D. F. P. Larkin

Penetrating and Deep Anterior Lamellar Keratoplasty for Keratoconus: A Comparison of Graft Outcomes in the United Kingdom

PURPOSE To compare outcomes after penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) for keratoconus in the United Kingdom. METHODS Patient outcome data were collected at the time of transplantation and at 1, 2, and 5 years after surgery. Data were analyzed by Kaplan-Meier survival curves, Cox regression, and binary logistic regression to determine the influence of surgical procedure on graft survival and visual outcome. RESULTS The risk of graft failure for DALK was almost twice that for PK (P = 0.02). Nineteen percent of the DALK failures occurred in the first 30 postoperative days compared with only 2% of PK failures. When these early failures were excluded, there was little difference between the 3-year graft survivals for DALK (92%; 95% confidence interval [CI], 85%-95%) and PK (94%; 95% CI, 92%-95%) (P = 0.8). Although the mean best corrected visual acuity (BCVA) was similar for the two procedures (P = 0.7), 33% of patients who underwent PK achieved a BCVA of 6/6 or better at 2 years compared with only 22% of those who underwent DALK (P < 0.001). Those with DALK were also likely to be more myopic (< -3 D) but there was little difference in scalar cylinder. CONCLUSIONS DALK had a higher overall failure rate than PK. The difference was largely accounted for by early failures, which appeared to be related to the surgeons experience. DALK recipients were less likely to achieve BCVA of 6/6 than were PK recipients and were more likely to have -3 D or worse myopia.

The effect of perioperative allergic conjunctivitis on corneal lymphangiogenesis after corneal transplantation

Introduction Perioperative allergic conjunctivitis accelerates the speed of corneal allograft rejection. This study examines the effect of allergic conjunctivitis, with and without dexamethasone treatment, on the early inflammatory response and lymphangiogenesis in the host cornea following corneal transplantation. Methods Allogeneic fully MHC-mismatched C57Bl/6 strain donor corneas were transplanted into naive A/J mice and into A/J mice with active allergic conjunctivitis. Further groups of allograft recipients with allergic conjunctivitis were treated post-operatively with twice daily topical dexamethasone 0.1% or phosphate-buffered saline. Mice were killed on days 2 and 6 and corneas were examined by (i) fluorescent immunohistochemistry of frozen sections using anti-CD11b, anti-F4/80 and anti-Gr-1 antibodies, or (ii) whole-mount staining with anti-LYVE-1 antibody. Lymphatic ingrowth and numbers of cells infiltrating the host cornea were compared between groups. Results There were significantly higher numbers of CD11b+ cells and LYVE-1+ vessels in the host cornea at day 2 in allergic compared with naive recipients, but no differences between naive and allergic recipients at day 6. In allergic eyes, dexamethasone treatment significantly inhibited LYVE-1 expression at days 2 and 6, and significantly improved allograft survival in recipients with allergic conjunctivitis if maintained for a week. Conclusions The innate immune response to allogeneic corneal tissue is more vigorous in the presence of allergic conjunctivitis than in naive eyes and is associated with accelerated lymphatic ingrowth to host cornea. Topical dexamethasone inhibits lymphatic ingrowth and this may be one mechanism by which topical steroid enhances graft survival.

The impact of donor age and endothelial cell density on graft survival following penetrating keratoplasty

Purpose To determine if donor age and preoperative endothelial cell density (ECD) affect corneal endothelial failure following penetrating keratoplasty (PK). Methods Preoperative and postoperative data for PKs performed in the UK between April 1999 and March 2012 were analysed. Donor age was split into three groups (0–60, 61–75 and >75 years) and donor ECD was split into three groups (≤2400, 2401–2600 and >2600 cells/mm2). Cox proportional hazards regression was used to determine whether the selected subgroups of donor age and donor ECD have an impact on endothelial failure and a systematic analysis of the interaction between donor ECD and donor age was conducted. The analysis was stratified for primary corneal diagnosis (Fuchs endothelial dystrophy (FED), pseudophakic bullous keratopathy (PBK) and other) and corrected for potentially confounding factors (human leukocyte antigen matching, donor trephine diameter, deep vascularisation, the occurrence of reversible rejection episodes and receipt of systemic antiviral medication, long-term steroids or other immunosuppressive agents). Results A total of 9415 patients, from the National Health Service Blood and Transplant UK Transplant Registry, who received their first PK for visual reasons were included in this study. The overall 5-year graft survival rate due to endothelial failure was 89%. Survival rates in recipients with FED, PBK and ‘all other indications’ were 95%, 83% and 89%, respectively. Our analysis shows that donor ECD did not affect outcome following corneal graft within the preselected categories, irrespective of diagnosis and after allowing for any potential confounding factors. Furthermore, HRs for each level of donor ECD, relative to >2600 cells/mm2, for each combination of age group and indication, were not statistically significant. Conclusions We were unable to detect a significant effect of donor age, up to 90 years, and preoperative donor ECD, above the lower limit of 2200 cells/mm2, on endothelial failure at 5 years following PK.

In situ regeneration of retinal pigment epithelium by gene transfer of E2F2 : a potential strategy for treatment of macular degenerations

The retinal pigment epithelium (RPE) interacts closely with photoreceptors to maintain visual function. In degenerative diseases such as Stargardt disease and age-related macular degeneration, the leading cause of blindness in the developed world, RPE cell loss is followed by photoreceptor cell death. RPE cells can proliferate under certain conditions, suggesting an intrinsic regenerative potential, but so far this has not been utilised therapeutically. Here, we used E2F2 to induce RPE cell replication and thereby regeneration. In both young and old (2 and 18 month) wildtype mice, subretinal injection of non-integrating lentiviral vector expressing E2F2 resulted in 47% of examined RPE cells becoming BrdU positive. E2F2 induced an increase in RPE cell density of 17% compared with control vector-treated and 14% compared with untreated eyes. We also tested this approach in an inducible transgenic mouse model of RPE loss, generated through activation of diphtheria toxin-A gene. E2F2 expression resulted in a 10-fold increase in BrdU uptake and a 34% increase in central RPE cell density. Although in mice this localised rescue is insufficiently large to be demonstrable by electroretinography, a measure of massed retinal function, these results provide proof-of-concept for a strategy to induce in situ regeneration of RPE for the treatment of RPE degeneration.