is made available following 12 month embargo from date of publication (Dec 2017) in accordance with the publisher’s archiving policyPurpose: Recent genome-wide association studies reported strong association of genetic variation at the CDKN2B/CDKN2B-AS1 locus on 9p21 with normal-tension glaucoma (NTG) in multiple populations. The mechanism by which this locus causes disease remains to be elucidated. We investigated the association of DNA methylation of CpG islands at this locus with NTG. Methods: We conducted a retrospective case–control study of 178 NTG cases and 202 unaffected controls from Australia. CDKN2B and CDKN2B-AS1 promoter methylation was measured quantitatively using the MassCleave assay, and assessed for association with the disease, and the genotype of the associated risk variants using IBM SPSS statistics 22.0 CpG sites at which methylation status was associated with NTG were validated using pyrosequencing. Results: We identified one CpG site (F1:13–14) in the CDKN2B promoter which showed significant association with NTG (p = 0.001). The association was highly significant in female cases (p = 0.006) but not in male cases (p = 0.054). The association was validated using an independent method confirming the likely association of DNA methylation with NTG in females (p = 0.015), but not in males (p = 0.497). In addition, methylation at CpG sites in CDKN2B was also associated with genotype at rs1063192, which is known to confer risk for NTG. Conclusion: This study reveals an association of methylation status in the CDKN2B promoter with NTG, particularly in females. This suggests that the observed genetic association with the disease at this locus could be in part due to epigenetic mechanisms, and is likely to be independent of the association of nonsynonymous coding variation within the gene

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)