Corneal Transplant Follow-up Study II: a randomised trial to determine whether HLA class II matching reduces the risk of allograft rejection in penetrating keratoplasty.

PURPOSE: A randomised trial to test the hypothesis that human leucocyte antigen (HLA) class II matching reduces the risk of allograft rejection in high-risk penetrating keratoplasty (PK). METHODS: All transplants were matched for HLA class I antigens (≤2 mismatches at the A and B loci) and corneas were allocated to patients by cohort minimisation to achieve 0, 1 or 2 HLA class II antigen mismatches. The corneal transplants (n=1133) were followed for 5 years. The primary outcome measure was time to first rejection episode. RESULTS: Cox regression analysis found no influence of HLA class II mismatching on risk of immunological rejection (HR 1.13; 95% CI 0.79 to 1.63; p=0.51). The risk of rejection in recipients older than 60 years was halved compared with recipients ≤40 years (HR 0.51; 95% CI 0.36 to 0.73; p=0.0003). Rejection was also more likely where cataract surgery had been performed after PK (HR 3.68; 95% CI 1.95 to 6.93; p<0.0001). In univariate analyses, preoperative factors including chronic glaucoma (p=0.02), vascularisation (p=0.01), inflammation (p=0.03), ocular surface disease (p=0.0007) and regrafts (p<0.001) all increased the risk of rejection. In the Cox model, however, none of these factors was individually significant but rejection was more likely where≥2 preoperative risk factors were present (HR 2.11; 95% CI 1.26 to 3.47; p<0.003). CONCLUSIONS: HLA class II matching, against a background of HLA class I matching, did not reduce the risk of allograft rejection. Younger recipient age, the presence of ≥2 preoperative risk factors and cataract surgery after PK all markedly increased the risk of allograft rejection. TRIAL REGISTRATION NUMBER: ISRCTN25094892.

High-risk Corneal Transplantation: Recent Developments and Future Possibilities.

Human corneal transplantation (keratoplasty) is typically considered to have superior short- and long-term outcomes and lower requirement for immunosuppression compared to solid organ transplants because of the inherent immune privilege and tolerogenic mechanisms associated with the anterior segment of the eye. However, in a substantial proportion of corneal transplants, the rates of acute rejection and/or graft failure are comparable to or greater than those of the commonly transplanted solid organs. Critically, while registry data and observational studies have helped to identify factors that are associated with increased risk of corneal transplant failure, the extent to which these risk factors operate through enhancing immune-mediated rejection is less clear. In this overview, we summarize a range of important recent clinical and basic insights related to high-risk corneal transplantation, the factors associated with graft failure, and the immunological basis of corneal allograft rejection. We highlight critical research areas from which continued progress is likely to drive improvements in the long-term survival of high-risk corneal transplants. These include further development and clinical testing of predictive risk scores and assays; greater use of multicenter clinical trials to optimize immunosuppressive therapy in high-risk recipients and robust clinical translation of novel, mechanistically-targeted immunomodulatory and regenerative therapies that are emerging from basic science laboratories. We also emphasize the relative lack of knowledge regarding transplant outcomes for infection-related corneal diseases that are common in the developing world and the potential for greater cross-pollination and synergy between corneal and solid organ transplant research communities.

Corneal transplant follow-up study II (CTFS II): a prospective clinical trial to determine the influence of HLA class II matching on corneal transplant rejection: baseline donor and recipient characteristics.

PURPOSE: To describe a study to determine the influence of HLA class II matching on allograft rejection of high-risk, full-thickness corneal transplants. METHODS: A prospective, longitudinal, clinical trial (ISRCTN25094892) with a primary outcome measure of time to first clinically determined rejection episode. Tissue typing used DNA-based techniques. Corneas were allocated to patients with ≤2 human leucocyte antigen (HLA) class I antigen mismatches by cohort minimisation to achieve 0, 1 or 2 HLA class II (HLA-DR) antigen mismatches. Transplants were to be followed up at 6 months and then annually on the anniversary of surgery for 5 years. Power calculations estimated a sample size of 856 transplants to detect a 0.1 difference in probability of rejection at 1 year between HLA class II matched and mismatched transplants at the 5% level of significance with 80% power. RESULTS: To allow for loss to follow-up, 1133 transplants in 980 patients were accrued to the study between 3 September 1998 and 2 June 2011. 17% of transplants had 0 HLA-DR mismatches. The most frequent indication was bullous keratopathy, accounting for 27% of transplants and 54% of the transplants were regrafts. Median waiting time for a matched graft was 3 months. Donor and recipient characteristics were distributed evenly across the study groups. CONCLUSION: Recruitment to the CFS II has closed with 1077/1133 transplants meeting all the study criteria. Follow-up has been completed and final analysis of the data has started. TRIAL REGISTRATION NUMBER: ISRCTN25094892 andUKCRNID9871, Pre-results.

Outcomes of sphincterotomy for small pupil phacoemulsification.

PURPOSE: Sphincterotomy, an alternative to iris hooks or pupil stretching, is a technique that can aid in small pupil phacoemulsification. The incidence of post-operative complications of this procedure, however, has not been studied. Our study evaluates the post-operative outcomes of phacoemulsification surgery with adjunctive pupillary sphincterotomy. METHODS: We conducted a retrospective review of case notes and Medisoft ® electronic record of patients that had undergone simultaneous sphincterotomy, phacoemulsification and intraocular lens (IOL) implantation by a single surgeon between March 2012 and February 2017. Our main outcome measures were post-operative ocular hypertension (IOP > 21 mmHg), uveitis and cystoid macular oedema (CMO). RESULTS: A total of 114 eyes of 114 patients were included in this study. The mean age was 81.2 years (range: 26-100). All patients had uncomplicated surgery. Transient (<1 month) ocular hypertension developed in five (4%) eyes. Sustained ocular hypertension (>1 month) occurred in one (1%) eye, which had pre-existing glaucoma. All four (4%) eyes that developed a persistent uveitis (>1 month) resolved with topical therapy except for one eye with a history of uveitis. The 6 (5%) eyes that developed CMO had a history significant for uveitis (n = 4), diabetic macular oedema (n = 1) and epiretinal membrane (n = 1). All CMO maculae resolved to their baseline. CONCLUSION: The incidence of post-operative complications following uncomplicated phacoemulsification and IOL implantation with pupillary sphincterotomy is low. The most important predisposing factors for development of a complication are ocular co-morbidities such as glaucoma, uveitis and the presence of a macular pathology.

Comparison of In Vivo Confocal Microscopy, PCR and Culture of Corneal Scrapes in the Diagnosis of Acanthamoeba Keratitis.

PURPOSE: Acanthamoeba keratitis (AK) is an uncommon but serious corneal infection, in which delayed diagnosis carries a poor prognosis. Conventional culture requires a long incubation period and has low sensitivity. Polymerase chain reaction (PCR) and in vivo confocal microscopy (IVCM) are available alternative diagnostic modalities that have increasing clinical utility. This study compares confocal microscopy, PCR, and corneal scrape culture in the early diagnosis of AK. METHODS: We reviewed the case notes of patients with a differential diagnosis of AK between June 2016 and February 2017 at the Bristol Eye Hospital, United Kingdom. Clinical features at presentation, and results of IVCM, PCR, and corneal scrape cultures were analyzed. RESULTS: A total of 25 case records were reviewed. AK was diagnosed in 14 patients (15 eyes). Based on the definition of "definite AK," the diagnostic sensitivities of IVCM, PCR, and corneal scrape cultures were 100% [95% confidence interval (CI), 63.1%-100%], 71.4% (95% CI, 41.9%-91.6%) and 33.3% (95% CI, 9.9%-65.1%), respectively. The 3 methods showed a specificity of 100% and a positive predictive value of 100%. Using a reference standard of only positive corneal cultures, IVCM, and PCR had a sensitivity of 100% (95% CI, 29.2%-100%) and 75% (95% CI, 19.4%-99.4%), respectively. CONCLUSIONS: All 3 diagnostic tests are highly specific, and a positive test result is highly predictive of disease presence. IVCM is both highly sensitive and specific when performed by an experienced operator. PCR is a useful adjunct in the diagnosis of AK because of its wider availability compared with IVCM, and it may be used in combination with IVCM for microbiologic confirmation.

Stability of visual outcome between 2 and 5 years following corneal transplantation in the UK.

BACKGROUND AND AIMS: Many studies of corneal transplantation focus on graft failure or rejection as endpoints, or report visual outcomes at one postoperative time point. We aimed to study the stability of visual outcomes between 2 and 5 years following corneal transplantation. METHODS: All patients with keratoconus (868) or Fuchs endothelial dystrophy (FED) (569) receiving their first corneal transplant for visual purposes in the UK between January 2003 and December 2009 were included. The probability of visual improvement or deterioration (gain or loss of ≥2 Snellen lines, respectively) between 2 and 5 years after keratoplasty was modelled by multivariable logistic regression. RESULTS: The majority of keratoconus patients with a penetrating keratoplasty (PK) or deep anterior lamellar keratoplasty maintained their visual acuity (651/868; 75%) while 15% (133/868) improved and 10% (84/868) deteriorated. Similarly, most patients with FED who received a PK maintained their vision (395/569; 70%) while 18% (105/569) improved and 12% (68/569) deteriorated.

Long-Term Outcomes of High-Risk Keratoplasty in Patients Receiving Systemic Immunosuppression.

PURPOSE: Immunological graft rejection after corneal transplantation remains the leading cause of graft failure. Systemic immunosuppression is used for keratoplasty at a high risk of rejection to improve graft survival. We examined the long-term outcomes of high-risk corneal grafts in patients receiving systemic immunosuppression. METHODS: Thirty-five corneal transplants with a high risk of rejection were identified from 29 patients within a regional immunosuppression service in the United Kingdom. Definition of keratoplasty at "high risk" of rejection included one or more of the following: a history of ipsilateral graft rejection and/or failure, 2 or more quadrants of stromal vascularization, perforation or ocular inflammation at the time of surgery, presence of atopy, and a large-diameter (≥9 mm) graft. Median follow-up duration was 5 years after transplantation. RESULTS: Graft survival at 5 years in patients receiving systemic immunosuppression was 73.5%. Rejection episodes occurred in 14 grafts (40%); these episodes were reversible in 10 grafts (71%). Indications for transplantation were mostly visual (n = 19; 54%) and tectonic (n = 14; 40%). Eighteen grafts (51%) had 2 or more high-risk characteristics. Most patients (n = 20; 69%) received monotherapy, commonly with tacrolimus (n = 15; 52%) or mycophenolate mofetil (n = 8; 28%). Three patients (10%) experienced severe systemic side effects. Median "day-to-day" logMAR visual acuity was 0.5 in grafts for all indications and 0.2 for visual indications. CONCLUSIONS: Systemic immunosuppression in patients with high-risk keratoplasty seems to improve graft survival with a median follow-up duration of 5 years and is tolerated by most patients. Despite rejection episodes occurring in 40% of grafts, these were mostly reversible.

Intraocular lens opacification after descemet stripping automated endothelial keratoplasty.

PURPOSE: Intraocular lens (IOL) opacification is a rare but serious complication that may necessitate its exchange. The use of intraocular gases is a known precipitant. Descemet stripping endothelial keratoplasty (DSAEK) involves injecting air into the anterior chamber. IOL opacification has been described after this procedure; however its incidence is currently unknown. METHODS: A retrospective review of case notes from a single center of all patients undergoing DSAEK, who were either already pseudophakic or had simultaneous cataract surgery. Cases with IOL opacification were analyzed, and any risk factors were identified. RESULTS: One hundred sixty-eight DSAEK were performed on 154 eyes of 137 patients. Fifty-four cases had simultaneous cataract surgery with implantation of an IOL. Fifteen (9.7%) eyes developed IOL opacification. This had a distinctive pattern, being limited to the anterior lens surface, in the pupillary zone. Median time interval from keratoplasty to the first observation of IOL opacification was 17 months (range, 4-34 months). The only statistically significant risk factor was rebubbling of detached endothelial grafts. Rebubbling was performed in 62.5% (10/15) of cases with IOL opacification, compared with 23% (32/139) with no opacification (P = 0.0009). CONCLUSIONS: This is the first study to report the incidence of IOL opacification after undergoing DSAEK. Although the mechanism is unknown, multiple injections of air into the anterior chamber statistically increase the risk of IOL opacification.

The suitability of corneas stored by organ culture for penetrating keratoplasty and influence of donor and recipient factors on 5-year graft survival.

PURPOSE: To determine the impact of donor factors on the suitability of corneas stored by organ culture for penetrating keratoplasty (PK) and the influence of donor and recipient factors on 5-year survival of first PK. METHODS: Logistic regression analyses were carried out to determine the influence of donor factors on, respectively, the risk of microbial contamination during organ culture, the suitability of corneas for PK (endothelial cell density ≥ 2200 cells/mm(2)), and the quality of corneas (endothelial cell density ≥ 2500 cells/mm(2)). Only one cornea, randomly selected, from each donor was included in these analyses. A Cox regression analysis was used to determine the influence of donor and recipient factors on 5-year PK survival. RESULTS: Risk of contamination (n = 8317): Causes of donor death including infection, respiratory disease, and cancer all increased the risk of contamination during organ culture (P < 0.0001). Suitability for PK and endothelial quality (n = 7107): Donor age (P < 0.0001) and storage time in organ culture (P < 0.0001) were the principal factors affecting suitability and quality. Death to enucleation and enucleation to processing times had little influence. Corneas from organ donors were more likely to be suitable for PK (P = 0.0003). Five-year graft survival (n = 3014): Graft survival was dominated by the indication for PK (P < 0.0001). Allograft rejection was also a major risk factor for failure (P < 0.0001). The only donor factor affecting survival was sex (P = 0.008). CONCLUSIONS: Donor age and storage time but not postmortem times influenced the suitability of corneas for PK. The indication for PK and other recipient factors were the main predictors of graft failure.

Peripheral ulcerative keratitis and corneal melt: a 10-year single center review with historical comparison.

PURPOSE: Management of noninfectious ulcerative keratitis (UK) and associated systemic disorders has changed over recent years. This study aimed to analyze a recent cohort of patients with UK in this context. METHODS: The case notes of all the patients attending a specialist corneal immunosuppression clinic between June 2002 and July 2012 were reviewed. A subgroup comparison of those with rheumatoid arthritis (RA) was made with those included in an earlier report from this same center (Malik et al. Eur J Ophthalmol. 2006;16:791-797). The Fisher exact test was used for statistical comparison, and a Bonferroni correction was applied. RESULTS: Seventy patients, whose mean age was 65.0 years (median, 64 years), were included. Fifteen (21%) had bilateral disease, and forty-six had RA (66%). At presentation, the mean (median) visual acuity (VA) was 0.59 (0.18) logarithm of the minimum angle of resolution equivalent to 6/24 (6/9) Snellen. All the patients were prescribed systemic corticosteroids, which were later stopped in 45 (64%) patients. All but 2 were treated with steroid-sparing immunosuppressive agents, with each patient being prescribed a mean of 1.5 medications (range, 0-4), including prednisolone. These included prednisolone (70, 100%), methotrexate (47, 67%), mycophenolate (15, 21%), tacrolimus (5, 7%), and azathioprine (4, 6%). No irreversible side effects occurred. After perforation, 12 eyes of 11 patients (16%) underwent a corneal transplantation, and 10 (83%) of these remained clear. The mean (median) VA of the affected eyes when last seen was 0.34 (0.18) logarithm of the minimum angle of resolution equivalent to 6/13 (6/9) Snellen. The subset of patients with RA had significantly lower rates of corneal perforation and a VA ≤ 6/60 when last seen (P < 0.05) compared with that of the earlier cohort. CONCLUSIONS: Ocular morbidity associated with UK has fallen, possibly because of a move toward more aggressive systemic antiinflammatory therapy.

Long-term topical steroid treatment after penetrating keratoplasty in patients with pseudophakic bullous keratopathy.

PURPOSE: To assess the use of long-term topical corticosteroid treatment in patients with pseudophakic bullous keratopathy (PBK) after penetrating keratoplasty (PK). DESIGN: Retrospective cohort study. PARTICIPANTS: This study considered patients with PBK undergoing an initial PK procedure for visual reasons in the United Kingdom between April 1999 and March 2004. There were 1274 initial PK procedures for PBK reported to United Kingdom Transplant in this period, of which 1184 (91%) were grafted for visual reasons. Of these 1184 grafts, follow-up was reported in 1033 instances (87%). METHODS: A Cox regression model was used to investigate the combined effects of all preoperative factors (recipient age, human leukocyte antigen [HLA] matching, trephine size, deep stromal vascularization, surgeon activity) on graft failure. The model was fitted using all preoperative factors first, and subsequently, factors associated with corticosteroid and other medications were included. MAIN OUTCOME MEASURES: Graft survival. RESULTS: Three-year survival of grafts for PBK was 65% (95% confidence interval [CI], 59%-70%). Topical corticosteroids were still being used beyond 18 months after surgery in 378 (37%) of the 1033 corneal grafts included in this study. The grafts of patients not currently receiving steroids were 1.5 times as likely to fail (hazard ratio [HR], 1.5; 95% CI, 1.0-2.2; P<0.03). Lack of HLA matching (P = 0.006), trephine size or=8.00 mm (P = 0.03), recipient age younger than 65 years (P = 0.003), and corneal vascularization (P = 0.04) all increased the risk of graft failure. CONCLUSIONS: The use of long-term postoperative corticosteroids improved graft survival after PK for PBK. Barring patient contraindications for long-term topical corticosteroid use, clinicians should consider maintaining patients with PBK on long-term postoperative corticosteroid maintenance.

Outcomes of same-sizing versus oversizing donor trephines in keratoconic patients undergoing first penetrating keratoplasty.

PURPOSE: To investigate whether use of same-size donor and recipient trephines reduced myopia after penetrating keratoplasty for keratoconus. DESIGN: Retrospective cohort study. PARTICIPANTS: Eight hundred seventy-eight first grafts for keratoconus were reported to UK Transplant between April 1999 and December 2003. There were 234 and 644 grafts in the same-size and oversize donor trephine groups, respectively. At 1 year, mean spherical equivalent (SE) data were available for 116 eyes (50%) and 295 eyes (46%) in the same-size and oversize groups. At 2 years, mean SE data were available for 64 eyes (27%) and 148 eyes (23%) in the same-size and oversize groups. METHODS: Logistic regression and univariate analysis of follow-up data submitted to UK Transplant. MAIN OUTCOME MEASURES: At 1 and 2 years postoperatively, mean SE, magnitude of the cylindrical component of the refraction, postoperative uncorrected visual acuity (VA), postoperative best-corrected VA, and postoperative complications were recorded. RESULTS: The mean SEs for the same-size and oversize donor trephine groups, respectively, were -1.45 diopters (D) and -1.41 D at 1 year (P = 0.6) and -1.74 D and -2.19 D at 2 years postoperatively (P = 0.3). Although there were no differences in graft survival between the groups at 1 and 2 years, there was a higher incidence of postoperative wound leaks in the same-size group (P = 0.03). CONCLUSION: Use of same-size donor and recipient trephines did not reduce myopia and was associated with an increased risk of postoperative complications.

Recovery from macular phototoxicity after corneal triple procedure.

PURPOSE: Visual recovery from macular phototoxicity in 2 cases after prolonged exposure to operating microscope light from uncomplicated corneal triple-procedure surgery. Recovery is discussed in the context of repair and regeneration. METHODS: Retrospective case reports. RESULTS: Immediately postoperatively, both patients reported positive scotomata and were found to have macular retinal pigment epithelial depigmentation. In 1 case, the fovea was involved. By 6 to 12 months, the scotomata had disappeared despite large areas of retinal pigment epithelial hyperpigmentation remaining. CONCLUSION: Recovery from macular phototoxicity occurs, although the mechanism remains unclear. Positive scotomata in these cases resolved over several months. The time scale of recovery was consistent with the time required for cellular replacement and possible differentiation from neural progenitor cells.

Electrolysis-needle cauterization of corneal vessels in patients with lipid keratopathy.

PURPOSE: To describe a technique of corneal vessel occlusion by using electrolysis-needle cautery. METHODS: A prospective case series of three patients. RESULTS: Corneal vessels were successfully occluded in all patients. Vessels remained occluded during the first 8 months post-cautery follow up. Two patients needed repeat cautery at 9 and 10 months respectively. Patients found the procedure comfortable. There was no post-operative induced astigmatism. CONCLUSION: The technique of ENC is simple, effective and controlled. This technique compares favorably and may prove to be more versatile than Fine Needle Diathermy in the occlusion of corneal vessels that lead to lipid keratopathy.

Ultrastructural evaluation of explanted opacified Hydroview (H60M) intraocular lenses.

AIM: To describe the ultrastructural appearance of explanted opacified Hydroview H60M intraocular lenses. METHODS: 14 explanted lenses were examined by scanning electron microscopy, and their appearance compared with a non-implanted H60M lens from the same time period. Wavelength-dispersive x ray spectroscopy (WDX) was performed on two opacified lenses. RESULTS: Subsurface deposits were seen in all explanted opacified lenses. These deposits broke only onto the surface of more densely opacified lenses. WDX confirmed that the deposits contained both calcium and phosphorous, consistent with their being calcium apatite. CONCLUSION: These findings challenge the widely accepted opinion that H60M intraocular lens opacification begins on the surface of the optic.