Alan Sugar

Risk Factors for Corneal Graft Failure and Rejection in the Collaborative Corneal Transplantation Studies

PURPOSE To evaluate comprehensively the magnitude of suspected risk factors for corneal graft failure from any cause, failure from rejection, and immunologic reaction in patients at high risk for graft failure after corneal transplantation. METHODS The records of the 457 participants in the Collaborative Corneal Transplantation Studies were reviewed. All participants had at least two quadrants of stromal vascularization and/or a history or previous graft rejection. Patients were followed for 2 to 5 years. Characteristics of the patient, study eye, donor, donor-recipient histocompatibility, and surgical procedure were examined for their association with the graft outcomes of failure from any cause, rejection failure, and immunologic reaction. Multivariate survival analysis techniques were used to estimate rates of graft outcome events and to estimate the magnitude of risk factors. RESULTS Many apparent risk factors did not maintain their association with graft outcomes after adjustment for other risk factors. Young recipient age, the number of previous grafts, history of previous anterior segment surgery, preoperative glaucoma, quadrants of anterior synechiae, quadrants of stromal vessels, a primary diagnosis of chemical burn, and blood group ABO incompatibility were among the strongest risk factors identified for graft failure. Donor and corneal preservation characteristics had little influence on graft outcome. CONCLUSIONS Risk of graft failure varies substantially, even within a high-risk population. The number of risk factors present should be considered by the patient and surgeon when contemplating transplantation and planning follow-up.

Ultrafast (femtosecond) laser refractive surgery.

Lasers with ultrafast pulses have been developed to decrease the energy necessary to incise tissues and to decrease damage to surrounding tissues. The IntraLase femtosecond (10-15 seconds) laser has been approved by the FDA for lamellar corneal surgery. It uses an infrared (1053 nm) scanning pulse focused to 3 microm with an accuracy of 1 microm to cut a spiral pattern in the corneal stroma creating precise lamellar flaps for LASIK. Clinical studies show that the flaps are uniformly of good quality with no flap complications. The flexibility of this system allows for intrastromal corneal surgery and may make it useful for other refractive and corneal procedures.

Phakic Intraocular Lens Implantation for the Correction of Myopia: A Report by the American Academy of Ophthalmology

OBJECTIVE To review the published literature for evaluation of the safety and outcomes of phakic intraocular lens (pIOL) implantation for the correction of myopia and myopic astigmatism. METHODS Literature searches of the PubMed and Cochrane Library databases were conducted on October 7, 2007, and July 14, 2008. The PubMed search was limited to the English language; the Cochrane Library was searched without language limitations. The searches retrieved 261 references. Of these, panel members chose 85 papers that they considered to be of high or medium clinical relevance to this assessment. The panel methodologist rated the articles according to the strength of evidence. RESULTS Two pIOLs have been approved by the US Food and Drug Administration (FDA): one iris-fixated pIOL and one posterior-chamber IOL. In FDA trials of iris-fixated pIOLs, uncorrected visual acuity (UCVA) was >or=20/40 in 84% and >or=20/20 in 31% after 3 years. In FDA trials of posterior-chamber pIOLs, UCVA was >or=20/40 in 81% and >or=20/20 in 41%. Satisfaction with the quality of vision with both types of pIOLs was generally high. Toric anterior- and posterior-chamber pIOLs have shown improved clinical results in European trials compared with spherical pIOLs. Comparative studies showed pIOLs to provide better best spectacle-corrected visual acuity (BSCVA) and refractive predictability and stability compared with LASIK and photorefractive keratectomy and to have a lower risk of retinal detachment compared with refractive lens exchange. Reported complications and long-term safety concerns include endothelial cell loss, cataract formation, secondary glaucoma (pupillary block, pigment dispersion), iris atrophy (pupil ovalization), and traumatic dislocation. CONCLUSIONS Phakic IOL implantation is effective in the correction of myopia and myopic astigmatism. In cases of high myopia of -8 diopters or more, pIOLs may provide a better visual outcome than keratorefractive surgeries and better safety than refractive lens exchange. The short-term rates of complications and loss of BSCVA are acceptable. Comprehensive preoperative evaluation and long-term postoperative follow-up examinations are needed to monitor for and prevent serious complications, and to establish long-term safety.

Mutations in TCF8 Cause Posterior Polymorphous Corneal Dystrophy and Ectopic Expression of COL4A3 by Corneal Endothelial Cells

Posterior polymorphous corneal dystrophy (PPCD, also known as PPMD) is a rare disease involving metaplasia and overgrowth of corneal endothelial cells. In patients with PPCD, these cells manifest in an epithelial morphology and gene expression pattern, produce an aberrant basement membrane, and, sometimes, spread over the iris and nearby structures in a way that increases the risk for glaucoma. We previously mapped PPCD to a region (PPCD3) on chromosome 10 containing the gene that encodes the two-handed zinc-finger homeodomain transcription factor TCF8. Here, we report a heterozygous frameshift mutation in TCF8 that segregates with PPCD in the family used to map PPCD3 and four different heterozygous nonsense and frameshift mutations in TCF8 in four other PPCD probands. Family reports of inguinal hernia, hydrocele, and possible bone anomalies in affected individuals suggest that individuals with TCF8 mutations should be examined for nonocular anomalies. We detect transcripts of all three identified PPCD genes (VSX1, COL8A2, and TCF8) in the cornea. We show presence of a complex (core plus secondary) binding site for TCF8 in the promoter of Alport syndrome gene COL4A3, which encodes collagen type IV alpha 3, and we present immunohistochemical evidence of ectopic expression of COL4A3 in corneal endothelium of the proband of the original PPCD3 family. Identification of TCF8 as the PPCD3 gene provides a valuable tool for the study of critical gene regulation events in PPCD pathology and suggests a possible role for TCF8 mutations in altered structure and function of cells lining body cavities other than the anterior chamber of the eye. Thus, this study has identified TCF8 as the gene responsible for approximately half of the cases of PPCD, has implicated TCF8 mutations in developmental abnormalities outside the eye, and has presented the TCF8 regulatory target, COL4A3, as a key, shared molecular component of two different diseases, PPCD and Alport syndrome.

Optisol Corneal Storage Medium

Optisol is an investigational, intermediate-term corneal storage medium containing chondroitin sulfate and dextran to enhance corneal dehydration during storage. We used scanning electron microscopy to grade endothelial cell morphologic characteristics in terms of cell shape, cell borders, cell swelling, and apical holes in pairs of corneas stored in Optisol and Dexsol. Optisolstored corneas showed significantly fewer morphologic changes after 14 days at 4 degrees C than did Dexsol-stored corneas. No significant differences were seen after 1 to 4 days at 26 degrees C. Temperature-reversal analysis showed no significant change in corneal thickness with warming after 2-week storage at 4 degrees C in either medium, although Optisol-stored corneas were significantly thinner than those stored in Dexsol at all times. The results of scanning electron microscopy suggest that preservation at refrigerator temperature for 2 weeks in Optisol is superior to preservation in Dexsol. Both media may be useful in preserving endothelial structure for limited periods at room temperature, which could provide a measure of safety in shipping or storage where refrigeration is unreliable.

The Indications for and Outcome in Pediatric Keratoplasty: A Multicenter Study

PURPOSE A multicenter study was undertaken to delineate the indications for and outcome of pediatric keratoplasty. METHODS The authors retrospectively studied 164 grafts in 131 eyes of 108 children younger than 12 years of age, with an average follow-up of 45 months. Multivariate linear and logistic regression was performed to evaluate potential risk factors for poor visual outcome and graft failure. Graft survival was depicted in terms of the Kaplan-Meier survival curve. RESULTS Corneal opacities were grouped into three diagnostic categories: congenital (64%), traumatic (17%), and acquired nontraumatic (19%) opacities. Overall graft survival was 80% at 12 months and 67% at 24 months postoperatively. There was no significant difference in retention of clarity among diagnostic groups. Vitrectomy-lensectomy, regrafts, and postoperative complications were associated significantly with poor allograft survival. Eighteen percent of all eyes had worse vision at the time of the last visit than preoperatively. Amblyopia treatment was the only independently significant prognosticator for visual improvement after surgery. Timing of keratoplasty was not demonstrated to be associated with visual outcome. Visual acuity in 33% of eyes that could be quantified was better than 20/200 at the last visit, whereas 62% of eyes retained full graft clarity. CONCLUSION The authors conclude that keratoplasty can be successful in most children, especially when combined with appropriate amblyopia management.

Wavefront-Guided LASIK for the Correction of Primary Myopia and Astigmatism A Report by the American Academy of Ophthalmology

OBJECTIVE To describe wavefront-guided (WFG) LASIK for the primary treatment of low to moderate levels of myopia and astigmatism and to examine the evidence on the safety and effectiveness of the procedure in comparison with conventional LASIK. METHODS Literature searches conducted in 2004, 2005, 2006, and 2007 retrieved 209 unique references from the PubMed and Cochrane Library databases. The panel selected 65 articles to review, and of these, chose 45 articles that they considered to be of sufficient clinical relevance to submit to the panel methodologist for review. During the review and preparation of this assessment, an additional 2 articles were included. A level I rating was assigned to properly conducted, well-designed, randomized clinical trials; a level II rating was assigned to well-designed cohort and case-controlled studies; and a level III rating was assigned to case series, case reports, and poorly designed prospective and retrospective studies. In addition, studies that were conducted by laser manufacturers before device approval (premarket approval) were reviewed as a separate category of evidence. RESULTS The assessment describes studies reporting results of WFG LASIK clinical trials, comparative trials, or both of WFG and conventional LASIK that were rated level II and level III. There were no studies rated as level I evidence. Four premarket approval studies conducted by 4 laser manufacturers were included in the assessment. The assessment did not compare study results or laser platforms because there were many variables, including the amount of follow-up, the use of different microkeratomes, and the level of preoperative myopia and astigmatism. CONCLUSIONS There is substantial level II and level III evidence that WFG LASIK is safe and effective for the correction of primary myopia or primary myopia and astigmatism and that there is a high level of patient satisfaction. Microkeratome and flap-related complications are not common but can occur with WFG LASIK, just as with conventional LASIK. The WFG procedure seems to have similar or better refractive accuracy and uncorrected visual acuity outcomes compared with conventional LASIK. Likewise, there is evidence of improved contrast sensitivity and fewer visual symptoms, such as glare and halos at night, compared with conventional LASIK. Even though the procedure is designed to measure and treat both lower- and higher-order aberrations (HOAs), the latter are generally increased after WFG LASIK. The reasons for the increase in HOA are likely multifactorial, but the increase typically is less than that induced by conventional LASIK. No long-term assessment of WFG LASIK was possible because of the relatively short follow-up (12 months or fewer) of most of the studies reviewed.

Pathogenic effects of bullous pemphigoid autoantibodies on rabbit corneal epithelium.

Bullous pemphigoid (BP) is associated with circulating autoantibodies reactive with an antigen(s) of the basement membrane zone (BMZ) of skin and mucosae. The pathogenicity of these autoantibodies, although suspected, is unconfirmed. We have investigated the effects of BP autoantibodies on a closely related tissue, the corneal epithelium of the rabbit. IgG fractions from the sera of seven patients with BP were purified by (a) ammonium sulfate precipitation, (b) ion exchange chromatography, or (c) gel filtration. Control IgG was prepared by ion exchange chromatography of pooled normal human gamma globulins. 32 rabbits received corneal intrastromal injections of BP IgG fractions (50 microliter, 0.95-2.05 mg total dose) in one eye, and control IgG (50 microliter, 1.8 mg) in the contralateral cornea. 28 of 32 BP IgG injections produced corneal inflammatory lesions, 10 of which developed visible blisters. Histologically, lesions showed polymorphonuclear cells clustering along the BMZ, and subepithelial blister formation. Immunofluorescence showed in vivo bound IgG and C3 at the BMZ. The intensity of inflammation was dose dependent and correlated often with in vitro complement fixation titers of the fractions. None of 32 corneas injected with control IgG became inflamed. BP IgG fractions injected intradermally into the ear skin of rabbits failed to produce inflammation. This may be due to slow clearance of IgG in the cornea, and optimal binding by the corneal epithelium. The intracorneal injections of BP IgG reproduce the clinical, histological, and immunological features of BP. This study provides evidence that BP autoantibodies are pathogenic.

Corneal Astigmatism after Penetrating Keratoplasty: The Role of Suture Technique

A randomized clinical trial was conducted to contrast two techniques of suturing in penetrating keratoplasty (PK) surgery: double running 10-0 and 11-0 sutures (DR), and a combination of 12 interrupted 10-0 sutures with a single running 11-0 suture (IR), followed by selective suture removal. The primary outcome evaluated in the 60 patients within each group was keratometric astigmatism. A decreasing trend in astigmatism over postoperative year 1 was observed only in the IR group (from 4.00 diopters [D] at 3 months to 2.50 D at 12 months). The difference in median astigmatism at 1 year (IR, 2.50 D; DR, 4.00 D) approached statistical significance (P = 0.06, Mann-Whitney U test). Both groups showed comparable steepening of almost 1 D during postoperative year 1. Assessment of the rate of visual rehabilitation was limited by a greater proportion of IR patients showing cystoid macular edema (CME) after surgery. These results, while favorable toward the IR/selective suture removal technique, must be substantiated by a final assessment after all sutures have been removed.

Central lamellar keratoplasty for optical indications

PURPOSE This study aims to evaluate the results of lamellar keratoplasty (LKP) for optical (nontectonic) indications over the past 19 years at our institution, noting the advantages and pitfalls of the procedure. METHODS The study is a retrospective review of 52 central LKPs in 37 patients. Snellen visual acuity, preoperative clinical indications, and postoperative status of the cornea (donor graft, graft-host interface, and recipient cornea) were assessed. RESULTS Postoperative follow-up ranged from 3 months to 18 years (median, 3 years). In descending order of frequency, corneal dystrophies, aniridic keratopathy, corneal scars, and keratoconus were the most common indications for surgery. After surgery, 38% of the eyes were able to achieve 20/50 or better visual acuity. The two most common causes of poor visual acuity were (1) opacification and/or blood vessel growth in the graft-host interface or on the graft surface and (2) high astigmatism. Persistent epithelial defects occurred in 21% of the eyes after LKP. CONCLUSION Although LKP provides a safer alternative to penetrating keratoplasty, it is limited by vision-reducing graft-host interface problems, astigmatism, and difficult surgical technique. We postulate that the current results of LKP may be improved by (1) removing as much recipient corneal stroma as possible (e.g., dissecting down to Descemets membrane) or, alternatively, using an automated microkeratome and (2) raising the currently used qualitative eyebank standards for accepting LKP donor tissue.