Topical cenegermin associated ocular surface and contact lens drug precipitate deposit formation.

Purpose: To report for the first time drug precipitate deposit formation on both the ocular surface and bandage contact lens (BCL) of a patient treated with topical cenegermin. Observations: A patient suffering from stage III neurotrophic keratitis developed extensive ocular surface and BCL deposits over the eight week course of her topical cenegermin therapy. The ocular surface deposits were weakly adherent, detaching and clearing from the cornea within minutes of BCL removal. They reappeared rapidly and repeatedly however after each of five BCL exchanges. Symptom wise, the patient was unaware of their presence. Of historical note, this patient: (1) developed BCL ciprofloxacin deposits while undergoing a traditional neurotrophic keratitis treatment regimen, (2) did not develop corneal drug precipitate deposits within the placebo arm of the cenegermin clinical trial (vehicle only without cenegermin or BCL), and (3) did not develop corneal deposits with a latter BCL-free cenegermin treatment course. Conclusions and Importance: Topical cenegermin can produce extensive drug precipitate deposits on both the ocular surface and contact lens when used in conjunction with a bandage contact lens. Such deposits: (1) may represent an esthetic issue only as at least in our patient they were not symptom provoking, questionably interfered with the clinical course of the cenegermin therapy and did not require drug cessation, (2) may implicate both contact lenses and high frequency drug application as previously unidentified but formal risk factors for drug precipitate deposit formation, and (3) may act as a time-release medication reservoir enhancing drug delivery and long-term treatment efficacy.

Topical Recombinant Human Nerve Growth Factor (Cenegermin) for Neurotrophic Keratopathy: A Multicenter Randomized Vehicle-Controlled Pivotal Trial.

PURPOSE: To evaluate the efficacy and safety of topical cenegermin (recombinant human nerve growth factor) in patients with neurotrophic keratopathy. DESIGN: Multicenter, randomized, double-masked, vehicle-controlled trial. PARTICIPANTS: Patients with neurotrophic persistent epithelial defect with or without stromal thinning. METHODS: The NGF0214 trial, conducted among 11 sites in the United States, randomized 48 patients 1:1 to cenegermin 20 µg/ml or vehicle eye drops, 6 drops daily for 8 weeks of masked treatment. Follow-up was 24 weeks. Safety was assessed in all patients who received study drug. Efficacy was assessed by intention to treat. MAIN OUTCOME MEASURES: The primary end point was healing of the neurotrophic lesion (persistent epithelial defect or corneal ulcer) after 8 weeks of masked treatment. Masked central readers measured neurotrophic lesions in randomized clinical pictures, then assessed healing status conventionally (<0.5 mm of fluorescein staining in the greatest dimension of the lesion area) and conservatively (0-mm lesion staining and no other residual staining). Secondary variables included corneal healing at 4 weeks of masked treatment (key secondary end point), overall changes in lesion size, rates of disease progression, and changes in visual acuity and corneal sensitivity from baseline to week 8. RESULTS: Conventional assessment of corneal healing showed statistically significant differences at week 8: compared to 7 of 24 vehicle-treated patients (29.2%), 16 of 23 cenegermin-treated patients (69.6%) achieved less than 0.5 mm of lesion staining (+40.4%; 95% confidence interval [CI], 14.2%-66.6%; P = 0.006). Conservative assessment of corneal healing also reached statistical significance at week 8: compared to 4 of 24 vehicle-treated patients (16.7%), 15 of 23 cenegermin-treated patients (65.2%) achieved 0 mm of lesion staining and no other residual staining (+48.6%; 95% CI, 24.0%-73.1%; P < 0.001). Moreover, the conservative measure of corneal healing showed statistical significance at week 4 (key secondary end point). Compared to vehicle, cenegermin-treated patients showed statistically significant reductions in lesion size and disease progression rates during masked treatment. Cenegermin was well tolerated; adverse effects were mostly local, mild, and transient. CONCLUSIONS: Cenegermin treatment showed higher rates of corneal healing than vehicle in neurotrophic keratopathy associated with nonhealing corneal defects.

A case of severe airbag related ocular alkali injury.

While airbags have saved many lives and are clearly beneficial overall, sodium hydroxide (NaOH) powder produced by the inflation reaction can cause significant alkali ocular injury if not irrigated promptly. Here we report a case of severe airbag related ocular alkali injury as a way to bring attention to the need for prompt ocular irrigation following motor vehicle accidents (MVA) with airbag deployment. A 47-year-old man was involved in a MVA with airbag deployment in a rural setting. Attention was paid to several other life-threatening traumatic injuries, however, ocular irrigation was not performed until some 6-7 hours after the MVA. Over the course of 6 months, airbag related alkali injury caused severe limbal ischemia, conjunctivalization of the cornea, corneal epithelial defects, cicatricial scarring, haze, and corneal/limbal vascularization despite amniotic membrane graft. Awareness of the importance of ocular irrigation following airbag deployment must be raised both in the ophthalmology and emergency medicine communities.

No pathogenic mutations identified in the TGFBI gene in polymorphic corneal amyloid deposition.

PURPOSE: To determine whether primary, polymorphic, corneal amyloid deposition is associated with a mutation of the TGFBI gene. METHODS: Interventional case series of 8 patients. Slit lamp examination of all patients and photodocumentation of 5 patients were performed. Genomic DNA was isolated from buccal mucosal swabs obtained from all patients and all 17 exons of the TGFBI gene were amplified and sequenced. RESULTS: Multiple polymorphic, refractile deposits were noted throughout the central corneal stroma in all patients. The deposits appeared gray-white on direct illumination and translucent on retroillumination, characteristic of amyloid. In 2 patients, linear, branching opacities, reminiscent of lattice corneal dystrophy, were identified. Histopathologic examination confirmed the presence of stromal amyloid in the cornea of 1 patient who required corneal transplantation for pseudophakic corneal edema. Screening of the entire coding region of the TGFBI gene revealed 4 previously described synonymous substitutions, Leu217Leu, Val327Val, Leu472Leu, and Phe540Phe. A previously unreported missense change, Asp299Asn, was identified in one affected patient but not in her affected sister. No pathogenic mutations, including the Ala546Asp missense mutation previously associated with polymorphic corneal amyloidosis, were identified in any of the patients. CONCLUSIONS: TGFBI gene mutations were not identified in a series of patients with polymorphic corneal amyloid deposition. As bilateral, discrete stromal amyloid deposits may be dystrophic or degenerative, differentiation between these phenotypically similar conditions is facilitated with the use of molecular genetic analysis.

Analysis of fifteen positional candidate genes for Schnyder crystalline corneal dystrophy.

PURPOSE: To identify the genetic basis of Schnyder crystalline corneal dystrophy (SCCD) through screening of positional candidate genes in affected patients. METHODS: Mutation screening of fifteen genes (CORT, CLSTN1, CTNNBIP1, DFFA, ENO1, GPR157, H6PD, KIF1B, LOC440559, LZIC, MGC4399, PEX14, PGD, PIK3CD, and SSB1) that lie within the candidate gene region for SCCD was performed in members of two families affected with SCCD. RESULTS: No presumed disease-causing mutations were identified in affected patients. Seventeen previously described single nucleotide polymorphisms (SNPs) were identified in eight of the candidate genes. Novel SNPs were identified in both affected and unaffected individuals in GPR157 (c.795C>T [Arg218Leu]; c.811C>T [Ala223Val]), MGC4399 (c.1024G>C [Leu277Leu]), and H6PD (c.754A>C [Asp151Ala]). CONCLUSIONS: No pathogenic mutations were identified in fifteen positional candidate genes in two families with SCCD. As the candidate gene region in each SCCD family previously examined with haplotype analysis has been mapped to the same chromosomal region, the absence of pathogenic mutations in these positional candidates in the families we examined reduces the number of remaining positional candidate genes by half, and the number of remaining candidate genes with a known gene function by two-thirds. We anticipate that screening of the remaining positional candidate genes will lead to the identification of the genetic basis of SCCD.

A unique corneal dystrophy of Bowman's layer and stroma associated with the Gly623Asp mutation in the transforming growth factor beta-induced (TGFBI) gene.

PURPOSE: To report a unique corneal dystrophy characterized by deposits at Bowman's layer and stromal lattice lines associated with the Gly623Asp missense mutation in the transforming growth factor beta-induced (TGFBI) gene. DESIGN: Experimental study. PARTICIPANTS AND CONTROLS: The proband, 3 affected siblings, 4 unaffected relatives, and 100 control individuals. METHODS: Slit-lamp examination, photographic documentation, and isolation of genomic DNA from buccal mucosal swabs obtained from each family member examined. Exons 4 and 11 to 14 of the TGFBI gene were amplified and sequenced in these family members and in control individuals. MAIN OUTCOME MEASURES: Clinical characteristics of corneal opacification in affected patients and presence of coding region changes in the TGFBI gene. RESULTS: Significant phenotypic variability, including polymorphic Bowman's layer opacities and stromal lattice lines, was noted in the 4 affected siblings who were examined. Screening of TGFBI exon 14 in the proband, 3 affected siblings, and a 19-year-old unaffected relative revealed a missense change, Gly623Asp, that was absent in the other 3 unaffected relatives screened and in 200 control chromosomes. CONCLUSIONS: We report a novel corneal dystrophy phenotype secondary to the Gly623Asp mutation in the TGFBI gene that is associated with clinical features of both lattice corneal dystrophy and a Bowman's layer dystrophy. The presence of clinical features considered atypical for a TGFBI-associated dystrophy in this pedigree, as well as the wide range of phenotypic expressions of the Gly623Asp mutation in affected members, underscore the clinical utility of molecular genetic analysis in the diagnosis of suspected corneal dystrophies.

Lattice corneal dystrophy associated with the Ala546Asp and Pro551Gln missense changes in the TGFBI gene.

PURPOSE: To report a phenotypic variant of lattice corneal dystrophy associated with two missense changes, Ala546Asp and Pro551Gln, in the transforming growth factor-beta-induced gene (TGFBI). DESIGN: Experimental study. METHODS: Genomic DNA was obtained from the proband as well as affected and unaffected family members. Exons 4, 11, 12, and 14 of the TGFBI gene were amplified and sequenced. Additionally, a corneal button excised from the proband was examined by light and transmission electron microscopy. Haplotype analysis was performed on the proband's family and members of a previously identified pedigree with the same TGFBI gene missense changes. RESULTS: Bilateral, symmetric, radially arranged, branching refractile lines within and surrounding an area of central anterior stromal haze were noted in the proband. Multiple polymorphic, refractile deposits were noted in the mid and posterior stroma in both the proband and her daughter. Light and electron microscopic analyses demonstrated amyloid and excluded the presence of deposits characteristic of granular corneal dystrophy. Screening of TGFBI exon 12 in the proband and her affected daughter revealed two missense changes, Ala546Asp and Pro551Gln (both absent in 250 control chromosomes). Haplotype analysis suggested that the mutations in this family and in a previously identified pedigree reflect a founder effect, rather than an independent occurrence. CONCLUSIONS: We present a phenotypic variant of lattice corneal dystrophy associated with the Ala546Asp and Pro551Gln missense changes in exon 12 of the TGFBI gene. A common ancestor appears to account for the missense mutations observed in this pedigree and in a previously reported family.

An unusual clinical phenotype of Avellino corneal dystrophy associated with an Arg124His beta iG-H3 mutation in an African-American woman.

PURPOSE: To describe the clinical features, histologic changes, and genetic analysis of Avellino corneal dystrophy in an African-American woman. DESIGN: Interventional case report. METHODS: A 79-year-old African-American woman with corneal deposits consistent with Avellino corneal dystrophy was studied with histologic and genetic analysis. RESULTS: The patient had multiple crumb-like opacities in the anterior stroma of both eyes. Deep to these lesions were numerous faint, stellate lattice lesions. Corneal scraping confirmed the presence of Masson trichrome and Congo red positive subepithelial deposits. Genetic analysis revealed a heterozygous CGC/CAC change in exon 4 of the beta iG-H3 gene, resulting in an arginine to histidine substitution at codon 124. CONCLUSIONS: This case reveals several novel findings, including surface changes resembling vortex dystrophy and large granular deposits protruding through the anterior corneal surface. This is the first case described in an African-American patient.