Anthony J. Aldave

The Boston Type I Keratoprosthesis: Improving Outcomes and Expanding Indications

PURPOSE To report the usefulness of the Boston type I keratoprosthesis (Massachusetts Eye and Ear Infirmary, Boston, MA) in the management of corneal opacification, corneal limbal stem cell failure, or both in a large single-surgeon series. DESIGN Retrospective review of consecutive clinical case series. PARTICIPANTS All patients undergoing keratoprosthesis implantation by a single surgeon (AJA) between May 1, 2004, and May 31, 2008. METHODS Data were collected regarding the preoperative characteristics of each eye undergoing keratoprosthesis implantation, the surgical procedure(s) performed, and the postoperative course. Statistical analysis was performed to identify factors influencing the incidence and severity of postoperative complications. MAIN OUTCOME MEASURES Interval visual acuities, keratoprosthesis retention, and significant postoperative complications. RESULTS Fifty-seven keratoprosthesis procedures were performed in 50 eyes of 49 patients. The primary indication for surgery was repeat corneal transplantation failure (68%), although no prior corneal surgery had been performed in 16% of eyes. Preoperative visual acuity was 20/200 or worse in all eyes, with 88% of eyes having preoperative vision of counting fingers, hand movements, or light perception. The percentage of eyes with postoperative visual acuity of 20/100 or better was 67% at 6 months (n = 45), 75% at 1 year (n = 28), 69% at 2 years (n = 13), and 100% at 3 years (n = 7). In the 31% of patients in whom preoperative vision in the contralateral eye was 20/50 or better, the postoperative vision in the operative eye improved to 20/50 or better in 47% at the last follow-up (average, 18 months; range, 4-49 months). The overall keratoprosthesis retention rate was 84% at an average follow-up of 17 months (79 person-years of follow-up), with 100% retention in 8 eyes with no history of prior corneal transplantation (14.8 person-years of follow-up). The most common postoperative complications were retroprosthetic membrane formation (22 eyes) and persistent epithelial defects (19 eyes). No cases of infectious endophthalmitis were encountered, and only 1 patient with a history of glaucoma required additional glaucoma surgery during the postoperative period. CONCLUSIONS The Boston type I keratoprosthesis is an effective means of managing repeat corneal graft failure and corneal limbal stem cell failure with or without corneal opacification in patients with both unilateral and bilateral visual impairment.

International Results with the Boston Type I Keratoprosthesis

PURPOSE To determine the indications and outcomes of Boston type 1 keratoprosthesis (Massachusetts Eye and Ear Infirmary, Boston, MA) surgery performed outside of North America and to compare them with those obtained in the United States by the surgeon who trained the international surgeons. DESIGN Retrospective review of consecutive clinical case series. PARTICIPANTS One hundred ninety-four patients (223 keratoprosthesis procedures performed in 205 eyes) who received Boston type 1 keratoprosthesis at 11 ophthalmology centers in Armenia, India, Indonesia, Nepal, Philippines, Russia, and Saudi Arabia between May 1, 2006, and July 1, 2011 (international series), and at the Jules Stein Eye Institute between May 1, 2004, and July 1, 2011 (University of California, Los Angeles [UCLA] series). METHODS Data were collected for each procedure regarding the preoperative characteristics of each eye, the surgical procedure(s) performed, and the postoperative outcomes. Statistical analysis was performed to identify significant differences between the international and UCLA series in terms of retention and complications. MAIN OUTCOME MEASURES Interval visual acuities, keratoprosthesis retention, and significant postoperative complications. RESULTS In the international series, 113 Boston type I keratoprostheses were implanted in 107 eyes of 100 patients. The most common indication for surgery was corneal graft failure (n = 50; 44%) followed by chemical injury (n = 30; 27%). Although only 2% of eyes had a preoperative corrected distance visual acuity (CDVA) of 20/20 to 20/200, 70%, 68%, and 59% of eyes had a postoperative CDVA of 20/20 to 20/200 at 6 months, 1 year, and 2 years after surgery, respectively. Ninety-one of the 113 keratoprostheses implanted (80.5%) were retained at a mean follow-up of 14.2 months, for a retention failure rate of 22 per 134.6 eye-years (0.163/eye-year). The most common postoperative complications were retroprosthetic membrane formation (27%) and sterile corneal necrosis (18%). The only postoperative complication that was more common in the international series than in the UCLA series was infectious endophthalmitis, which developed in 9% of eyes. CONCLUSIONS Boston keratoprosthesis is a viable means of managing repeat graft failure and ocular chemical injury outside of North America, with similar visual acuity outcomes, retention rates, and incidence rates of postoperative complications to those obtained by North American surgeons.

Ic3d Classification of Corneal Dystrophies—edition 2

Purpose: To update the 2008 International Classification of Corneal Dystrophies (IC3D) incorporating new clinical, histopathologic, and genetic information. Methods: The IC3D reviewed worldwide peer-reviewed articles for new information on corneal dystrophies published between 2008 and 2014. Using this information, corneal dystrophy templates and anatomic classification were updated. New clinical, histopathologic, and confocal photographs were added. Results: On the basis of revisiting the cellular origin of corneal dystrophy, a modified anatomic classification is proposed consisting of (1) epithelial and subepithelial dystrophies, (2) epithelial–stromal TGFBI dystrophies, (3) stromal dystrophies, and (4) endothelial dystrophies. Most of the dystrophy templates are updated. The entity “Epithelial recurrent erosion dystrophies” actually includes a number of potentially distinct epithelial dystrophies (Franceschetti corneal dystrophy, Dystrophia Smolandiensis, and Dystrophia Helsinglandica) but must be differentiated from dystrophies such as TGFBI-induced dystrophies, which are also often associated with recurrent epithelial erosions. The chromosome locus of Thiel-Behnke corneal dystrophy is only located on 5q31. The entity previously designated as a variant of Thiel-Behnke corneal dystrophy on chromosome 10q24 may represent a novel corneal dystrophy. Congenital hereditary endothelial dystrophy (CHED, formerly CHED2) is most likely only an autosomal recessive disorder. The so-called autosomal dominant inherited CHED (formerly CHED1) is insufficiently distinct to continue to be considered a unique corneal dystrophy. On review of almost all of the published cases, the description appeared most similar to a type of posterior polymorphous corneal dystrophy linked to the same chromosome 20 locus (PPCD1). Confocal microscopy also has emerged as a helpful tool to reveal in vivo features of several corneal dystrophies that previously required histopathologic examination to definitively diagnose. Conclusions: This revision of the IC3D classification includes an updated anatomic classification of corneal dystrophies more accurately classifying TGFBI dystrophies that affect multiple layers rather than are confined to one corneal layer. Typical histopathologic and confocal images have been added to the corneal dystrophy templates.

Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus

PURPOSE Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease. METHODS Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype. RESULTS The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 × 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 × 10(-7)) and rs17501108 (P = 9.9 × 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036). CONCLUSIONS Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

Long-term outcomes of Boston type 1 keratoprosthesis implantation: A retrospective multicenter cohort

PURPOSE To study the long-term outcomes of Boston type 1 keratoprosthesis (KPro) surgery. DESIGN Retrospective, multicenter case series. PARTICIPANTS A total of 158 eyes of 150 patients underwent KPro implantation at 5 participating tertiary centers in the United States between January 2003 and December 2006. Of those, 139 eyes of 133 patients were included in the analyses. METHODS The medical records of consecutive adult patients who received KPro surgery were reviewed. All patients with at least 1 postoperative visit were retained in the outcomes analyses. In eyes in which a repeat KPro procedure was performed, only the outcomes of the initial surgery were analyzed. MAIN OUTCOME MEASURES Visual acuity (VA) outcomes, postoperative complications, and device retention. RESULTS The mean follow-up was 46.7 ± 26 months with all but 4 eyes having at least 6 months of follow-up. Preoperatively, only 10.8% of the eyes had VA of ≥ 20/200. Postoperatively, the VA in 70% of eyes improved to ≥ 20/200. The probability of maintaining VA of ≥ 20/200 at 7 years was 50%. The device retention rate was estimated at 67% at 7 years. The 7-year cumulative incidence of complications was 49.7% for retroprosthetic membrane formation, 21.6% for glaucoma surgery, 18.6% for retinal detachment, and 15.5% for endophthalmitis. CONCLUSIONS Although the risk for complications with longer follow-up seemed to increase, this large multicenter cohort demonstrates favorable outcomes with KPro, with a large number of patients achieving and retaining useful vision over a 7-year period.

A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries

Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case-control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case-control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 × 10(-8), 2.4 × 10(-7) and 3.1 × 10(-7), respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 × 10(-6), while rs6442925 and rs4954218 were less significant (P= 1.9 × 10(-5) and 2.6 × 10(-4)). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 × 10(-7) (unadjusted P= 1.2 × 10(-9)). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus.

Drug-induced corneal complications.

Purpose of review To review the common corneal manifestations of systemic medications in order to describe the characteristic clinical features associated with particular systemic drugs, the indications for drug cessation, and the risks for irreversible ocular toxicity. Recent findings Systemic medications may reach the cornea via the tear film, aqueous humor, and limbal vasculature. The corneal changes are often the result of the underlying chemical properties of medications. Amphiphilic medications (amiodarone, chloroquine, suramin, clofazimine, etc.) may produce a drug-induced lipidosis and development of a vortex keratopathy. Antimetabolites (cytarabine) may lead to a degeneration of basal epithelial cells with formation of epithelial microcysts. Additionally, systemically administered medications and drug metabolites may lead to a stromal or endothelial deposition. Corneal changes may result in reduced visual acuity, photophobia, and ocular irritation, though these symptoms typically resolve following drug cessation. Corneal manifestations of systemic medications are often dose related, and may reflect the potential risk for lenticular or retinal changes. Summary Corneal changes secondary to systemic medications may affect all layers of the cornea. While corneal deposition is typically not an indication for drug cessation, patients receiving particular medications should be monitored for symptoms related to corneal deposition as well as for signs of irreversible ocular toxicity.

Variation in the lysyl oxidase (LOX) gene is associated with keratoconus in family-based and case-control studies.

PURPOSE Keratoconus is a bilateral noninflammatory progressive corneal disorder with complex genetic inheritance and a common cause for cornea transplantation in young adults. A genomewide linkage scan in keratoconus families identified a locus at 5q23.2, overlapping the gene coding for the lysyl oxidase (LOX). LOX encodes an enzyme responsible for collagen cross-linking in a variety of tissues including the cornea. Corneal collagen cross-linking with long-wave ultraviolet light and riboflavin is a promising new treatment for keratoconus. To determine whether LOX is a genetic determinant of the pathogenesis of keratoconus, we analyzed association results of LOX polymorphisms in two independent case-control samples and in keratoconus families. METHODS Association results were analyzed of single-nucleotide polymorphisms (SNPs) in the LOX gene from a Genome-Wide Association Study (GWAS) investigation in two independent panels of patients with keratoconus and controls and in keratoconus families. RESULTS Evidence of association was found at SNPs rs10519694 and rs2956540 located in intron 4 of LOX in the GWAS discovery case-control panel with P values of 2.3×10(-3) and 7×10(-3), respectively. The same two SNPs were found to be associated with keratoconus by family-based association testing with P values of 2.7×10(-3) and 7.7×10(-4), respectively. Meta P values of 4.0×10(-5) and 4.0×10(-7) were calculated for SNPs rs10519694 and rs2956540 by analyzing case-control and family samples simultaneously. Sequencing of LOX exons in a subset of keratoconus patients identified two polymorphisms, rs1800449 and rs2288393, located in LOX transcripts I and II, associated with keratoconus in case-control and family samples with a meta P value of 0.02. CONCLUSIONS Results provided strong genetic evidence that LOX variants lead to increased susceptibility to developing of keratoconus.

The IC3D Classification of the Corneal Dystrophies

BACKGROUND The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes can cause a single phenotype, whereas different defects in a single gene can cause different phenotypes. Some disorders termed corneal dystrophies do not appear to have a genetic basis. PURPOSE The purpose of this study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. METHODS The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. RESULTS This anatomic classification continues to organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a well-defined corneal dystrophy in which a gene has been mapped and identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. CONCLUSIONS The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is user-friendly and upgradeable and can be retrieved on the website www.corneasociety.org/ic3d .

Recommendations for Genetic Testing of Inherited Eye Diseases: Report of the American Academy of Ophthalmology Task Force on Genetic Testing

Genetic testing can make a very positive impact on individuals and families affected with inherited eye disease in a number of ways. When properly performed, interpreted, and acted on, genetic tests can improve the accuracy of diagnoses and prognoses, can improve the accuracy of genetic counseling, can reduce the risk of disease occurrence or recurrence in families at risk, and can facilitate the development and delivery of mechanism-specific care. However, like all medical interventions, genetic testing has some specific risks that vary from patient to patient. For example, the results of a genetic test can affect a patients plans to have children, can create a sense of anxiety or guilt, and can even perturb a patients relationships with other family members. For these reasons, skilled counseling should be provided to all individuals who undergo genetic testing to maximize the benefits and minimize the risks associated with each test.